2024/04/28 更新

写真a

イシウラ ヒロユキ
石浦 浩之
Ishiura Hiroyuki
所属
医歯薬学域 教授
職名
教授
外部リンク

学位

  • 博士(医学) ( 2011年3月   東京大学 )

  • 学士(医学) ( 2002年3月   東京大学 )

研究キーワード

  • 次世代シーケンサー

  • リピート伸長病

  • 神経遺伝学

研究分野

  • ライフサイエンス / 神経内科学  / 神経遺伝学

学歴

  • 東京大学   Graduate School of Medicine  

    2007年4月 - 2011年3月

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    備考: Ph.D.

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  • 東京大学   Faculty of Medicine  

    1996年4月 - 2002年3月

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    備考: M.D.

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経歴

  • 岡山大学   学術研究院医歯薬学域脳神経内科学   教授

    2022年11月 - 現在

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  • 東京大学   医学部附属病院 脳神経内科   講師

    2020年4月 - 2022年10月

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    国名:日本国

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  • 東京大学医学部付属病院   神経内科   助教

    2012年4月 - 2020年3月

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  • 日本学術振興会   特別研究員

    2010年4月 - 2012年3月

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  • 国際医療センター   神経内科   レジデント

    2006年4月 - 2007年3月

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  • 東京大学医学部付属病院   神経内科   医員

    2004年6月 - 2006年3月

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  • 関東中央病院   内科   内科研修医

    2003年6月 - 2004年5月

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  • 東京大学医学部付属病院   内科   内科研修医

    2002年6月 - 2003年5月

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委員歴

  • 日本神経治療学会   評議員  

    2023年11月 - 現在   

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    団体区分:学協会

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  • 日本内科学会   評議員  

    2023年4月 - 現在   

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    団体区分:その他

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  • 日本神経学会   代議員  

    2021年5月 - 現在   

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    団体区分:学協会

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  • 日本人類遺伝学会   評議員  

    2019年11月 - 現在   

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    団体区分:学協会

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  • 日本人類遺伝学会   臨床遺伝専門医  

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    団体区分:学協会

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  • 日本神経学会   臨床神経学 編集委員・幹事  

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    団体区分:学協会

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  • 日本神経学会   専門医、指導医  

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    団体区分:学協会

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  • 日本内科学会   総合内科専門医  

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    団体区分:学協会

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  • 日本人類遺伝学会   Editorial board of Journal of Human Genetics  

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    団体区分:学協会

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  • Human Genome Variation   Associate Editor  

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    団体区分:その他

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論文

  • Expanded clinical spectrum of oculopharyngodistal myopathy type 1 査読

    Takahiro Shimizu, Hiroyuki Ishiura, Manato Hara, Shota Shibata, Atsushi Unuma, Akatsuki Kubota, Kaori Sakuishi, Kiyoharu Inoue, Jun Goto, Yuji Takahashi, Yuichiro Shirota, Masashi Hamada, Jun Shimizu, Shoji Tsuji, Tatsushi Toda

    Muscle & Nerve   2022年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/mus.27717

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  • Isolated Paravermal Hyperintensities in Neuronal Intranuclear Inclusion Disease. 国際誌

    Ryo Tokimura, Meiko Hashimoto, Akihiko Mitsutake, Souichi Sakai, Fumio Suzuki, Keiko Sugasawa, Chisato Fujimoto, Hiroyuki Ishiura, Tatsushi Toda

    Neurology   98 ( 22 )   938 - 939   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1212/WNL.0000000000200590

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  • Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes. 国際誌

    Theerawat Kumutpongpanich, Masashi Ogasawara, Ayami Ozaki, Hiroyuki Ishiura, Shoji Tsuji, Narihiro Minami, Shinichiro Hayashi, Satoru Noguchi, Aritoshi Iida, Ichizo Nishino, Madoka Mori-Yoshimura, Yasushi Oya, Kenjiro Ono, Toshio Shimizu, Akihiro Kawata, Shun Shimohama, Keiko Toyooka, Kaoru Endo, Shuta Toru, Oga Sasaki, Kenji Isahaya, Masanori P Takahashi, Kazuo Iwasa, Jun-Ichi Kira, Tatsuya Yamamoto, Michi Kawamoto, Tadanori Hamano, Kazuma Sugie, Nobuyuki Eura, Tomo Shiota, Mizuho Koide, Kanako Sekiya, Hideaki Kishi, Takuto Hideyama, Shigeru Kawai, Satoshi Yanagimoto, Hiroyasu Sato, Hajime Arahata, Shigeo Murayama, Kayoko Saito, Hideo Hara, Takashi Kanda, Hiroshi Yaguchi, Noboru Imai, Yuichi Kawagashira, Mitsuru Sanada, Kazuki Obara, Misako Kaido, Minori Furuta, Takashi Kurashige, Wataru Hara, Daisuke Kuzume, Mamoru Yamamoto, Jun Tsugawa, Hitaru Kishida, Naoki Ishizuka, Kohei Morimoto, Yukio Tsuji, Atsuko Tsuneyama, Atsuhiro Matsuno, Ryo Sasaki, Daigo Tamakoshi, Erika Abe, Shinichiro Yamada, Akiyuki Uzawa

    JAMA neurology   78 ( 7 )   853 - 863   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

    DOI: 10.1001/jamaneurol.2021.1509

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  • Loss-of-function variants in NEK1 are associated with an increased risk of sporadic ALS in the Japanese population. 国際誌

    Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Jun Goto, Tatsushi Toda, Shoji Tsuji

    Journal of human genetics   66 ( 3 )   237 - 241   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Loss-of-function (LoF) variants in NEK1 have recently been reported to be associated with amyotrophic lateral sclerosis (ALS). In this study, we investigated the association of NEK1 LoF variants with an increased risk of sporadic ALS (SALS) and the clinical characteristics of patients with SALS carrying LoF variants in a Japanese case series. Whole-exome sequencing analysis was performed for a series of 446 SALS patients in whom pathogenic variants in familial ALS-causative genes have not been identified and 1163 healthy control subjects in our Japanese series. We evaluated LoF variants, defined as nonsense, splice-site disrupting single-nucleotide variants (SNVs), or short insertion/deletion (indel) variants predicted to cause frameshifts in NEK1. We identified seven NEK1 LoF variants in patients with SALS (1.57%), whereas only one was identified in control subjects (0.086%) (P = 0.00073, Fisher's exact test). This finding is consistent with those in recent reports from other regions in the world. In conclusion, we demonstrated that NEK1 LoF variants are also associated with an increased risk of SALS in the Japanese population.

    DOI: 10.1038/s10038-020-00830-9

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  • Splice-site mutations in KIF5A in the Japanese case series of amyotrophic lateral sclerosis. 国際誌

    Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Kaori Sakuishi, Kiyotaka Nakamagoe, Zenshi Miyake, Akira Tamaoka, Jun Goto, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Tatsushi Toda, Shoji Tsuji

    Neurogenetics   22 ( 1 )   11 - 17   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.

    DOI: 10.1007/s10048-020-00626-1

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  • SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report. 国際誌

    Kishin Koh, Ryusuke Takaki, Hiroyuki Ishiura, Shoji Tsuji, Yoshihisa Takiyama

    BMC neurology   21 ( 1 )   64 - 64   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: ALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A. CASE PRESENTATION: A Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine. CONCLUSIONS: Since the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.

    DOI: 10.1186/s12883-021-02087-x

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  • Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature. 国際誌

    Junko Kanda Kikuchi, Yu Nagashima, Tatsuo Mano, Hiroyuki Ishiura, Toshihiro Hayashi, Jun Shimizu, Takashi Matsukawa, Yaeko Ichikawa, Yuji Takahashi, Shotaro Karino, Takashi Kanbayashi, Junichi Kira, Jun Goto, Shoji Tsuji

    Journal of molecular neuroscience : MN   71 ( 9 )   1796 - 1801   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The phenotypes of patients with disease-associated variants in DNMT1 have been classified into two syndromes: hereditary sensory and autonomic neuropathy type 1E (HSAN1E, MIM614116, https://www.omim.org/ ) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN, MIM604121). The amino acid codon 511 is a hotspot, and p.Y511C is the most frequently observed disease-associated variant among those in HSAN1E patients, whereas there have been only a few reports on patients with p.Y511H. In this study, we report on the cases of a kindred carrying the DNMT1 variant NM_001130823.2:c.1531 T > C (p.Y511H) presenting with the ADCA-DN phenotype. The review of the literature further revealed that later ages at onset and the presence of cerebellar ataxia are the main characteristics of patients carrying the DNMT1 p.Y511H as compared with those carrying DNMT1 p.Y511C. Although HSAN1E and ADCA-DN are proposed to be called DNMT1-complex disorders owing to their overlapping symptoms, this finding suggests a distinct genotype-phenotype correlation regarding the DNMT1 p.Y511H and p.Y511C variants.

    DOI: 10.1007/s12031-020-01784-5

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  • Advances in repeat expansion diseases and a new concept of repeat motif-phenotype correlation. 国際誌

    Hiroyuki Ishiura, Shoji Tsuji

    Current opinion in genetics & development   65   176 - 185   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently repeat expansions have been found in more than 10 diseases in the past two years. Because the same repeat motifs are found in similar disease (as exemplified by benign adult familial myoclonic epilepsy) or in diseases with overlapping phenotype (as exemplified by fragile X tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukoencephalopathy, and oculopharyngodistal myopathy), we propose a new concept of 'repeat motif-phenotype correlation', which argue for toxic gain-of-function mechanism caused by expanded repeats, rather than altered functions of genes harboring expanded repeats. The concept is expected to help identify repeat expansions taking the similar or overlapping clinical presentations as the clues. Although repeat expansions have been identified predominantly in autosomal dominant diseases, recent progresses have demonstrated that they are also observed in autosomal recessive diseases. Furthermore, repeat expansions are not infrequently observed in patients without family histories, which urges us to pay attention to sporadic diseases. We should expand our views toward repeat expansion diseases to accelerate discovery of diseases caused by repeat expansions, better understanding the disease mechanisms, and development of therapeutic measures.

    DOI: 10.1016/j.gde.2020.05.029

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  • Juvenile amyotrophic lateral sclerosis with complex phenotypes associated with novel SYNE1 mutations. 国際誌

    Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Tatsushi Toda, Shoji Tsuji

    Amyotrophic lateral sclerosis & frontotemporal degeneration   22 ( 7-8 )   1 - 3   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mutations in SYNE1 have been originally described to cause a slowly progressive, pure cerebellar ataxia (spinocerebellar ataxia, autosomal-recessive 8; SCAR8). Notably, recent studies revealed that affected patients with SYNE1-associated ataxia can present with complex phenotypes rather than pure cerebellar ataxia, including motor neuron and brainstem dysfunctions. We herein report a Japanese patient diagnosed with juvenile amyotrophic lateral sclerosis (ALS) with a complex phenotype, who carried compound heterozygous pathogenic variants in SYNE1. Of the variants, one was a novel frameshift variant and the other was a nonsense variant previously reported as pathogenic for SCAR8. The patient showed an early age at onset with a relatively slow but progressive course of ALS, accompanied by cognitive decline. Our findings suggest that the clinical spectrum of patients carrying pathogenic SYNE1 variants is broader than expected, and SYNE1 variants should be considered in patients diagnosed with juvenile ALS, even without prominent cerebellar ataxia.

    DOI: 10.1080/21678421.2020.1813312

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  • Adult-onset neuronal intranuclear inclusion disease mimicking Fragile X-associated tremor-ataxia syndrome in ethnic Chinese patients. 査読 国際誌

    Shen-Yang Lim, Hiroyuki Ishiura, Norlisah Ramli, Shota Shibata, M Asem Almansour, Ai Huey Tan, Henry Houlden, Anthony E Lang, Shoji Tsuji

    Parkinsonism & related disorders   74   25 - 27   2020年4月

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    記述言語:英語  

    Two ethnic Chinese men with clinico-radiologic features of Fragile X-associated tremor-ataxia syndrome (FXTAS) were found on genetic testing to have neuronal intranuclear inclusion disease (NIID), highlighting that NIID should be considered in the differential diagnosis of FXTAS. NIID may also be much more common than FXTAS in certain Asian populations.

    DOI: 10.1016/j.parkreldis.2020.03.025

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  • An autopsy case of GM1 gangliosidosis type II in a patient who survived a long duration with artificial respiratory support. 査読 国際誌

    Akiko Uchino, Makiko Nagai, Naomi Kanazawa, Masaaki Ichinoe, Nobuyuki Yanagisawa, Kaori Adachi, Eiji Nanba, Hiroyuki Ishiura, Jun Mitsui, Shoji Tsuji, Kinuko Suzuki, Shigeo Murayama, Kazutoshi Nishiyama

    Neuropathology : official journal of the Japanese Society of Neuropathology   40 ( 4 )   379 - 388   2020年3月

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    記述言語:英語  

    GM1 gangliosidosis is a storage disorder with autosomal recessive inheritance caused by deficiency of β-galactosidase (GLB1), which is a lysosomal hydrolase, due to mutations in GLB1. We describe here an autopsy case of GM1 gangliosidosis in a female patient who survived for 38 years with a long period of artificial respiratory support (ARS). She was born after a normal pregnancy and delivery. Although development was normal until one year old, she was unable to walk at two years old and started having seizures by nine years old. At 21 years old, she became unable to communicate and was bed-ridden. At 36 years old, she suffered from pneumonia and required ARS. She died of pneumonia at 40 years old. Neuropathological examination revealed severe atrophy, predominantly found in the frontal lobes. Microscopically, severe gliosis and neuronal loss were observed in the cerebral cortex, putamen, cerebellum, the latter including Purkinje cell and granule cell layers. The hippocampus was relatively preserved. Severe neuronal swelling was observed in the limbic regions and stored a material in these neurons negative for periodic acid-Schiff (PAS). A PAS-positive granular storage material in neurons and macrophages was mainly observed in the brainstem and limbic regions. Exome analysis showed a known c.152T>C (p.I51T) variant that has been described in type III patients and a novel c.1348-2A>G variant in GLB1. Detailed analysis of reverse transcription-polymerase chain reaction products of GLB1 mRNA revealed that these variants were present in a compound heterozygous state. In our case, clinical features and neuropathological findings were most consistent with type II, although the entire course was longer than any previously reported cases. This may be explained by the residual enzyme activity in this patient whose severity lay between types II and III. Our finding of relative preservation of the limbic regions suggests that neuronal loss in GM1 gangliosidosis has regional selectivity.

    DOI: 10.1111/neup.12651

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  • A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia. 査読

    Masanori Kurihara, Hiroyuki Ishiura, Taro Bannai, Jun Mitsui, Jun Yoshimura, Shinichi Morishita, Toshihiro Hayashi, Jun Shimizu, Tatsushi Toda, Shoji Tsuji

    Internal medicine (Tokyo, Japan)   59 ( 6 )   839 - 842   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A [c.37C>T (p.R13C)]. Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case suggests that alterations in this arginine at codon 13 might lead to a common clinical spectrum and further expand the genetic and clinical spectra associated with KIF1A mutations.

    DOI: 10.2169/internalmedicine.3661-19

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  • Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. 査読 国際誌

    Hiroyuki Ishiura, Shota Shibata, Jun Yoshimura, Yuta Suzuki, Wei Qu, Koichiro Doi, M Asem Almansour, Junko Kanda Kikuchi, Makiko Taira, Jun Mitsui, Yuji Takahashi, Yaeko Ichikawa, Tatsuo Mano, Atsushi Iwata, Yasuo Harigaya, Miho Kawabe Matsukawa, Takashi Matsukawa, Masaki Tanaka, Yuichiro Shirota, Ryo Ohtomo, Hisatomo Kowa, Hidetoshi Date, Aki Mitsue, Hiroyuki Hatsuta, Satoru Morimoto, Shigeo Murayama, Yasushi Shiio, Yuko Saito, Akihiko Mitsutake, Mizuho Kawai, Takuya Sasaki, Yusuke Sugiyama, Masashi Hamada, Gaku Ohtomo, Yasuo Terao, Yoshihiko Nakazato, Akitoshi Takeda, Yoshio Sakiyama, Yumi Umeda-Kameyama, Jun Shinmi, Katsuhisa Ogata, Yutaka Kohno, Shen-Yang Lim, Ai Huey Tan, Jun Shimizu, Jun Goto, Ichizo Nishino, Tatsushi Toda, Shinichi Morishita, Shoji Tsuji

    Nature genetics   51 ( 8 )   1222 - 1232   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

    DOI: 10.1038/s41588-019-0458-z

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  • Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS. 査読 国際誌

    Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Masaki Tanaka, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Goto, Tatsushi Toda, Shoji Tsuji

    Journal of neurology, neurosurgery, and psychiatry   90 ( 5 )   537 - 542   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: To evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series. METHODS: We conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups. RESULTS: Whole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants. CONCLUSIONS: A substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.

    DOI: 10.1136/jnnp-2018-318568

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  • Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations. 査読 国際誌

    Hiroya Naruse, Takashi Matsukawa, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Hiroki Takano, Jun Goto, Tatsushi Toda, Shoji Tsuji

    Neurogenetics   20 ( 2 )   65 - 71   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of "large normal alleles" defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.

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  • Neuroimaging, genetic, and enzymatic study in a Japanese family with a GBA gross deletion. 査読 国際誌

    Yuta Ichinose, Hiroyuki Ishiura, Masaki Tanaka, Jun Yoshimura, Koichiro Doi, Takako Umeda, Hajime Yamauchi, Mai Tsuchiya, Kishin Koh, Nobuo Yamashiro, Jun Mitsui, Jun Goto, Hiroshi Onishi, Toshihisa Ohtsuka, Kazumasa Shindo, Shinichi Morishita, Shoji Tsuji, Yoshihisa Takiyama

    Parkinsonism & related disorders   61   57 - 63   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Glucocerebrosidase gene (GBA) variants are associated with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The molecular mechanisms underlying these diseases with GBA variants, however, are not well understood. In order to determine the effect of a deletion mutation in GBA, we performed a neuroimaging, genetic, and enzymatic study in a Japanese family with a gross deletion of exons 3 to 11 in GBA. METHODS: We performed [123I] FP-CIT SPECT and [123I] N-isopropyl-p-iodoamphetamine SPECT (IMP-SPECT), and determined GBA expression and glucocerebrosidase (GCase) activity in leukocytes in two GBA-associated PD patients and nine unaffected individuals (including four mutation carriers) in a Japanese family with a heterozygous gross deletion mutation in the GBA gene. RESULTS: The two PD patients and two of the four clinically unaffected carriers showed decreased [123I] FP-CIT uptake. IMP-SPECT showed a pattern like that in DLB in one patient. When we compared PD patients with GBA mutations with clinically unaffected carriers, there was a poor correlation between the development of PD and the expression level of GBA or GCase activity. CONCLUSION: We confirmed the gross deletion mutation in the GBA gene, which appeared to be associated with the PD or reduced [123I] FP-CIT in this family. However, since we cannot conclude whether a reduction of GCase activity is directly correlated with the pathogenesis of PD or not, longitudinal follow-up of this family is needed.

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  • Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. 査読

    Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, Toyoshima Y, Kakita A, Takahashi H, Suzuki Y, Sugano S, Qu W, Ichikawa K, Yurino H, Higasa K, Shibata S, Mitsue A, Tanaka M, Ichikawa Y, Takahashi Y, Date H, Matsukawa T, Kanda J, Nakamoto FK, Higashihara M, Abe K, Koike R, Sasagawa M, Kuroha Y, Hasegawa N, Kanesawa N, Kondo T, Hitomi T, Tada M, Takano H, Saito Y, Sanpei K, Onodera O, Nishizawa M, Nakamura M, Yasuda T, Sakiyama Y, Otsuka M, Ueki A, Kaida KI, Shimizu J, Hanajima R, Hayashi T, Terao Y, Inomata-Terada S, Hamada M, Shirota Y, Kubota A, Ugawa Y, Koh K, Takiyama Y, Ohsawa-Yoshida N, Ishiura S, Yamasaki R, Tamaoka A, Akiyama H, Otsuki T, Sano A, Ikeda A, Goto J, Morishita S, Tsuji S

    Nature genetics   50 ( 4 )   581 - 590   2018年4月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41588-018-0067-2

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  • Molecular epidemiological study of familial amyotrophic lateral sclerosis in Japanese population by whole-exome sequencing and identification of novel HNRNPA1 mutation 査読

    Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Hidetoshi Date, Yuji Takahashi, Takashi Matsukawa, Masaki Tanaka, Akiko Ishii, Akira Tamaoka, Keiichi Hokkoku, Masahiro Sonoo, Mari Segawa, Yoshikazu Ugawa, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Goto, Shoji Tsuji

    NEUROBIOLOGY OF AGING   61   255.e9 - 255.e16   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    To elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) in the Japanese population, we conducted whole-exome sequencing analysis of 30 FALS families in whom causative mutations have not been identified in previous studies. Consequently, whole-exome sequencing analysis revealed novel mutations in HNRNPA1, TBK1, and VCP. Taken together with our previous results of mutational analyses by direct nucleotide sequencing analysis, a microarray-based resequencing method, or repeat-primed PCR analysis, causative mutations were identified in 41 of the 68 families (60.3%) with SOD1 being the most frequent cause of FALS (39.7%). Of the mutations identified in this study, a novel c.862/1018C&gt;G (p.P288A/340A) mutation in HNRNPA1 located in the nuclear localization signal domain of hnRNPA1, enhances the recruitment of mutant hnRNPA1 into stress granules, indicating that an altered nuclear localization signal activity plays an essential role in amyotrophic lateral sclerosis pathogenesis. (C) 2017 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.neurobiolaging.2017.08.030

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  • Partial duplication of DHH causes minifascicular neuropathy A novel mutation detection of DHH 査読

    Naoko Saito Sato, Risa Maekawa, Hiroyuki Ishiura, Jun Mitsui, Hiroya Naruse, Shin-ichi Tokushige, Kazuma Sugie, Genshu Tate, Jun Shimizu, Jun Goto, Shoji Tsuji, Yasushi Shiio

    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY   4 ( 6 )   415 - 421   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Minifascicular neuropathy (MN) is an extremely rare developmental malformation in which peripheral nerves are composed of many small fascicles. Only one patient with MN with 46XY gonadal dysgenesis (GD) was found to carry a mutation affecting the start codon in desert hedgehog (DHH). We identified an identical novel rearrangement mutation of DHH in two consanguineous families with MN, confirming mutations in DHH cause MN with 46XY GD. The patients with the 46XY karyotype developed GD, whereas a patient with the 46XX karyotype did not. These findings further support that DHH has important roles in perineural formation and male gonadal differentiation.

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  • Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum. 査読 国際誌

    Kagari Koshi Mano, Takashi Matsukawa, Jun Mitsui, Hiroyuki Ishiura, Shin-Ichi Tokushige, Yuji Takahashi, Naoko Saito Sato, Fumiko Kusunoki Nakamoto, Yaeko Ichikawa, Yu Nagashima, Yasuo Terao, Jun Shimizu, Masashi Hamada, Yoshikazu Uesaka, Genko Oyama, Go Ogawa, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Jun Goto

    Neurology. Genetics   2 ( 1 )   e48   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To delineate molecular and clinical characteristics of 3 families with PRNP P105L mutation, a variant of Gerstmann-Sträussler-Scheinker syndrome whose main motor symptoms were parkinsonism and/or involuntary movements. METHODS: The causative mutation was first determined in the affected patients of family 1 using whole-exome sequencing, and then mutational analysis was extended to families 2 and 3. The clinical features of the patients of these 3 families were summarized. Haplotype analysis was performed using high-density single nucleotide polymorphism array. RESULTS: The whole-exome sequencing revealed that the heterozygous mutation c.314C>T (p.P105L) in PRNP was the only known pathogenic mutation shared by the 3 patients of the family with autosomal dominant parkinsonism. We further identified the same mutation in patients of the other 2 families with autosomal dominant parkinsonism and/or involuntary movements. The clinical features of our patients with PRNP P105L mutation included various motor symptoms such as parkinsonism and involuntary movements in addition to progressive dementia. The clinical features in part overlapped with those of other forms of inherited prion diseases, such as fatal familial insomnia and Huntington disease-like type 1. The patients with PRNP P105L mutation shared a haplotype spanning 7.1 Mb around PRNP, raising the possibility that the mutations in the patients originated from a common founder. CONCLUSION: Most of the patients presented with parkinsonism in addition to progressive dementia. Although spastic paraparesis has been emphasized as the main clinical feature, the clinical spectrum of patients with PRNP P105L is broader than expected.

    DOI: 10.1212/NXG.0000000000000048

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  • Epidemiology and molecular mechanism of frontotemporal lobar degeneration/amyotrophic lateral sclerosis with repeat expansion mutation in C9orf72 査読

    Hiroyuki Ishiura, Shoji Tsuji

    JOURNAL OF NEUROGENETICS   29 ( 2-3 )   85 - 94   2015年

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS LTD  

    GGGGCC hexanucleotide repeat expansions in C9orf72 were identified in 2011 as the genetic cause of frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS) linked to chromosome 9. Since then, a number of studies have been conducted to delineate the molecular epidemiology of the repeat expansions and the molecular pathophysiology of the disease. The frequency of the repeat expansions considerably varied among countries. The frequency of the repeat expansions was high in European populations and populations of European descent and a substantial proportion of sporadic FTLD or ALS patients also have the mutations in these populations. On the other hand, the frequency was extremely low in Asia or Oceania except for limited regions including Kii Peninsula of Japan. A founder effect seems to strongly influence the regional differences in the frequency, but there is no definitive evidence that supports the notion that the repeat expansions arose in a single founder or multiple founders. As a disease-causing mechanism, several molecular mechanisms have been proposed, including conformational changes of DNA (G-quadruplex formation and hypermethylation) or RNA (G-quadruplex formation) molecules, altered transcriptional levels of C9orf72, sequestration of RNA-binding proteins, bidirectional transcription, formation of RNA foci, and neurotoxicity of dipeptide repeat proteins generated by repeat-associated non-ATG-initiated translation. Further investigations on the molecular mechanisms of neurodegeneration are expected to lead to the development of therapeutic interventions for this disease as well as for other diseases associated with non-coding repeat expansions.

    DOI: 10.3109/01677063.2015.1085980

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  • Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses 査読

    Hiroyuki Ishiura, Yuji Takahashi, Toshihiro Hayashi, Kayoko Saito, Hirokazu Furuya, Mitsunori Watanabe, Miho Murata, Mikiya Suzuki, Akira Sugiura, Setsu Sawai, Kazumoto Shibuya, Naohisa Ueda, Yaeko Ichikawa, Ichiro Kanazawa, Jun Goto, Shoji Tsuji

    JOURNAL OF HUMAN GENETICS   59 ( 3 )   163 - 172   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because 430 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.

    DOI: 10.1038/jhg.2013.139

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  • ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19 査読

    Yuji Takahashi, Yoko Fukuda, Jun Yoshimura, Atsushi Toyoda, Kari Kurppa, Hiroyoko Moritoyo, Veronique V. Belzil, Patrick A. Dion, Koichiro Higasa, Koichiro Doi, Hiroyuki Ishiura, Jun Mitsui, Hidetoshi Date, Budrul Ahsan, Takashi Matsukawa, Yaeko Ichikawa, Takashi Moritoyo, Mayumi Ikoma, Tsukasa Hashimoto, Fumiharu Kimura, Shigeo Murayama, Osamu Onodera, Masatoyo Nishizawa, Mari Yoshida, Naoki Atsuta, Gen Sobue, Jennifer A. Fifita, Kelly L. Williams, Ian P. Blair, Garth A. Nicholson, Paloma Gonzalez-Perez, Robert H. Brown, Masahiro Nomoto, Klaus Elenius, Guy A. Rouleau, Asao Fujiyama, Shinichi Morishita, Jun Goto, Shoji Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS   93 ( 5 )   900 - 905   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (PALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G&gt;A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C&gt;T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.

    DOI: 10.1016/j.ajhg.2013.09.008

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  • Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy 査読

    Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Yoko Fukuda, Yaeko Ichikawa, Hidetoshi Date, Budrul Ahsan, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Atsushi Iwata, Jun Goto, Yorihiro Yamamoto, Makiko Komata, Katsuhiko Shirahige, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hiroshi Takashima, Ryozo Kuwano, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Hiroyuki Soma, Ichiro Yabe, Hidenao Sasaki, Masashi Aoki, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alexandra Duerr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Clifford W. Shults, Caroline M. Tanner, Walter A. Kukull, Virginia M. -Y. Lee, Eliezer Masliah, Phillip A. Low, Paola Sandroni, John Q. Trojanowski, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji

    NEW ENGLAND JOURNAL OF MEDICINE   369 ( 3 )   233 - 244   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MASSACHUSETTS MEDICAL SOC  

    Background
    Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.
    Methods
    In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q(10). Levels of coenzyme Q(10) in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.
    Results
    We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.
    Conclusions
    Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.)
    Multiple-system atrophy is a rare neurodegenerative disease characterized by autonomic failure. Mutations affecting an enzyme essential for the synthesis of coenzyme Q10 confer susceptibility to the disease in some persons.

    DOI: 10.1056/NEJMoa1212115

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  • C9ORF72 Repeat Expansion in Amyotrophic Lateral Sclerosis in the Kii Peninsula of Japan 査読

    Hiroyuki Ishiura, Yuji Takahashi, Jun Mitsui, Sohei Yoshida, Tameko Kihira, Yasumasa Kokubo, Shigeki Kuzuhara, Laura P. W. Ranum, Tomoko Tamaoki, Yaeko Ichikawa, Hidetoshi Date, Jun Goto, Shoji Tsuji

    ARCHIVES OF NEUROLOGY   69 ( 9 )   1154 - 1158   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: In the Kii peninsula of Japan, high prevalences of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex have been reported. There are 2 major foci with a high prevalence, which include the southernmost region neighboring the Koza River (Kozagawa and Kushimoto towns in Wakayama prefecture) and the Hohara district (Mie prefecture).
    Objective: To delineate the molecular basis of ALS in the Kii peninsula of Japan, we analyzed hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene, which has recently been identified as a frequent cause of ALS and frontotemporal dementia in the white population.
    Design: Case series.
    Setting: University hospitals.
    Patients: Twenty-one patients (1 familial patient and 20 sporadic patients) with ALS from Wakayama prefecture, and 16 patients with ALS and 16 patients with parkinsonism-dementia complex originating from Mie prefecture surveyed in 1994 through 2011 were enrolled in the study. In addition, 40 probands with familial ALS and 217 sporadic patients with ALS recruited from other areas of Japan were also enrolled in this study.
    Main Outcome Measures: After screening by repeatprimed polymerase chain reaction, Southern blot hybridization analysis was performed to confirm the expanded alleles.
    Results: We identified 3 patients with ALS (20%) with the repeat expansion in 1 of the 2 disease foci. The proportion is significantly higher than those in other regions in Japan. Detailed haplotype analyses revealed an extended shared haplotype in the 3 patients with ALS, suggesting a founder effect.
    Conclusions: Our findings indicate that the repeat expansion partly accounts for the high prevalence of ALS in the Kii peninsula. Arch Neurol. 2012; 69(9): 1154-1158. Published online June 4, 2012. doi: 10.1001/archneurol.2012.1219

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  • The TRK-Fused Gene Is Mutated in Hereditary Motor and Sensory Neuropathy with Proximal Dominant Involvement 査読

    Hiroyuki Ishiura, Wataru Sako, Mari Yoshida, Toshitaka Kawarai, Osamu Tanabe, Jun Goto, Yuji Takahashi, Hidetoshi Date, Jun Mitsui, Budrul Ahsan, Yaeko Ichikawa, Atsushi Iwata, Hiide Yoshino, Yuishin Izumi, Koji Fujita, Kouji Maeda, Satoshi Goto, Hidetaka Koizumi, Ryoma Morigaki, Masako Ikemura, Naoko Yamauchi, Shigeo Murayama, Garth A. Nicholson, Hidefumi Ito, Gen Sobue, Masanori Nakagawa, Ryuji Kaji, Shoji Tsujii

    AMERICAN JOURNAL OF HUMAN GENETICS   91 ( 2 )   320 - 329   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, and atrophy followed by distal sensory involvement. To date, large families affected by HMSN-P have been reported from two different regions in Japan. Linkage and haplotype analyses of two previously reported families and two new families with the use of high-density SNP arrays further defined the minimum candidate region of 3.3 Mb in chromosomal region 3q12. Exome sequencing showed an identical c.854C&gt;T (p.Pro285-Leu) mutation in the TRK-fused gene (TFG) in the four families. Detailed haplotype analysis suggested two independent origins of the mutation. Pathological studies of an autopsied patient revealed TFG- and ubiquitin-immunopositive cytoplasmic inclusions in the spinal and cortical motor neurons. Fragmentation of the Golgi apparatus, a frequent finding in amyotrophic lateral sclerosis, was also observed in the motor neurons with inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive cytoplasmic inclusions were also demonstrated. In cultured cells expressing mutant TFG, cytoplasmic aggregation of TDP-43 was demonstrated. These findings indicate that formation of TFG-containing cytoplasmic inclusions and concomitant mislocalization of TDP-43 underlie motor neuron degeneration in HMSN-P. Pathological overlap of proteinopathies involving TFG and TDP-43 highlights a new pathway leading to motor neuron degeneration.

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  • Clinical features and haplotype analysis of newly identified Japanese patients with gelsolin-related familial amyloidosis of Finnish type 査読

    Makiko Taira, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Toshihiro Hayashi, Jun Shimizu, Takashi Matsukawa, Naoko Saito, Kazumasa Okada, Sadatoshi Tsuji, Hiromasa Sawamura, Shiro Amano, Jun Goto, Shoji Tsuji

    NEUROGENETICS   13 ( 3 )   237 - 243   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Familial amyloidosis of the Finnish type (FAF) is an autosomal dominant form of systematic amyloidosis characterized by lattice corneal dystrophy, cranial neuropathy, and cutis laxa. Although FAF has been frequently found in the Finnish population, FAF is a considerably rare disorder in other regions. In this study, we examined the clinical characteristics as well as the haplotypes of six Japanese patients with FAF from five families. They showed the typical clinical presentations of FAF, but we found a broad range of ages at onset of neurological symptoms. All members had the c.654G > A mutation in GSN. To evaluate the disease haplotypes, high-density single-nucleotide polymorphism (SNP) arrays were used and disease-relevant haplotypes were reconstructed. Haplotype analysis in the four apparently unrelated families suggested a common founder haplotype. In a sporadic FAF patient, however, the haplotype was dissimilar to the founder haplotype. The present study demonstrated that a founder mutation in most of the Japanese families with FAF, except for a sporadic patient in whom a de novo mutation event was suggested as the origin of the mutation.

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  • Posterior column ataxia with retinitis pigmentosa in a Japanese family with a novel mutation in FLVCR1 査読

    Hiroyuki Ishiura, Yoko Fukuda, Jun Mitsui, Yasuo Nakahara, Budrul Ahsan, Yuji Takahashi, Yaeko Ichikawa, Jun Goto, Tetsuo Sakai, Shoji Tsuji

    NEUROGENETICS   12 ( 2 )   117 - 121   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive neurodegenerative disorder characterized by retinitis pigmentosa and sensory ataxia. Previous studies of PCARP in two families showed a linkage to 1q31-q32. However, detailed investigations on the clinical presentations as well as molecular genetics of PCARP have been limited. Here, we describe a Japanese consanguineous family with PCARP. Two affected siblings suffered from childhood-onset retinitis pigmentosa and slowly progressive sensory ataxia. They also showed mild mental retardation, which has not been described in patients with PCARP. Parametric linkage analysis using high-density single nucleotide polymorphism arrays supported a linkage to the same locus. Target capture and high-throughput sequencing technologies revealed a novel homozygous c.1477G &gt; C (G493R) mutation in FLVCR1, which cosegregated with the disease. A recent study has identified three independent mutations in FLVCR1 in the original and other families. Our results further confirmed that PCARP is caused by mutations in FLVCR1.

    DOI: 10.1007/s10048-010-0271-4

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  • TRPM7 Is Not Associated With Amyotrophic Lateral Sclerosis-Parkinsonism Dementia Complex in the Kii Peninsula of Japan 査読

    Kenju Hara, Yasumasa Kokubo, Hiroyuki Ishiura, Yuko Fukuda, Akinori Miyashita, Ryozo Kuwano, Ryogen Sasaki, Jun Goto, Masatoyo Nishizawa, Shigeki Kuzuhara, Shoji Tsuji

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   153B ( 1 )   310 - 313   2010年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS/PDC) is a distinct neurodegenerative disorder characterized by ALS pathology with neurofibrillary tangles (NFTs) in the spinal cord and brain. Recent clinical studies have revealed a high incidence and a high familial occurrence of ALS/PDC in both Guam and the Kii peninsula of Japan, suggesting a strong genetic predisposition to this disorder. The T1482I variant (rs8042919) of TRPM7 gene which is suggested to play roles in regulating the cellular homeostasis of Ca(2+), Mg(2+), and trace metals, has recently been reported to be associated with Guamanian patients with ALS/PDC. To investigate whether TRPM7 is associated with Kii ALS/PDC, we conducted parametric linkage analyses of the TRPM7 locus in a large extended family with ALS/PDC. Linkage analysis did not reveal any evidence supporting the linkage to the TRPM7 locus. Resequencing of the entire coding region of TRPM7 did not reveal any pathogenic mutations in an affected individual in this family. The allele frequencies of the T1482I in affected individuals in this family or in those from other families are not significantly different from those in regional controls or those in HapMap-JPT samples. These results indicate that TRPM7 is not associated with ALS/PDC in the Kii peninsula of Japan. (C) 2009 Wiley-Liss, Inc.

    DOI: 10.1002/ajmg.b.30966

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  • RESPONSE OF ANTI-NMDA RECEPTOR ENCEPHALITIS WITHOUT TUMOR TO IMMUNOTHERAPY INCLUDING RITUXIMAB 査読

    H. Ishiura, S. Matsuda, M. Higashihara, M. Hasegawa, A. Hida, R. Hanajima, T. Yamamoto, J. Shimizu, J. Dalmau, S. Tsuji

    NEUROLOGY   71 ( 23 )   1921 - 1923   2008年12月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1212/01.wnl.0000336648.43562.59

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  • Development of a high-throughput microarray-based resequencing system for neurological disorders and its application to molecular genetics of amyotrophic lateral sclerosis 査読

    Yuji Takahashi, Naomi Seki, Hiroyuki Ishiura, Jun Mitsui, Takashi Matsukawa, Atsushi Kishino, Osamu Onodera, Masashi Aoki, Nobuyuki Shimozawa, Shigeo Murayama, Yasuto Itoyama, Yasuyuki Suzuki, Gen Sobue, Masatoyo Nishizawa, Jun Goto, Shoji Tsuji

    ARCHIVES OF NEUROLOGY   65 ( 10 )   1326 - 1332   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: Comprehensive resequencing of the causative and disease-related genes of neurodegenerative diseases is expected to enable (1) comprehensive mutational analysis of familial cases, (2) identification of sporadic cases with de novo or low-penetrant mutations, (3) identification of rare variants conferring disease susceptibility, and ultimately (4) better understanding of the molecular basis of these diseases.
    Objective: To develop a microarray-based high-throughput resequencing system for the causative and disease-related genes of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
    Design: Validation of the system was conducted in terms of the signal-to-noise ratio, accuracy, and throughput. Comprehensive gene analysis was applied for patients with ALS.
    Subjects: Ten patients with familial ALS, 35 patientswith sporadic ALS, and 238 controls.
    Results: The system detected point mutations with 100% accuracy and completed the resequencing of 270 kilobase pairs in 3 working days with greater than 99.9% accuracy of base calls, or the determination of base(s) at each position. Analysis of patients with familial ALS revealed 2 SOD1 mutations. Analysis of the 35 patients with sporadic ALS revealed a previously known SOD1 mutation, S134N, a novel putative pathogenic DCTN1 mutation, R997W, and 9 novel variants including 4 nonsynonymous heterozygous variants consisting of 2 in ALS2, 1 in ANG, and 1 in VEGF that were not found in the controls.
    Conclusion: The DNA microarray-based resequencing system is a powerful tool for high-throughput comprehensive analysis of causative and disease-related genes. It can be used to detect mutations in familial and sporadic cases and to identify numerous novel variants potentially associated with genetic risks.

    DOI: 10.1001/archneur.65.10.1326

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  • Lymphomatoid granulomatosis involving central nervous system successfully treated with rituximab alone 査読

    Hiroyuki Ishiura, Masato Morikawa, Masashi Hamada, Takuro Watanabe, Shinichi Kako, Shigeru Chiba, Toru Motokura, Akira Hangaishi, Junji Shibahara, Masaaki Akahane, Jun Goto, Shin Kwak, Mineo Kurokawa, Shoji Tsuji

    ARCHIVES OF NEUROLOGY   65 ( 5 )   662 - 665   2008年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Objective: To report the successful treatment of a patient with lymphomatoid granulomatosis (LYG), a rare Epstein-Barr virus - positive lymphoproliferative disorder, using rituximab (anti-CD20 monoclonal antibody). The prognosis for LYG has been reported to be poor, and no satisfactory treatment has been established. Because central nervous system (CNS) involvement of LYG has been known to show poor prognosis, the establishment of an effective treatment for CNS LYG with mild adverse effects is desired.
    Design: Case report. Setting: University hospital.
    Patient: A 48-year-old Japanese man presenting with slowly progressive spastic paraparesis diagnosed as LYG involving the CNS and lungs.
    Interventions: The patient was treated with rituximab (375 mg/m(2), once weekly for 1 month) alone.
    Main Outcome Measure: Improvement of the lesions on imaging.
    Results: The neurological signs resolved and the lesions in the CNS and lungs were mostly diminished after the rituximab monotherapy without any adverse effects. The patient stayed in remission for 18 months.
    Conclusion: Rituximab monotherapy was effective in treating the patient; hence, rituximab should be considered as the initial treatment against LYG involving the CNS.

    DOI: 10.1001/archneur.65.5.662

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  • RFC1-related disorder presenting recurrent syncope. 国際誌

    Yoko Tsuboyama, Akiko Takahashi, Sawako Furukawa, Asem Almansour, Masashi Hamada, Akatsuki Kubota, Jun Shimizu, Makoto Kinoshita, Chisato Fujimoto, Jun Mitsui, Takashi Matsukawa, Hiroya Naruse, Hiroyuki Ishiura, Shoji Tsuji, Tatsushi Toda

    Journal of neurology   2024年3月

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  • SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis. 国際誌

    Hiroya Naruse, Hiroyuki Ishiura, Kayoko Esaki, Jun Mitsui, Wataru Satake, Peter Greimel, Nanoka Shingai, Yuka Machino, Yasumasa Kokubo, Hirotoshi Hamaguchi, Tetsuya Oda, Tomoko Ikkaku, Ichiro Yokota, Yuji Takahashi, Yuta Suzuki, Takashi Matsukawa, Jun Goto, Kishin Koh, Yoshihisa Takiyama, Shinichi Morishita, Takeo Yoshikawa, Shoji Tsuji, Tatsushi Toda

    Annals of clinical and translational neurology   2024年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.

    DOI: 10.1002/acn3.52013

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  • Proximal sensory neuropathy and cerebellar ataxia as presenting symptoms of NOTCH2NLC-related neuronal intranuclear inclusion disease. 国際誌

    Kai Funakawa, Masanori Kurihara, Kensuke Takahashi, Mana Higashihara, Manato Hara, Akihiko Mitsutake, Hiroyuki Ishiura, Aya Midori Tokumaru, Masahiro Sonoo, Shigeo Murayama, Yuko Saito, Atsushi Iwata

    Journal of the neurological sciences   122915 - 122915   2024年2月

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  • 神経伝導検査と免疫固定電気泳動法からPOEMS症候群と診断し得た59歳男性例

    時村 瞭, 原 涼, 久保田 暁, 石浦 浩之, 小玉 聡, 代田 悠一郎, 濱田 雅, 戸田 達史

    臨床神経生理学   51 ( 6 )   651 - 657   2023年12月

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    記述言語:日本語   出版者・発行元:(一社)日本臨床神経生理学会  

    症例は59歳男性。4ヵ月の経過で進行する歩行障害と両下肢遠位の異常感覚を主訴に受診した。診察上,両下肢遠位筋筋力低下,四肢腱反射減弱,両下腿以遠の全感覚鈍麻,異常感覚を認めた。血清蛋白電気泳動法ではM蛋白は検出されなかった。神経伝導検査では尺骨神経前腕部での脱髄性所見と下肢にアクセントのある神経障害を認めた。この結果から追加検査を行ったところ,血清免疫固定電気泳動法でIgA-λ型のM蛋白を認め,血清VEGFが1526pg/mlと上昇していた。以上からPOEMS症候群と診断した。サリドマイド・デキサメタゾン療法と自家末梢血幹細胞移植を行い,下肢筋力が僅かに改善した。神経遠位部より中間部に伝導速度の低下が目立ち,下肢にアクセントのある神経障害の合併はPOEMS症候群と他の脱髄性ニューロパチーとの鑑別に有用である。POEMS症候群を疑った場合は免疫固定電気泳動法によるM蛋白測定が必要である。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J03414&link_issn=&doc_id=20240111330005&doc_link_id=10.11422%2Fjscn.51.651&url=https%3A%2F%2Fdoi.org%2F10.11422%2Fjscn.51.651&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • 成人発症の神経核内封入体病関連網膜症患者の臨床的および電気生理学的特徴(Clinical and electrophysiological characteristics of patients with adult-onset neuronal intranuclear inclusion disease related retinopathy)

    Nakamura Natsuko, Tsunoda Kazushige, Mitsutake Akihiko, Shibata Shota, Ishiura Hiroyuki, Maeda Meiko, Hamada Masashi, Satake Wataru, Tsuji Shoji, Toda Tatsushi, Sawamura Hiromasa

    眼科臨床紀要   16 ( 12 )   891 - 891   2023年12月

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    記述言語:英語   出版者・発行元:眼科臨床紀要会  

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  • Case Report: Intraventricular Cerliponase Alfa Treatment in a Patient with Advanced Neuronal Ceroid Lipofuscinosis Type 2.

    Saki Nakashima, Masashi Hamada, Tomohiko Kimura, Shuichi Tanifuji, Akiko Takahashi, Daiki Yashita, Yu Kakimoto, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2023年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive lysosomal disease caused by decreased activity of the enzyme tripeptidyl peptidase 1 (TPP1) due to pathogenic variants in the TPP1 gene. Cerliponase alfa, a recombinant proenzyme form of TPP1, has shown efficacy in preventing motor and language function decline in early-stage CLN2. However, the safety and effects of this therapy in advanced-stage CLN2 are unclear. We herein report a case of intraventricular cerliponase alfa treatment for over a year in a patient with advanced-stage CLN2. The results suggest the safety and potential efficacy of treatment at an advanced stage of CLN2.

    DOI: 10.2169/internalmedicine.2563-23

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  • 網膜色素変性症と軽度の小脳失調及び脳波異常を認めNeurogenic muscle weakness,ataxia,and retinitis pigmentosa(NARP)と診断した25歳女性例

    横山 敬士, 井川 彩土, 角元 利行, 石浦 浩之, 濱田 雅, 青木 修一郎, 佐竹 渉, 戸田 達史

    臨床神経学   63 ( 11 )   774 - 774   2023年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Exogenous amyloid-β oligomers exacerbate cognitive deficits and activated necroptosis in APP23 mice(タイトル和訳中)

    胡 欣冉, 于 海波, 山下 徹, 森原 隆太, 福井 裕介, 石浦 浩之

    脳循環代謝   35 ( 1 )   122 - 122   2023年11月

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    記述言語:英語   出版者・発行元:(一社)日本脳循環代謝学会  

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  • Protective Effects of Rivaroxaban on White Matter Integrity and Remyelination in a Mouse Model of Alzheimer's Disease Combined with Cerebral Hypoperfusion. 国際誌

    Zhihong Bian, Xinran Hu, Xia Liu, Haibo Yu, Yuting Bian, Hongming Sun, Yusuke Fukui, Ryuta Morihara, Hiroyuki Ishiura, Toru Yamashita

    Journal of Alzheimer's disease : JAD   96 ( 2 )   609 - 622   2023年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive dysfunction and memory loss that is accompanied by pathological changes to white matter. Some clinical and animal research revealed that AD combined with chronic cerebral hypoperfusion (CCH) exacerbates AD progression by inducing blood-brain barrier dysfunction and fibrinogen deposition. Rivaroxaban, an anticoagulant, has been shown to reduce the rates of dementia in atrial fibrillation patients, but its effects on white matter and the underlying mechanisms are unclear. OBJECTIVE: The main purpose of this study was to explore the therapeutic effect of rivaroxaban on the white matter of AD+CCH mice. METHODS: In this study, the therapeutic effects of rivaroxaban on white matter in a mouse AD+CCH model were investigated to explore the potential mechanisms involving fibrinogen deposition, inflammation, and oxidative stress on remyelination in white matter. RESULTS: The results indicate that rivaroxaban significantly attenuated fibrinogen deposition, fibrinogen-related microglia activation, oxidative stress, and enhanced demyelination in AD+CCH mice, leading to improved white matter integrity, reduced axonal damage, and restored myelin loss. CONCLUSIONS: These findings suggest that long-term administration of rivaroxaban might reduce the risk of dementia.

    DOI: 10.3233/JAD-230413

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  • Injection of exogenous amyloid-β oligomers aggravated cognitive deficits, and activated necroptosis, in APP23 transgenic mice. 国際誌

    Haibo Yu, Ryuta Morihara, Ricardo Ota-Elliott, Zhihong Bian, Yuting Bian, Xinran Hu, Hongming Sun, Yusuke Fukui, Koji Abe, Hiroyuki Ishiura, Toru Yamashita

    Brain research   1821   148565 - 148565   2023年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by the loss of synapses and neurons in the brain, and the accumulation of amyloid plaques. Aβ oligomers (AβO) play a critical role in the pathogenesis of AD. Although there is increasing evidence to support the involvement of necroptosis in the pathogenesis of AD, the exact mechanism remains elusive. In the present study, we explored the effect of exogenous AβO injection on cell necroptosis and cognitive deficits in APP23 transgenic mice. We found that intrahippocampal injection of AβO accelerated the development of AD pathology and caused cognitive impairment in APP23 mice. Specifically, AβO injection significantly accelerated the accumulation of AβO and increased the expression level of phosphorylated-tau, and also induced necroptosis. Behavioral tests showed that AβO injection was associated with cognitive impairment. Furthermore, necroptosis induced by AβO injection occurred predominantly in microglia of the AD brain. We speculate that AβO increased necroptosis by activating microglia, resulting in cognitive deficits. Our results may aid in an understanding of the role played by AβO in AD from an alternative perspective and provide new ideas and evidence for necroptosis as a potential intervention and therapeutic target for AD.

    DOI: 10.1016/j.brainres.2023.148565

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  • CANVASにおける運動神経・筋障害の検討

    小巻 奨吾, 久保田 暁, 前田 明子, 北村 明日香, 清水 潤, 大澤 一太, 近藤 篤史, 池村 雅子, 光武 明彦, 小玉 聡, アルマンスール・アセム, 松川 敬志, 三井 純, 石浦 浩之, 戸田 達史

    臨床神経学   63 ( Suppl. )   S324 - S324   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 抗AQP4抗体陽性のNMOsd患者の髄液におけるIL-6測定の有用性の検討

    柚木 太淳, 中田 有美, 松岡 千加, 田所 功, 佐々木 諒, 中野 由美子, 武本 麻実, 森原 隆太, 山下 徹, 石浦 浩之

    臨床神経学   63 ( Suppl. )   S298 - S298   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 脊髄性筋萎縮症患者7名に対するリスジプラムの治療効果

    山下 徹, 柚木 太淳, 中田 有美, 松岡 千加, 佐々木 涼, 田所 功, 中野 由美子, 武本 麻美, 森原 隆太, 石浦 浩之

    臨床神経学   63 ( Suppl. )   S215 - S215   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • エフガルチギモドへのスイッチを行った抗アセチルコリン受容体抗体・抗横紋筋抗体陽性の全身型重症筋無力症の一例

    中野 由美子, 佐々木 諒, 中田 有美, 松岡 千加, 小坂田 陽介, 田所 功, 野村 恵美, 柚木 太淳, 武本 麻美, 森原 隆太, 山下 徹, 石浦 浩之

    臨床神経学   63 ( 9 )   621 - 621   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Foix-Chavany-Marie症候群を呈した持続性部分てんかんの一例

    佐々木 諒, 柚木 太淳, 中田 有美, 松岡 千加, 田所 功, 中野 由美子, 武本 麻美, 森原 隆太, 山下 徹, 石浦 浩之

    臨床神経学   63 ( 9 )   620 - 620   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 成人発症NOTCH2NLC関連神経核内封入体病における感覚障害・小脳性運動失調の検討

    舟川 開, 栗原 正典, 高橋 健祐, 小松 大樹, 波多野 敬子, 井原 涼子, 東原 真奈, 仁科 裕史, 徳丸 阿耶, 原 愛徒, 齊藤 祐子, 光武 明彦, 柴田 頌太, 石浦 浩之, 金丸 和富, 村山 繁雄, 岩田 淳

    臨床神経学   63 ( Suppl. )   S390 - S390   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 日本における常染色体劣性遺伝性脊髄小脳変性症8型の臨床、遺伝、病理学的研究(A clinical, genetic, and pathological study of autosomal recessive spinocerebellar ataxia-8 in Japan)

    Mitsutake Akihiko, Kawai Mizuho, Arakawa Akira, Kakumoto Toshiyuki, Matsukawa Takashi, Shirota Yuichiro, Sakuishi Kaori, Mitsui Jun, Yogo Makiko, Suzuki Masahiko, Hattori Nobutaka, Ishiura Hiroyuki, Murayama Shigeo, Tsuji Shoji, Toda Tatsushi

    臨床神経学   63 ( Suppl. )   S335 - S335   2023年9月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • A Case of Adrenomyeloneuropathy with Later Development of Cerebral Form Caused by a Hemizygous Splice-site Variant in ABCD1.

    Naoki Takegami, Takashi Matsukawa, Masashi Hamada, Shuichi Tanifuji, Takayuki Tamura, Nanaka Yamaguchi-Takegami, Hiroyuki Ishiura, Jun Mitsui, Kaori Sakuishi, Shoji Tsuji, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2023年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adrenomyeloneuropathy (AMN)/adrenoleukodystrophy (ALD) is an X-linked genetic disorder caused by pathogenic variants in ABCD1. We treated a 54-year-old man with slowly progressive spastic paraparesis with later development of the cerebral form. A pathogenic splice-site variant of ABCD1 (c.1489-1G>A, p. Val497Alafs*51) and elevated levels of very long-chain fatty acids were found, leading to the diagnosis of AMN. Detailed ABCD1 mRNA expression analyses revealed decreased levels of ABCD1 mRNA accompanied by deletion of the first 31 bp in exon 6. The altered mRNA transcriptional patterns associated with splice site variants are diverse and may provide important insights into ALD pathogenesis.

    DOI: 10.2169/internalmedicine.2240-23

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  • Late-onset Myoclonic Seizure in a 78-year-old Woman with Gaucher Disease.

    Nanaka Yamaguchi-Takegami, Akiko Takahashi, Jun Mitsui, Yusuke Sugiyama, Ayaka Chikada, Kristine Joyce L Porto, Naoki Takegami, Kaori Sakuishi, Hiroyuki Ishiura, Kaoru Yamada, Jun Shimizu, Shoji Tsuji, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2023年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We herein report a 78-year-old woman with Gaucher disease (GD) who was initially diagnosed with GD type 1, had been receiving long-term enzyme replacement therapy since 58 years old, and developed neurological manifestations in her 70s. The neurological manifestations included myoclonic seizures and progressive cognitive decline. Although it is rare for GD patients to first develop neurologic manifestations at such an advanced age, physicians engaged in long-term care for GD patients should be alert for this possibility.

    DOI: 10.2169/internalmedicine.1699-23

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  • A Japanese family with idiopathic basal ganglia calcification carrying a novel XPR1 variant 国際誌

    Kenta Orimo, Toshiyuki Kakumoto, Ryo Hara, Ryoji Goto, Hiroyuki Ishiura, Jun Mitsui, Chiharu Yoshida, Yoshikazu Uesaka, Yuta Suzuki, Shinichi Morishita, Wataru Satake, Shoji Tsuji, Tatsushi Toda

    Journal of the Neurological Sciences   451   120732 - 120732   2023年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.jns.2023.120732

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  • Anti-neurofascin 155 Antibody-positive Neuropathy in a Human Immunodeficiency Virus-infected Patient.

    So Okubo, Tatsuo Mano, Atsushi Sudo, Ryoji Goto, Satoka Yano, Manato Hara, Hiroyuki Ishiura, Wataru Satake, Shintaro Yanagimoto, Hidenori Ogata, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human immunodeficiency virus (HIV)-associated neuropathy is a common complication of HIV infection and has several clinical subtypes. HIV-associated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a demyelinating neuropathy whose clinical features are known to differ from those of CIDP in the HIV-uninfected population. We herein report a case of CIDP in an HIV-infected patient who was finally diagnosed with anti-neurofascin 155 (NF155) antibody-positive neuropathy. The clinical features, including clinical findings and therapeutic responses, were typical of paranodal antibody-mediated neuropathy. To our knowledge, this is the first case of anti-NF155 antibody-associated neuropathy in an HIV-infected patient.

    DOI: 10.2169/internalmedicine.1919-23

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  • Nine Hereditary Movement Disorders First Described in Asia: Their History and Evolution. 国際誌

    Priya Jagota, Yoshikazu Ugawa, Zakiyah Aldaajani, Norlinah Mohamed Ibrahim, Hiroyuki Ishiura, Yoshiko Nomura, Shoji Tsuji, Cid Diesta, Nobutaka Hattori, Osamu Onodera, Saeed Bohlega, Amir S N AlDin, Shen-Yang Lim, Jee-Young Lee, Beomseok Jeon, Pramod Kumar Pal, Huifang Shang, Shinsuke Fujioka, Prashanth Lingappa Kukkle, Onanong Phokaewvarangkul, Chin-Hsien Lin, Cholpon Shambetova, Roongroj Bhidayasiri

    Journal of movement disorders   16 ( 3 )   231 - 247   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia - Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism (XDP), dentatorubral-pallidoluysian atrophy (DRPLA), Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy (BAFME), Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 (CAMTA2) gene, and paroxysmal kinesigenic dyskinesia (PKD). We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

    DOI: 10.14802/jmd.23065

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  • Insights into familial adult myoclonus epilepsy pathogenesis: How the same repeat expansion in six unrelated genes may lead to cortical excitability. 国際誌

    Christel Depienne, Arn M J M van den Maagdenberg, Theresa Kühnel, Hiroyuki Ishiura, Mark A Corbett, Shoji Tsuji

    Epilepsia   64 Suppl 1   S31-S38   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Familial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular localizations and very different functions, which poses the issue of what causes the neurobiological disturbances that lead to the clinical phenotype. Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects. FAME expansions, contrary to the same expansion in DAB1 causing spinocerebellar ataxia type 37, seem to have no or limited impact on their recipient gene expression, which suggests a pathophysiological mechanism independent of the gene and its function. Current hypotheses include toxicity of the RNA molecules carrying UUUCA repeats, or toxicity of polypeptides encoded by the repeats, a mechanism known as repeat-associated non-AUG translation. The analysis of postmortem brains of FAME1 expansion (in SAMD12) carriers has revealed the presence of RNA foci that could be formed by the aggregation of RNA molecules with abnormal UUUCA repeats, but evidence is still lacking for other FAME subtypes. Even when the expansion is located in a gene ubiquitously expressed, expression of repeats remains undetectable in peripheral tissues (blood, skin). Therefore, the development of appropriate cellular models (induced pluripotent stem cell-derived neurons) or the study of affected tissues in patients is required to elucidate how FAME repeat expansions located in unrelated genes lead to disease.

    DOI: 10.1111/epi.17504

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  • Neurofilament light chain levels in cerebrospinal fluid as a sensitive biomarker for cerebral adrenoleukodystrophy. 国際誌

    Toshiyuki Kakumoto, Takashi Matsukawa, Hiroyuki Ishiura, Harushi Mori, Shoji Tsuji, Tatsushi Toda

    Annals of clinical and translational neurology   10 ( 7 )   1230 - 1238   2023年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Adrenoleukodystrophy (ALD) has a poor prognosis when it progresses to the cerebral form (CALD). The aim of this study is to investigate whether cerebrospinal fluid (CSF) neurofilament light chain (cNfL) is a sensitive biomarker for detecting CALD and assessing response to hematopoietic stem cell transplantation (HSCT). METHODS: We conducted a cross-sectional study of 41 male ALD patients. The cNfL levels in patients with the cerebral form of ALD (CALD) or the cerebello-brainstem form of ALD were compared with those in patients with adrenomyeloneuropathy (AMN). The correlation between cNfL levels and MRI-based Loes severity scores was investigated. A longitudinal analysis was performed on patients who underwent multiple CSF examinations. RESULTS: The cNfL levels in 22 patients with CALD were significantly higher than those in 14 patients with AMN (median, 5545 vs. 1490 pg/mL; p < 0.001). The cutoff cNfL level of 1930 pg/mL showed good sensitivity (95.5%) and specificity (85.7%) for distinguishing CALD from AMN. The cNfL levels were positively correlated with Loes scores (p < 0.001). The cNfL levels in three AMN patients who later converted to CALD increased above the cutoff level during the conversion period, while the cNfL levels in four patients who remained in AMN were consistently below the cutoff. In 10 ALD patients who underwent HSCT, their cNfL levels decreased 3-24 months after HSCT. Two patients whose cNfL increased after HSCT showed deterioration in cognitive functions. INTERPRETATION: The cNfL level is useful for evaluating the disease activities of ALD and the response to HSCT.

    DOI: 10.1002/acn3.51818

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  • Clinical features of a family with late-onset distal hereditary motor neuropathy harboring p.Pro39Leu variant of HSPB1. 国際誌

    Hiroya Naruse, So Okubo, Atsushi Sudo, Jun Mitsui, Takashi Mikata, Hiroyuki Ishiura, Shinichi Morishita, Shoji Tsuji, Tatsushi Toda

    Journal of the peripheral nervous system : JPNS   28 ( 3 )   518 - 521   2023年5月

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    記述言語:英語  

    BACKGROUND AND AIMS: Pathogenic variants of HSPB1, the gene encoding the small heat shock protein 27, have been reported to cause autosomal dominant distal hereditary motor neuropathy (dHMN) type II and autosomal dominant Charcot-Marie-Tooth (CMT) disease with minimal sensory involvement (CMT2F). This study aimed to describe the clinical features of patients in a family with late-onset dHMN carrying the Pro39Leu variant of HSPB1. METHODS: Whole-exome sequence analysis identified a heterozygous pathogenic variant (Pro39Leu) of HSPB1 in the proband. The presence of the HSPB1 Pro39Leu variant in two affected individuals was confirmed using direct nucleotide sequence analysis. RESULTS: Both patients exhibited distal muscle weakness with lower extremity predominance and no obvious sensory deficits, leading to a clinical diagnosis of late-onset dHMN. Nerve conduction studies (NCSs) revealed a subclinical complication of sensory disturbance in one of the patients. The clinical and electrophysiological findings of patients with the HSPB1 Pro39Leu variant in this study and previous reports are summarized. INTERPRETATION: This study suggests that the clinical spectrum of patients carrying HSPB1 Pro39Leu variants, especially the disease onset, might be broader than expected, and HSPB1 variants should be considered in patients diagnosed with late-onset dHMN. Furthermore, patients with dHMN may have concomitant sensory deficits that should be evaluated using NCSs.

    DOI: 10.1111/jns.12567

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  • Noncanonical splice-site variant in peripheral myelin protein 22 gene (PMP22) in a patient with hereditary neuropathy with liability to pressure palsies. 国際誌

    Norifumi Kawamoto, Yuichi Hamada, Shunsuke Kobayashi, Hiroya Naruse, Hiroyuki Ishiura, Takashi Matsukawa, Jun Mitsui, Shoji Tsuji, Masahiro Sonoo, Tatsushi Toda

    Journal of the peripheral nervous system : JPNS   28 ( 3 )   513 - 517   2023年5月

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    記述言語:英語  

    AIM: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral neuropathy with autosomal dominant inheritance. Diagnosis can be made from the characteristic abnormalities determined by nerve conduction studies (NCS), including subclinical deficits at physiological compression sites. Heterozygous deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein 22 gene (PMP22) is the cause in the majority of cases. However, the loss of function of PMP22 due to frameshift-causing insertion/deletion, missense, nonsense, or splice-site disrupting variants cause HNPP in some patients. We report a case of a patient diagnosed with HNPP on the basis of clinical features and the results of NCS. No deletions of PMP22 were detected by fluorescence in situ hybridization. METHODS: We performed direct nucleotide sequence analysis and identified a heterozygous variant, c.78 + 3G > T, in PMP22. Since this variant is located outside the canonical splice site at the exon 2-intron 2 junction, we investigated whether the variant causes aberrant splicing and leads to the skipping of exon 2 of PMP22 by in vitro minigene splicing assay. RESULTS: We demonstrated that the c.78 + 3G > T variant causes the skipping of exon 2 and leads to loss of function of the mutant allele. CONCLUSION: Searching for sequence variants located outside the canonical splice sites should also be considered even when deletion of PMP22 is not found in a patient with a clinical diagnosis suggesting HNPP.

    DOI: 10.1111/jns.12558

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  • A case of intravascular lymphoma presenting with a lesion in the splenium of the corpus callosum. 国際誌

    Haruka Masuzawa, Fumio Suzuki, Shiori Amemiya, Kenta Orimo, Hiroyuki Ishiura, Ryo Hara, Tatsushi Toda, Teruo Nakazawa, Akira Honda, Mariko Tanaka, Munetoshi Hinata, Osamu Abe

    Radiology case reports   18 ( 5 )   1929 - 1932   2023年5月

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    記述言語:英語  

    Intravascular lymphoma (IVL) is difficult to diagnose because its clinical presentation and laboratory and imaging findings are nonspecific. Herein, we report a case of IVL presenting as a lesion in the splenium of the corpus callosum. A 52-year-old man attended the emergency department with a 2-week history of progressively worsening abnormal behavior and gait disturbance. Magnetic resonance imaging on admission revealed an oval lesion in the splenium of the corpus callosum. The follow-up magnetic resonance imaging performed 2 months after disease onset revealed multiple high-signal areas in the bilateral cerebral white matter on T2-weighted images and diffusion-weighted images. The blood test results showed an elevated level of lactate dehydrogenase and serum-soluble interleukin-2 receptor. These findings were compatible with the diagnosis of IVL. IVL is often difficult to diagnose due to a wide variety of clinical presentations and imaging findings.

    DOI: 10.1016/j.radcr.2023.02.025

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  • High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. 国際誌

    Jun Mitsui, Takashi Matsukawa, Yukari Uemura, Takuya Kawahara, Ayaka Chikada, Kristine Joyce L Porto, Hiroya Naruse, Masaki Tanaka, Hiroyuki Ishiura, Tatsushi Toda, Haruko Kuzuyama, Mari Hirano, Ikue Wada, Toshio Ga, Takashi Moritoyo, Yuji Takahashi, Hidehiro Mizusawa, Kinya Ishikawa, Takanori Yokota, Satoshi Kuwabara, Nobukatsu Sawamoto, Ryosuke Takahashi, Koji Abe, Tomohiko Ishihara, Osamu Onodera, Dai Matsuse, Ryo Yamasaki, Jun-Ichi Kira, Masahisa Katsuno, Ritsuko Hanajima, Katsuhisa Ogata, Hiroshi Takashima, Masaaki Matsushima, Ichiro Yabe, Hidenao Sasaki, Shoji Tsuji

    EClinicalMedicine   59   101920 - 101920   2023年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. METHODS: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. FINDINGS: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). INTERPRETATION: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. FUNDING: Japan Agency for Medical Research and Development.

    DOI: 10.1016/j.eclinm.2023.101920

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  • Favorable outcome of hematopoietic stem cell transplantation in late-onset Krabbe disease. 国際誌

    Akihiko Mitsutake, Takashi Matsukawa, Atsushi Iwata, Hiroyuki Ishiura, Jun Mitsui, Harushi Mori, Takashi Toya, Akira Honda, Mineo Kurokawa, Norio Sakai, Shoji Tsuji, Tatsushi Toda

    Brain & development   45 ( 7 )   408 - 412   2023年4月

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    記述言語:英語  

    BACKGROUND: Late-onset Krabbe disease is a disorder with autosomal recessive inheritance caused by a deficiency in galactocerebrosidase (GALC) activity. Its late-onset form usually shows slow disease progression with atypical symptoms including spastic paresis. The efficacy of hematopoietic stem cell transplantation (HSCT) in late-onset Krabbe disease has not been fully established. CASE REPORT: We describe the case of a patient with late-onset Krabbe disease showing progressive spastic paraparesis. At the age of 18, one and a half years after the development of symptoms, the patient underwent HSCT. After HSCT, the patient's GALC activity returned to a normal level and the lesions in the brain and spinal cord became faint on images. Over two and a half years after the HSCT, the patient's gait remained spastic, however, an improvement in gait speed and modified Rankin Scale score was observed. No severe adverse events occurred during this period. CONCLUSION: Our experience reported herein provides additional evidence for a favorable course in HSCT conducted in the early course of late-onset Krabbe disease.

    DOI: 10.1016/j.braindev.2023.04.001

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  • BAFMEでの皮質興奮性における経時的進行の変性機構の解明:分子遺伝子学的・電気生理学的検討

    音成 秀一郎, 人見 健文, 戸島 麻耶, 小林 勝哉, 石浦 浩之, 池田 昭夫

    臨床神経生理学   51 ( 2 )   62 - 66   2023年4月

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    記述言語:日本語   出版者・発行元:一般社団法人 日本臨床神経生理学会  

    近年の分子遺伝学的研究により, SAMD12のイントロンのTTTCAならびにTTTTAからなる5塩基リピート伸長変異が良性成人型家族性ミオクローヌスてんかん (BAFME) を引き起こすことが明らかになり, リピート数とてんかん発作の初発年齢に負の相関があることが示された (Ishiura et al, Nature Genetics 2018) 。しかし, 非翻訳領域のリピート数が, 発症後の慢性期における長期的な症状進行にどのように影響を与えているかは不明である。BAFMEでは中高年以降において皮質興奮性が徐々に悪化するため, リピート数が長期的に神経予後に影響を与えているのか, あるいは他の関連因子が存在するのかは, 変性疾患の進行の病態機構を解明する上で興味深い。そこで, BAFME1型と診断された18名の患者を対象に, リピート伸長変異のリピート数と表現型 (皮質振戦・発作の発症年齢, SEP解析による皮質興奮性, 罹患期間) の相関を評価した。その結果, 既報告と同様に, 発症年齢はてんかん発作と負の相関があり, 加えて皮質振戦の発症年齢もリピート数と負の相関があることが示された。さらに偏相関分析によって皮質興奮性はSEP検査時の年齢 (加齢) には有意な相関があることが示され, 大脳皮質の一次感覚運動野における興奮性の経時的な増大は, 疾患進行における「加齢」の影響を受けていると考えられ, 特に中高年以降でのBAFME患者では加齢そのものが症状進行因子として異なる役割を担っている可能性がある。

    DOI: 10.11422/jscn.51.62

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  • 【「BAFME:臨床神経生理学と分子遺伝学のupdate」】BAFMEでの皮質興奮性における経時的進行の変性機構の解明 分子遺伝子学的・電気生理学的検討

    音成 秀一郎, 人見 健文, 戸島 麻耶, 小林 勝哉, 石浦 浩之, 池田 昭夫

    臨床神経生理学   51 ( 2 )   62 - 66   2023年4月

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    記述言語:日本語   出版者・発行元:(一社)日本臨床神経生理学会  

    近年の分子遺伝学的研究により,SAMD12のイントロンのTTTCAならびにTTTTAからなる5塩基リピート伸長変異が良性成人型家族性ミオクローヌスてんかん(BAFME)を引き起こすことが明らかになり,リピート数とてんかん発作の初発年齢に負の相関があることが示された(Ishiura et al,Nature Genetics 2018)。しかし,非翻訳領域のリピート数が,発症後の慢性期における長期的な症状進行にどのように影響を与えているかは不明である。BAFMEでは中高年以降において皮質興奮性が徐々に悪化するため,リピート数が長期的に神経予後に影響を与えているのか,あるいは他の関連因子が存在するのかは,変性疾患の進行の病態機構を解明する上で興味深い。そこで,BAFME1型と診断された18名の患者を対象に,リピート伸長変異のリピート数と表現型(皮質振戦・発作の発症年齢,SEP解析による皮質興奮性,罹患期間)の相関を評価した。その結果,既報告と同様に,発症年齢はてんかん発作と負の相関があり,加えて皮質振戦の発症年齢もリピート数と負の相関があることが示された。さらに偏相関分析によって皮質興奮性はSEP検査時の年齢(加齢)には有意な相関があることが示され,大脳皮質の一次感覚運動野における興奮性の経時的な増大は,疾患進行における「加齢」の影響を受けていると考えられ,特に中高年以降でのBAFME患者では加齢そのものが症状進行因子として異なる役割を担っている可能性がある。(著者抄録)

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  • Recent advances in CGG repeat diseases and a proposal of fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculophryngodistal myopathy (FNOP) spectrum disorder. 国際誌

    Hiroyuki Ishiura, Shoji Tsuji, Tatsushi Toda

    Journal of human genetics   68 ( 3 )   169 - 174   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    While whole genome sequencing and long-read sequencing have become widely available, more and more focuses are on noncoding expanded repeats. Indeed, more than half of noncoding repeat expansions related to diseases have been identified in the five years. An exciting aspect of the progress in this field is an identification of a phenomenon called repeat motif-phenotype correlation. Repeat motif-phenotype correlation in noncoding repeat expansion diseases is first found in benign adult familial myoclonus epilepsy. The concept is extended in the research of CGG repeat expansion diseases. In this review, we focus on newly identified CGG repeat expansion diseases, update the concept of repeat motif-phenotype correlation in CGG repeat expansion diseases, and propose a clinical concept of FNOP (fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculopharyngodistal myopathy)-spectrum disorder, which shares clinical features and thus probably share some common disease pathophysiology, to further facilitate discussion and progress in this field.

    DOI: 10.1038/s10038-022-01116-y

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  • The Myocardial Accumulation of Aggregated Desmin Protein in a Case of Desminopathy with a de novo DES p.R406W Mutation.

    Naoki Takegami, Akihiko Mitsutake, Tatsuo Mano, Yukako Shintani-Domoto, Atsushi Unuma, Nanaka Yamaguchi-Takegami, Hiroyuki Ishiura, Kaori Sakuishi, Masahiko Ando, Haruo Yamauchi, Minoru Ono, Shinichi Morishita, Jun Mitsui, Jun Shimizu, Shoji Tsuji, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   62 ( 19 )   2883 - 2887   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Desminopathy is a cardiac and skeletal myopathy caused by disease-causing variants in the desmin (DES) gene and represents a subgroup of myofibrillar myopathies, where cytoplasmic desmin-postive immunoreactivity is the pathological hallmark. We herein report a 28-year-old Japanese man who was initially diagnosed with sporadic hypertrophic cardiomyopathy with atrioventricular block at 9 years old and developed weakness in the soft palate and extremities. The myocardial tissue dissected during implantation of the ventricular-assisted device showed a dilated phase of hypertrophic cardiomyopathy and intracellular accumulation of proteinase K-resistant desmin aggregates. Genetic testing confirmed a de novo mutation of DES, which has already been linked to desminopathy. As the molecular diagnosis of desminopathy is challenging, particularly if patients show predominantly cardiac signs and a routine skeletal muscle biopsy is unavailable, these characteristic pathological findings of endomyocardial proteinase K-resistant desmin aggregates might aid in clinical practice.

    DOI: 10.2169/internalmedicine.0992-22

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  • Proteomic profile of nuclei containing p62-positive inclusions in a patient with neuronal intranuclear inclusion disease. 国際誌

    Masanori Kurihara, Tatsuo Mano, Fumihiro Eto, Ikuko Yao, Kenichiro Sato, Gaku Ohtomo, Taro Bannai, Shota Shibata, Hiroyuki Ishiura, Masako Ikemura, Tomoyasu Matsubara, Maho Morishima, Yuko Saito, Shigeo Murayama, Tatsushi Toda, Mitsutoshi Setou, Atsushi Iwata

    Neurobiology of disease   177   105989 - 105989   2023年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Ubiquitin- and p62-positive intranuclear inclusions are the pathological hallmark of NIID. Targeted immunostaining studies have identified several other proteins present in these inclusions. However, the global molecular changes within nuclei with these inclusions remained unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in a NIID patient with CGG repeat expansion in NOTCH2NLC to discover candidate proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins was confirmed via immunofluorescence in autopsy brain samples from three patients with genetically confirmed NIID. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A2/B1, hnRNP A3, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than in those without, which were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. Although larger studies are needed to validate our results, these proteomic data may form the basis for understanding the pathophysiology of NIID.

    DOI: 10.1016/j.nbd.2023.105989

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  • Recovery after Prolonged Disturbance of Consciousness and Repeated Cerebral Perfusion Changes in Neuronal Intranuclear Inclusion Disease

    Hirokazu Uchigami, Masashi Hamada, Hirotaka Maekawa, Hiroyuki Ishiura, Satoshi Kodama, Yuichiro Shirota, Miwako Takahashi, Toshimitsu Momose, Tatsushi Toda

    Internal Medicine   2023年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Society of Internal Medicine  

    Encephalitic episodes are a clinical manifestation of neuronal intranuclear inclusion disease (NIID) and often show transient disturbance of consciousness. We herein report a genetically confirmed patient with NIID who initially presented progressive dementia and showed prolonged disturbance of consciousness preceded by an acute-onset headache. During that time, we performed N-isopropyl-p-[123I]iodoamphetamine single-photon-emission computed tomography twice and found that the blood flow increased in different regions. Prolonged disturbance of consciousness following an encephalitic episode may be associated with repeated hyperperfusion in various regions resulting from mitochondrial dysfunction. NIID patients presenting with encephalitic episodes can recover gradually and spontaneously even after prolonged disturbances of consciousness.

    DOI: 10.2169/internalmedicine.1015-22

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  • A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis. 国際誌

    Masaki Tanaka, Satoru Takase, Hiroyuki Ishiura, Toshimasa Yamauchi, Sachiko Okazaki, Hiroaki Okazaki

    Journal of clinical lipidology   17 ( 3 )   327 - 331   2023年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hypertriglyceridemia (HTG)-induced pancreatitis during pregnancy could lead to maternal and fetal death. However, its genetic bases are not fully understood, and its treatment strategies are yet to be established. Here we report a case with a novel homozygous nonsense variant of LMF1 in pregnancy-associated HTG with acute pancreatitis. Our patient had childhood-onset severe HTG that had been well-controlled by dietary management in the non-pregnant period with plasma triglyceride (TG) levels at around 200 mg/dL. Milky plasma was noted at the first-trimester pregnancy checkup, followed by a severe increase in plasma TG (10,500 mg/dL) that resulted in pancreatitis in the last trimester. The implementation of strict dietary fat restriction (less than 4 grams per day) reduced plasma TG levels and led to successful delivery. Exome sequencing revealed a novel homozygous nonsense variant in LMF1 (c.697C>T, p.Arg233Ter). The activities of lipoprotein lipase (LPL) and hepatic lipase in post-heparin plasma were not abolished but reduced. The use of pemafibrate decreased plasma TG levels with a concomitant increase in LPL activity. HTG in childhood or early pregnancy is commonly assumed to be polygenic in origin but should be regarded as a feature suggestive of monogenic hyperchylomicronemia. Adequate TG monitoring and dietary fat restriction should be implemented to prevent potentially lethal events of pancreatitis.

    DOI: 10.1016/j.jacl.2023.03.005

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  • CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease

    Masanori Kurihara, Hiroki Komatsu, Renpei Sengoku, Mari Shibukawa, Satoru Morimoto, Tomoyasu Matsubara, Akira Arakawa, Makoto Orita, Kenji Ishibashi, Akihiko Mitsutake, Shota Shibata, Hiroyuki Ishiura, Kaori Adachi, Kensuke Ohse, Keiko Hatano, Ryoko Ihara, Mana Higashihara, Yasushi Nishina, Aya Midori Tokumaru, Kenji Ishii, Yuko Saito, Shigeo Murayama, Kazutomi Kanemaru, Atsushi Iwata

    Neurology   10.1212/WNL.0000000000201647 - 10.1212/WNL.0000000000201647   2022年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Ovid Technologies (Wolters Kluwer Health)  

    Background and Objectives:

    CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer’s disease (AD) and has recently been regarded to reflect amyloid-beta and/or p-tau deposition in the AD brain. Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by intranuclear inclusions in neurons, glial cells, and other somatic cells. Symptoms include dementia, neuropathy, and others. CSF biomarkers were not reported. The objective of this study was to investigate whether CSF biomarkers including p-tau181 are altered in patients with NIID.

    Methods:

    This was a retrospective observational study. CSF concentrations of p-tau181, total tau, amyloid-beta 1-42 (Aβ42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with Alzheimer’s clinical syndrome biologically confirmed based on CSF biomarker profiles, and patients clinically diagnosed with other neurocognitive disorders (dementia with Lewy bodies [DLB], 24; frontotemporal dementia [FTD], 13; progressive supranuclear palsy [PSP], 21; and corticobasal syndrome [CBS], 13). Amyloid PET using Pittsburgh compound B (PiB) was performed in six NIID patients.

    Results:

    The mean age of patients with NIID, AD, DLB, FTD, PSP, and CBS were 71.3, 74.6, 76.8, 70.2, 75.5, and 71.9 years old, respectively. CSF p-tau181 was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared to DLB, PSP, and CBS and was comparable between NIID and AD. CSF p-tau181 was above the cutoff value (50.0 pg/mL) in 11 of 12 NIID patients (91.7%). Within these patients, only two patients showed decreased CSF Aβ42, and these patients showed negative or mild local accumulation in PiB PET, respectively. PiB PET scans were negative in the remaining 4 patients tested. The proportion of patients with increased CSF p-tau181 and normal Aβ42 (A−T+) was significantly higher in NIID (75%) compared to DLB, PSP, and CBS (4.2%, 4.8%, and 7.7%, respectively). CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared to disease controls.

    Discussion:

    CSF p-tau181 was increased in patients with NIID without amyloid accumulation. Although the deposition of p-tau has not been reported in NIID brains, molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.

    DOI: 10.1212/wnl.0000000000201647

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  • 急性の頭痛と左片麻痺で発症した神経核内封入体病の60歳女性例

    古川 裕一, 神林 隆道, 松倉 清司, 近藤 あむろ, 小林 俊輔, 松原 知恭, 齊藤 祐子, 村山 繁雄, 光武 明彦, 石浦 浩之, 任 久美, 大場 洋, 園生 雅弘

    臨床神経学   62 ( 12 )   972 - 972   2022年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 足関節拘縮と特徴的な筋CT所見を呈し、COL6A3の新規変異にRYR1変異を伴ったBethlem myopathyの親子例

    坂井 悠人, 河合 三津保, 光武 明彦, 石浦 浩之, 斎藤 良彦, 永迫 友規, 時村 瞭, 西野 一三, 坪山 耀子, 後藤 順, 岩田 信恵

    臨床神経学   62 ( 12 )   963 - 963   2022年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • APOE Alleles With Tau and Aβ Pathology in Patients With Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex in the Kii Peninsula. 国際誌

    Ryogen Sasaki, Satoru Morimoto, Fumiko Ozawa, Hideyuki Okano, Mari Yoshida, Hiroyuki Ishiura, Shoji Tsuji, Shigeki Kuzuhara, Yasumasa Kokubo

    Neurology   99 ( 22 )   e2437-e2442   2022年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND OBJECTIVES: To examine the association of the APOE ε4 and ε2 alleles with the pathologic features of patients with amyotrophic lateral sclerosis and parkinsonism-dementia complex cases in the Kii peninsula of Japan (Kii ALS/PDC). METHODS: We analyzed APOE variants in 18 autopsy patients with ALS/PDC, consisting of 9, 8, and 1 patient with PDC, ALS, and PDC followed by ALS, respectively. Moreover, we revealed the relationship between APOE variants and Aβ and tau pathologies. RESULTS: The frequency of the ε4 allele was not different between patients with Kii ALS/PDC and control participants. APOE ε4 was associated with increased Aβ pathology (p = 0.005 by the χ 2 test), but not with increased tau pathology (p = 0.984). The frequency of the ε2 allele was apparently higher than that of control participants (p = 0.254). The APOE ε2 allele was associated with increased tau pathology (p = 0.009) and not with reduced Aβ pathology (p = 0.383) in patients with Kii ALS/PDC. DISCUSSION: Although there was no overrepresentation of the frequency of the ε4 or ε2 allele, our findings suggest that the ε2 allele is associated with increased tau pathology and not with reduced Aβ pathology in patients with Kii ALS/PDC.

    DOI: 10.1212/WNL.0000000000201156

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  • Valosin-containing protein Asp395Gly mutation in a patient with frontotemporal dementia: a case report. 国際誌

    Ryota Kobayashi, Hiroya Naruse, Shinobu Kawakatsu, Chifumi Iseki, Yuya Suzuki, Shingo Koyama, Daichi Morioka, Hiroyuki Ishiura, Jun Mitsui, Yasuyuki Ohta, Shoji Tsuji, Tatsushi Toda, Koichi Otani

    BMC neurology   22 ( 1 )   406 - 406   2022年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Variants in the valosin-containing protein (VCP) gene were identified as one of the causes for inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (FTD). Previously identified pathogenic variants in VCP are associated with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) pathologically, but p.Asp395Gly VCP was recently reported to cause familial FTD with tauopathy characterized by neurofibrillary tau tangles (NFT) and not FTLD-TDP. We describe the clinical and genetic findings of a patient with p.Asp395Gly valosin-containing protein (VCP), who was diagnosed with FTD without a family history and in the absence of muscle or bone disease comorbidity. CASE PRESENTATION: The patient was a 62-year-old man, who developed atypical depression at the age of 37 years. Subsequently, he presented with self-centered behavior at the age of 45 years. The self-centered behavior intensified from around the age of 50 years, which was accompanied by the development of executive dysfunction; therefore, he visited our hospital at 52 years of age. Magnetic resonance imaging revealed bilateral frontal lobe atrophy. Brain perfusion single-photon emission computed tomography revealed bilateral frontal lobe hypoperfusion. The patient fulfilled the diagnostic criteria for behavioral variant of FTD. Ten years after the diagnosis, computed tomography of the trunk and limbs, muscle biopsy, and bone scintigraphy revealed the absence of concomitant muscle and bone disease. The concentrations of cerebrospinal fluid (CSF) total tau and phosphorylated tau proteins were 389 pg/mL and 53.2 pg/mL (cut-off: 50 pg/mL), respectively. Genetic analyses were performed using the whole-exome and Sanger sequencing methods. We identified p.Asp395Gly VCP in this patient with pure FTD. CONCLUSIONS: p.Asp395Gly VCP was identified in a patient with likely sporadic FTD without concomitant muscle and bone disease. The CSF analysis suggested that our patient may have FTD due to NFT accumulation similar to the familial FTD patients with p.Asp395Gly VCP recently reported. Our findings suggest that a genetic search for the pathogenic variants of VCP should be considered not only for familial FTD, but also for patients with sporadic FTD, even in the absence of comorbid muscle or bone disease.

    DOI: 10.1186/s12883-022-02951-4

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  • The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15

    Afshin Saffari, Melanie Kellner, Catherine Jordan, Helena Rosengarten, Alisa Mo, Bo Zhang, Oleksandr Strelko, Sonja Neuser, Marie Y Davis, Nobuaki Yoshikura, Naonobu Futamura, Tomoya Takeuchi, Shin Nabatame, Hiroyuki Ishiura, Shoji Tsuji, Huda Shujaa Aldeen, Elisa Cali, Clarissa Rocca, Henry Houlden, Stephanie Efthymiou, Birgit Assmann, Grace Yoon, Bianca A Trombetta, Pia Kivisäkk, Florian Eichler, Haitian Nan, Yoshihisa Takiyama, Alessandra Tessa, Filippo M Santorelli, Mustafa Sahin, Craig Blackstone, Edward Yang, Rebecca Schüle, Darius Ebrahimi-Fakhari

    Brain   2022年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press (OUP)  

    ABSTRACT

    In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood (median: 24 months, IQR = 24), a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps, and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale (SPRS) scores, SPATAX Disability Scores and the 4-Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney-U test, p &amp;lt; 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = −0.65, p = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

    DOI: 10.1093/brain/awac391

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  • A Novel de novo KIF1A Mutation in a Patient with Ataxia, Intellectual Disability and Mild Foot Deformity. 国際誌

    Yuka Hama, Hidetoshi Date, Akiko Fujimoto, Ayano Matsui, Hiroyuki Ishiura, Jun Mitsui, Toshiyuki Yamamoto, Shoji Tsuji, Hidehiro Mizusawa, Yuji Takahashi

    Cerebellum (London, England)   2022年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Early-onset ataxias are often difficult to diagnose due to the genetic and phenotypic heterogeneity of patients. Whole exome sequencing (WES) is a powerful method for determining causative mutations of early-onset ataxias. We report a case in which a novel de novo KIF1A mutation was identified in a patient with ataxia, intellectual disability and mild foot deformity.A patient presented with sporadic forms of ataxia with mild foot deformity, intellectual disability, peripheral neuropathy, pyramidal signs, and orthostatic hypotension. WES was used to identify a novel de novo mutation in KIF1A, a known causative gene of neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment syndrome (NESCAVS).We report a novel phenotype of NESCAVS that is associated with a novel de novo missense mutation in KIF1A, which provides valuable information for the diagnosis of NESCAVS even in the era of WES. Early rehabilitation of patients with NESCAVS may prevent symptom worsening and improve the disease course.

    DOI: 10.1007/s12311-022-01489-y

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  • 良性成人型家族性ミオクローヌスてんかん(BAFME):臨床神経生理学と分子遺伝学のupdate BAFME1型における皮質興奮性の進行に及ぼす加齢の役割(A role of aging in the progression of cortical excitability in BAFME type 1)

    音成 秀一郎, 人見 健文, 戸島 麻耶, 小林 勝哉, 石浦 浩之, 池田 昭夫

    臨床神経生理学   50 ( 5 )   302 - 302   2022年10月

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    記述言語:英語   出版者・発行元:(一社)日本臨床神経生理学会  

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  • Asymptomatic myocardial infarction in a patient with myotonic dystrophy type 1.

    Yuka Seki, Takanobu Yamada, Arihiro Kiyosue, Koichi Kimura, Masae Uehara, Masaru Hatano, Takayoshi Sasako, Yuichiro Shirota, Atsushi Sudo, Hiroyuki Ishiura, Tatsushi Toda, Toshimasa Yamauchi, Issei Komuro

    Journal of cardiology cases   26 ( 4 )   248 - 251   2022年10月

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    記述言語:英語  

    Myotonic dystrophy type 1 (DM1) displays a wide range of cardiac manifestations, including conduction system disturbances, arrhythmias, and cardiomyopathy. As a result of progressive myocardial injury and fibrosis, patients with DM1 frequently show electrocardiogram (ECG) abnormalities which sometimes cannot be differentiated from myocardial ischemia. Even in DM1 cases with ECG findings indicative of coronary artery disease, coronary angiography and coronary computed tomography often demonstrate intact coronary arteries. In this article, we report a case of a 56-year-old DM1 patient with ST segment change on ECG, who was admitted to our hospital for further examination. Echocardiography revealed severe hypokinesis in the anteroseptal wall and left ventricular thrombus in the apex, suggesting the possibility of an old myocardial infarction in the left anterior descending artery (LAD) region. Coronary computed tomography angiography and coronary angiography demonstrated a severe stenosis suggestive of vulnerable plaque in the proximal part of LAD, although fractional flow reserve of the lesion did not indicate functional ischemia. A beta-blocker and a sodium-glucose cotransporter 2 inhibitor were introduced expecting a cardioprotective effect. One year after his discharge, the patient died of septic and cardiogenic shock triggered by aspiration pneumonia. Learning objective: Although the prevalent cardiac manifestations of patients with myotonic dystrophy type 1 are conduction abnormalities and cardiomyopathy, the possibility of having coronary artery disease should be considered because they often have some atherosclerotic risk factors with their tendency toward metabolic abnormalities such as diabetes mellitus due to insulin resistance and dyslipidemia and with diagnostic difficulty due to asymptomatic or non-specific manifestations.

    DOI: 10.1016/j.jccase.2022.05.004

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  • 神経伝導検査と血清免疫固定法からPOEMS症候群と診断した一例

    時村 瞭, 原 涼, 久保田 暁, 石浦 浩之, 千葉 晶輝, 小玉 聡, 代田 悠一郎, 濱田 雅, 戸田 達史

    臨床神経生理学   50 ( 5 )   414 - 414   2022年10月

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    記述言語:英語   出版者・発行元:(一社)日本臨床神経生理学会  

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  • 多発性硬化症及び視神経脊髄炎関連疾患における体性感覚誘発電位の有用性の検討

    坪山 耀子, 濱田 雅, 代田 悠一郎, 小玉 聡, 時村 瞭, 石浦 浩之, 戸田 達史, 高橋 利幸

    臨床神経学   62 ( Suppl. )   S336 - S336   2022年10月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 特発性大脳基底核石灰化症における白質病変(White matter lesions in idiopathic basal ganglia calcification)

    Orimo Kenta, Mitsutake Akihiko, Tanaka Masaki, Satake Shunya, Ishiura Hiroyuki, Itaya Sakiko, Inaba Akira, Orimo Satoshi, Shiio Yasushi, Matsukawa Takashi, Mitsui Jun, Tsuji Shoji, Toda Tatsushi

    臨床神経学   62 ( Suppl. )   S355 - S355   2022年10月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • 当院で経験したCharcot-Marie-Tooth病2A型 5例の臨床像の比較検討

    小谷 理紗, 中島 紗樹, 矢下 大輝, 成瀬 紘也, 間野 達雄, 久保田 暁, 石浦 浩之, 戸田 達史

    臨床神経学   62 ( Suppl. )   S267 - S267   2022年10月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • LEMS様の電気生理検査所見と錐体路徴候を認め,高Mg血症の関与が疑われた一例

    宮野 涼, 代田 悠一郎, 原 涼, 間野 達雄, 石浦 浩之, 濱田 雅, 戸田 達史

    臨床神経生理学   50 ( 5 )   462 - 462   2022年10月

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    記述言語:日本語   出版者・発行元:(一社)日本臨床神経生理学会  

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  • Clinical and Genetic Features of Multiplex Families with Multiple System Atrophy and Parkinson's Disease. 国際誌

    Takashi Matsukawa, Kristine Joyce L Porto, Jun Mitsui, Ayaka Chikada, Hiroyuki Ishiura, Yuji Takahashi, Fumiko Kusunoki Nakamoto, Tomonari Seki, Yasushi Shiio, Tatsushi Toda, Shoji Tsuji

    Cerebellum (London, England)   2022年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    While multiple system atrophy (MSA) has been considered a sporadic disease, there were previously reported multiplex families with MSA. Furthermore, several families with multiple patients with MSA and Parkinson's disease (PD) have been reported. As genetic risk factors for MSA, functionally impaired variants in COQ2 and Gaucher-disease-causing GBA variants have been reported. While it has been established that GBA variants are associated with PD, COQ2 may also be associated with PD. In 672 patients with MSA, we identified 12 multiplex families of patients with MSA and PD in first-degree relatives. We conducted a detailed analysis of the clinical presentations of these patients and genetic analyses of GBA and COQ2. In the multiplex families, a patient with MSA with predominant parkinsonism (MSA-P) was observed in nine families, while a patient with MSA cerebellar subtype (MSA-C) was observed in three families. Six families had siblings with MSA and PD, five families had a parent-offspring pair with MSA and PD, and in one family, a sibling and a parent of an MSA patient had PD. In genetic analyses of these patients, GBA variants were identified in one of the 12 MSA patients and two of the seven PD patients. Functionally impaired variants of COQ2 were identified in two of the 12 MSA patients and not identified in the seven PD patients. This study further emphasizes the occurrence of MSA and PD in first-degree relatives, raising the possibility that a common genetic basis underlies MSA and PD. Even though variants of COQ2 and GBA were identified in some patients in multiplex families with MSA and PD, it is necessary to further explore as yet unidentified genetic risk factors shared by MSA and PD.

    DOI: 10.1007/s12311-022-01426-z

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  • A Case of Copper Deficiency in Wilson's Disease with a Normal Zinc Value.

    Masayuki Ueda, Kazuto Katsuse, Toshiyuki Kakumoto, Satoshi Kobayashi, Hiroyuki Ishiura, Jun Mitsui, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   62 ( 7 )   1073 - 1076   2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Copper deficiency (CD) is a rare complication of long-term treatment of Wilson's disease (WD) and is usually accompanied by high serum zinc levels. A 57-year-old woman with WD presented with limb weakness and sensory disturbance due to myeloneuropathy and macrocytic anemia after 36 years of treatment. Markedly reduced serum free copper values confirmed CD, which was considered to be caused by progressive dysphagia and severe diarrhea rather than zinc overdose because of the normal serum zinc levels. Discontinuing copper-reducing therapy and increasing copper intake improved her symptoms. Physicians should be alert for the risk of CD in WD patients, especially those with dysphagia.

    DOI: 10.2169/internalmedicine.9366-22

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  • Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations. 査読 国際誌

    Hiroki Hongo, Satoru Miyawaki, Yu Teranishi, Jun Mitsui, Hiroto Katoh, Daisuke Komura, Kinya Tsubota, Takashi Matsukawa, Masakatsu Watanabe, Masakazu Kurita, Jun Yoshimura, Shogo Dofuku, Kenta Ohara, Daiichiro Ishigami, Atsushi Okano, Motoi Kato, Fumihiko Hakuno, Ayaka Takahashi, Akiko Kunita, Hiroyuki Ishiura, Masahiro Shin, Hirofumi Nakatomi, Toshitaka Nagao, Hiroshi Goto, Shin-Ichiro Takahashi, Tetsuo Ushiku, Shumpei Ishikawa, Mutsumi Okazaki, Shinichi Morishita, Shoji Tsuji, Nobuhito Saito

    Angiogenesis   26 ( 1 )   37 - 52   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

    DOI: 10.1007/s10456-022-09846-5

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  • Expression profile analysis in cells overexpressing <scp>DRPLA cDNA</scp> to explore the roles of <scp>DRPLAp</scp> as a transcriptional coregulator

    Keiko Hatano, Hidetoshi Date, Hiroyuki Ishiura, Takashi Matsukawa, Masaki Tanaka, Jun Mitsui, Jun Goto, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji

    Neurology and Clinical Neuroscience   10 ( 4 )   210 - 217   2022年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/ncn3.12607

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12607

  • Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible. 国際誌

    Masahiro Ando, Yujiro Higuchi, Junhui Yuan, Akiko Yoshimura, Takaki Taniguchi, Fumikazu Kojima, Yutaka Noguchi, Takahiro Hobara, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima

    Biomedicines   10 ( 7 )   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

    DOI: 10.3390/biomedicines10071546

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  • Nonsyndromic arteriopathy and aortopathy and vascular Ehlers–Danlos syndrome <scp> causing COL3A1 </scp> variants

    Hiroki Yagi, Norifumi Takeda, Eisuke Amiya, Nana Akiyama, Hyangri Chang, Hiroyuki Ishiura, Jiro Sato, Hiroshi Akazawa, Hiroyuki Morita, Issei Komuro

    American Journal of Medical Genetics Part A   2022年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/ajmg.a.62774

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  • <scp>TDP</scp> ‐43 Proteinopathy Presenting with Typical Symptoms of Parkinson's Disease

    Rika Yamashita, Goichi Beck, Yuki Yonenobu, Kimiko Inoue, Akihiko Mitsutake, Hiroyuki Ishiura, Masato Hasegawa, Shigeo Murayama, Hideki Mochizuki

    Movement Disorders   2022年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/mds.29048

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  • Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan. 国際誌

    Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Ruriko Kitao, Takehiko Morimoto, Takaki Taniguchi, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima

    Annals of clinical and translational neurology   9 ( 5 )   747 - 755   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. METHODS: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. RESULTS: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

    DOI: 10.1002/acn3.51555

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  • Efficacy of canakinumab on AA amyloidosis in late-onset NLRP3-associated autoinflammatory disease with an I574F somatic mosaic mutation. 国際誌

    Takahiro Itamiya, Toshihiko Komai, Hiroko Kanda, Yasuo Nagafuchi, Hyangri Chang, Shota Shibata, Hiroyuki Ishiura, Hirofumi Shoda, Tatsushi Toda, Keishi Fujio

    Clinical rheumatology   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    There have been hundreds of reports on mutations in the NLRP3 gene related to NLRP3-associated autoinflammatory disease, but few of these mutations have occurred as both germline and somatic mosaic mutations. In this case-based review, we report a 68-year-old man with an NLRP3-associated autoinflammatory disease. He developed secondary amyloidosis, including a renal and colorectal presentation in his 50 s. Sequencing of the NLRP3 gene revealed an I574F somatic mosaic mutation, which has up to now only been reported in germline mutations. The patient was treated with canakinumab, which had great efficacy not only on the NLRP3-mediated inflammation, but also on the chronic renal failure and proteinuria provoked by secondary renal amyloidosis. To evaluate the effectiveness of canakinumab, we conducted a literature research on renal amyloidosis related to NLRP3-associated autoinflammatory disease treated with canakinumab. Although our patient had a relatively long medical history and greater amounts of proteinuria than other reported cases, canakinumab had great efficacy on renal impairment, in similar to other reported cases. Along with the first report of a late-onset I574F somatic mosaic mutation in NLRP3-associated autoinflammatory disease, this report demonstrates the effectiveness of canakinumab on renal amyloidosis, probably through the way that IL-1β blockade minimizes podocyte injury.

    DOI: 10.1007/s10067-022-06130-1

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  • Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes. 国際誌

    Yu Hiramatsu, Yuji Okamoto, Akiko Yoshimura, Jun-Hui Yuan, Masahiro Ando, Yujiro Higuchi, Akihiro Hashiguchi, Eiji Matsuura, Fumihito Nozaki, Tomohiro Kumada, Kei Murayama, Mikiya Suzuki, Yuki Yamamoto, Naoko Matsui, Yoshimichi Miyazaki, Masamitsu Yamaguchi, Youji Suzuki, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Shinichi Morishita, Ichizo Nishino, Shoji Tsuji, Hiroshi Takashima

    Journal of neurology   269 ( 8 )   4129 - 4140   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot-Marie-Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

    DOI: 10.1007/s00415-022-11026-w

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  • Muscle Transcriptomics Shows Overexpression of Cadherin 1 in Inclusion Body Myositis. 国際誌

    Chiseko Ikenaga, Hidetoshi Date, Motoi Kanagawa, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Iago Pinal-Fernandez, Andrew L Mammen, Thomas E Lloyd, Shoji Tsuji, Jun Shimizu, Tatsushi Toda, Jun Goto

    Annals of neurology   91 ( 3 )   317 - 328   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: This study aimed to elucidate the molecular features of inclusion body myositis (IBM). METHODS: We performed RNA sequencing analysis of muscle biopsy samples from 67 participants, consisting of 58 myositis patients with the pathological finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class I (43 IBM, 6 polymyositis, and 9 unclassifiable myositis), and 9 controls. RESULTS: Cluster analysis, principal component analysis, and pathway analysis showed that differentially expressed genes and pathways identified in IBM and polymyositis were mostly comparable. However, pathways related to cell adhesion molecules were upregulated in IBM as compared with polymyositis and controls (p < 0.01). Notably, CDH1, which encodes the epidermal cell junction protein cadherin 1, was overexpressed in the muscles of IBM, which was validated by another RNA sequencing dataset from previous publications. Western blotting confirmed the presence of mature cadherin 1 protein in the muscles of IBM. Immunohistochemical staining confirmed the positivity for anti-cadherin 1 antibody in the muscles of IBM, whereas there was no muscle fiber positive for anti-cadherin 1 antibody in immune-mediated necrotizing myopathy, antisynthetase syndrome, and controls. The fibers stained with anti-cadherin 1 antibody did not have rimmed vacuoles or abnormal protein accumulation. Experimental skeletal muscle regeneration and differentiation systems showed that CDH1 is expressed during skeletal muscle regeneration and differentiation. INTERPRETATION: CDH1 was detected as a differentially expressed gene, and immunohistochemistry showed that cadherin 1 exists in the muscles of IBM, whereas it was rarely seen in those of other idiopathic inflammatory myopathies. Cadherin 1 upregulation in muscle could provide a valuable clue to the pathological mechanisms of IBM. ANN NEUROL 2022;91:317-328.

    DOI: 10.1002/ana.26304

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  • Family with congenital contractural arachnodactyly due to a novel multiexon deletion of the FBN2 gene. 国際誌

    Hiroki Yagi, Hiroshi Takiguchi, Norifumi Takeda, Ryo Inuzuka, Yuki Taniguchi, Kristine Joyce Porto, Hiroyuki Ishiura, Jun Mitsui, Hiroyuki Morita, Issei Komuro

    Clinical case reports   10 ( 2 )   e05335   2022年2月

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    記述言語:英語  

    Congenital contractural arachnodactyly (CCA) is caused by pathogenic FBN2 variants; however, the contributions of copy number variations (CNVs) to CCA are still unknown. Here, we report on a familial case of CCA, in which a novel multiexon deletion of exons 35-39 in FBN2 was identified after simple CNV prediction.

    DOI: 10.1002/ccr3.5335

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  • An immigrant family with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. 国際誌

    Yasumasa Kokubo, Satoru Morimoto, Ryogen Sasaki, Masato Hasegawa, Hiroyuki Ishiura, Shoji Tsuji, Mari Yoshida, Naohisa Yamazoe, Mitsukazu Miyazaki, Shigeki Kuzuhara

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology   43 ( 2 )   1423 - 1425   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a unique endemic on Guam island of the USA, the Kii Peninsula of Japan, and Papua state of Indonesia. The pathomechanism of ALS/PDC remains to be solved, although interaction between some environmental factors and genetic background is plausible. This is the first autopsy-proven immigrant family of ALS/PDC of the Kii Peninsula. METHODS: A daughter and her father immigrated to the high incident area from outside the Kii Peninsula. The father developed ALS 18 years later after immigration, and his daughter also developed ALS 65 years after immigration. They showed pure ALS phenotype without parkinsonism and dementia. RESULTS: The daughter was diagnosed neuropathologically with Kii ALS/PDC with multiple proteinopathies: tauopathy, α-synucleinopathy, and TDP-43 proteinopathy. Gene analysis of familial ALS-related genes, including C9orf72, showed no mutation. DISCUSSION: The findings in an immigrant family established that certain environmental factors play a critical role in the pathogenesis of Kii ALS/PDC.

    DOI: 10.1007/s10072-021-05737-7

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  • An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families. 国際誌

    Masahiro Ando, Yujiro Higuchi, Yuji Okamoto, Junhui Yuan, Akiko Yoshimura, Jun Takei, Takaki Taniguchi, Yu Hiramatsu, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Hiroto Nakagawa, Ken Sonoda, Toru Yamashita, Akiko Tamura, Hideo Terasawa, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima

    Journal of human genetics   67 ( 7 )   399 - 403   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND AIMS: Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. METHODS: We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). RESULTS: We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. INTERPRETATION: This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

    DOI: 10.1038/s10038-022-01019-y

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  • Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments. 国際誌

    Takaki Taniguchi, Masahiro Ando, Yuji Okamoto, Akiko Yoshimura, Yujiro Higuchi, Akihiro Hashiguchi, Nozomu Matsuda, Mamoru Yamamoto, Eisuke Dohi, Makoto Takahashi, Masanao Yoshino, Taichi Nomura, Masaaki Matsushima, Ichiro Yabe, Yui Sanpei, Hiroyuki Ishiura, Jun Mitsui, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima

    Journal of human genetics   67 ( 6 )   353 - 362   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND AIMS: Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot-Marie-Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments. METHODS: We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489). RESULTS: The median (interquartile range) age at onset of neurological symptoms was 69 (64.2-70) years in the ATTRv amyloidosis vs 12 (5-37.2) years in CMT group (Mann-Whitney U, p < 0.01). The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher's exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher's exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived. INTERPRETATION: For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

    DOI: 10.1038/s10038-021-01005-w

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  • Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy. 国際誌

    Jun-Hui Yuan, Yujiro Higuchi, Masahiro Ando, Eiji Matsuura, Akihiro Hashiguchi, Akiko Yoshimura, Tomonori Nakamura, Yusuke Sakiyama, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroshi Takashima

    Frontiers in neurology   13   986504 - 986504   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Non-coding repeat expansions within RFC1 and NOTCH2NLC genes have lately been linked to multisystem neurodegenerative diseases, which also shed light on yet undiagnosed patients with inherited peripheral neuropathies. The aim of this study was to identify the genetic basis of patients with hereditary sensory and autonomic neuropathy (HSAN). We collected 79 unrelated DNA samples clinically suspected with HSAN from multiple regions of Japan. Mutation screening was first performed using gene panel sequencing and whole-exome sequencing. Pathogenic/likely pathogenic variants were identified from genes of WNK1/HSN2 (6 cases), SCN9A (3 cases), NTRK1 (3 cases), and DNMT1 (2 cases). Subsequently, long-range flanking PCR and repeat-primed PCR were applied to analyze repeat expansions in RFC1 and NOTCH2NLC. Bi-allelic RFC1 repeat expansions were detected from 20 adult-onset HSAN patients, consisting of [(AAGGG)exp/(AAGGG)exp] (8 cases), [(ACAGG)exp/(ACAGG)exp] (8 cases), and [(AAGGG)exp/(ACAGG)exp] (4 cases). GGC repeat expansion in NOTCH2NLC was found in 1 case. Single-nucleotide variant-based haplotype analysis of patients harboring disease-associated repeat expansions in RFC1 revealed distinguishable haplotypes among subgroups with different repeat genotypes. These findings substantially redefine the genetic spectrum of HSAN, where multi-type RFC1 repeat expansions account for 25.3% of all patients, highlighting the necessity of genetic screening, particularly for adult-onset patients.

    DOI: 10.3389/fneur.2022.986504

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  • DMD exon 2 duplication due to a complex genomic rearrangement is associated with a somatic mosaicism. 国際誌

    Akatsuki Kubota, Hiroyuki Ishiura, Kristine Joyce Linay Porto, Masaki Tanaka, Jun Mitsui, Atsushi Unuma, Hisataka Maki, Issei Komuro, Shoji Tsuji, Jun Shimizu, Tatsushi Toda

    Neuromuscular disorders : NMD   32 ( 3 )   263 - 269   2021年12月

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    記述言語:英語  

    We report the case of a patient with dystrophinopathy caused by DMD exon 2 duplication, showing marked asymmetric muscle atrophy. Immunostaining of the biopsied muscle tissue showed a mosaic staining, suggesting a somatic mosaicism. Polymerase chain reaction (PCR) analysis showed only one breakpoint, and long-read whole-genome sequencing revealed the entire structure of the rearranged sequence. The complex rearrangement was composed of two tandem duplications: one showed a microhomology near the breakpoint, suggesting a microhomology-mediated mechanism, whereas the other was associated with flanking short tandem repeats. The long-read sequencing also suggested the presence of a wild-type nonduplicated sequence, supporting somatic mosaicism. Whereas complementary DNA and western blot analyses were not useful, droplet digital PCR (ddPCR) analysis showed an average copy number of 1.61, enabling accurate estimation of the proportion of cells containing the duplication. Long-read sequencing and ddPCR analysis were useful for revealing the rearrangements and the precise copy number.

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  • Randomized, double-blind, placebo-controlled phase 1 study to evaluate the safety and pharmacokinetics of high doses of ubiquinol in healthy adults

    Jun Mitsui, Takashi Matsukawa, Masaki Tanaka, Naoko Saito-Sato, Fumiko Kusunoki Nakamoto, Tsutomu Yasuda, Hiroya Naruse, Miho Kawabe Matsukawa, Hiroyuki Ishiura, Midori Nagase, Yorihiro Yamamoto, Haruko Kuzuyama, Ikue Wada, Toshio Ga, Tsutomu Yamazaki, Takashi Moritoyo, Shoji Tsuji

    NEUROLOGY AND CLINICAL NEUROSCIENCE   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Background: Multiple system atrophy (MSA) is an intractable neurodegenerative disease. Higher frequencies of carriers of the V393A variant in COQ2 and lower levels of coenzyme Q10 (CoQ10) in body tissues have been reported in patients with MSA than in healthy controls. On the basis of the hypothesis that CoQ10 supplementation may slow the progression of MSA, we have been developing CoQ10 as an investigational drug for MSA.Methods: A single-center, randomized, double-blind, placebo-controlled phase 1 study of ubiquinol in healthy adult male volunteers was conducted. Participants were randomly assigned to groups that orally receive 900, 1200, and 1500 mg of ubiquinol or placebo daily for 14 days. Safety was assessed by examining the frequency and severity of adverse events. The levels of ubiquinol in plasma and total CoQ10 in peripheral blood mononuclear cells and cerebrospinal fluid were investigated.Results: Thirty-two participants provided informed consent to participate in this study. No clinically relevant changes in standard laboratory tests, physical examination, vital signs, or electrocardiogram attributable to ubiquinol administration were observed in any groups. The trough of plasma ubiquinol levels after repeated administration for 14 days reached a steady state, and the plasma ubiquinol levels in the 1500 mg/day-administered group tended to be the highest.Conclusions: High-dose ubiquinol supplementation was shown to be safe and tolerated when administered orally to healthy adult males at a maximum dosage of 1500 mg/day for 14 days.

    DOI: 10.1111/ncn3.12566

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  • Frequency of FMR1 Premutation Alleles in Patients with Undiagnosed Cerebellar Ataxia and Multiple System Atrophy in the Japanese Population. 国際誌

    Asem Almansour, Hiroyuki Ishiura, Jun Mitsui, Takashi Matsukawa, Miho Kawabe Matsukawa, Hideaki Shimizu, Atsuhiko Sugiyama, Tatsushi Toda, Shoji Tsuji

    Cerebellum (London, England)   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.

    DOI: 10.1007/s12311-021-01329-5

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  • Diagnostic Values of Venous Peak Lactate, Lactate-to-pyruvate Ratio, and fold Increase in Lactate from Baseline in Aerobic Exercise Tests in Patients with Mitochondrial Diseases.

    Masanori Kurihara, Yusuke Sugiyama, Masaki Tanaka, Kenichiro Sato, Akihiko Mitsutake, Hiroyuki Ishiura, Akatsuki Kubota, Kaori Sakuishi, Toshihiro Hayashi, Atsushi Iwata, Jun Shimizu, Kei Murayama, Shoji Tsuji, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   61 ( 13 )   1939 - 1946   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective Although aerobic exercise tests on cycle ergometry have long been used for initial assessments of cases of suspected mitochondrial disease, the test parameters in patients with final diagnoses of other diseases via the widely used 15 W for 15 min exercise protocol have not been fully characterized. Methods and Patients We retrospectively reviewed all patients who underwent the test at our institution. We classified the patients with genetic diagnoses or those who met previously reported clinical criteria as having mitochondrial diseases and those with a final diagnosis of another disease as having other diseases. Results were available from 6 patients with mitochondrial disease and 15 with other diseases. Results During the test, elevated venous peak lactate above the upper normal limit of healthy controls at rest (19.2 mg/dL [2.13 mM]) was observed in 3 patients with mitochondrial diseases (50.0%) and 5 with other diseases (33.3%). In the group of patients with elevated venous peak lactate, a lactate-to-pyruvate ratio of >20 was observed in all 3 patients with mitochondrial disease but in only 1 of the 5 with other diseases. More than a 2-fold increase in venous lactate from baseline was observed in 4 patients with mitochondrial disease (66.7%) and 1 with another disease (6.7%). Conclusion Elevated venous peak lactate levels were observed in patients with final diagnoses of other diseases, even under a low 15-min workload at 15 W. The lactate-to-pyruvate ratio and increase in lactate level from baseline may add diagnostic value to venous peak lactate levels alone.

    DOI: 10.2169/internalmedicine.8629-21

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  • COQ2 V393A confers high risk susceptibility for multiple system atrophy in East Asian population. 国際誌

    Kristine Joyce Porto, Makito Hirano, Jun Mitsui, Ayaka Chikada, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda, Susumu Kusunoki, Shoji Tsuji

    Journal of the neurological sciences   429   117623 - 117623   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Multiple system atrophy (MSA) is a rare, late-onset, and devastating neurodegenerative disease characterized by autonomic failure, alongside with various combination of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Since we first identified biallelic mutations in the COQ2 gene in two multiplex MSA families and further reported that heterozygous COQ2 V393A variant confers a susceptibility to sporadic MSA, the results of nearly a decade of investigating this association globally were quite remarkable. COQ2 V393A was virtually absent in the American and European populations but was shown to have varying associations with sporadic MSA in the East Asian populations. In our attempt to clarify the latter and provide a coherent regional conclusion, we conducted two independent case-control series which showed clear association of the V393A variant with sporadic MSA in the Japanese population. We then pooled the results with other studies from the East Asian population and conducted a meta-analysis which broadened and established the association regionally (pooled OR 2.12, 95% CI: 1.35-3.31, PI: 0.63-7.15, p = 0.0047). The subgroup analysis identified a strong association of V393A with MSA-C (pooled OR 2.57, 95% CI: 1.98-3.35; p = 2.56 × 10-12) but not with MSA-P (pooled OR 1.41, 95% CI: 0.88-2.26; p = 0.16). Our results highlighted the importance of investigating region-specific and pan-regional genetic variants that may potentially underlie the pathomechanisms of neurodegenerative diseases. COQ2 V393A variant remains a susceptibility variant rather than causative for MSA particularly, MSA-C subtype, in the East Asian population.

    DOI: 10.1016/j.jns.2021.117623

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  • Severe dilated cardiomyopathy and ventricular arrhythmia in a patient with Emery‐Dreifuss muscular dystrophy harboring a novel frameshift mutation in EMD

    Akihiko Mitsutake, Atsushi Unuma, Mizuho Kawai, Akatsuki Kubota, Hiroyuki Ishiura, Kaori Sakuishi, Jun Shimizu, Hisataka Maki, Eisuke Amiya, Masaru Hatano, Issei Komuro, Shoji Tsuji, Tatsushi Toda

    Neurology and Clinical Neuroscience   9 ( 6 )   490 - 493   2021年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/ncn3.12552

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  • Clinical Impact of Copy Number Variation on the Genetic Diagnosis of Syndromic Aortopathies. 国際誌

    Norifumi Takeda, Ryo Inuzuka, Hiroki Yagi, Hiroyuki Morita, Masahiko Ando, Haruo Yamauchi, Yuki Taniguchi, Kristine Joyce Porto, Tsubasa Kanaya, Hiroyuki Ishiura, Jun Mitsui, Shoji Tsuji, Tatsushi Toda, Minoru Ono, Issei Komuro

    Circulation. Genomic and precision medicine   14 ( 4 )   CIRCGEN121003458   2021年7月

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  • A Role of Aging in the Progression of Cortical Excitability in Benign Adult Familial Myoclonus Epilepsy type 1 Patients. 国際誌

    Shuichiro Neshige, Takefumi Hitomi, Maya Tojima, Kazuki Oi, Katsuya Kobayashi, Masao Matsuhashi, Akihiro Shimotake, Riki Matsumoto, Masutaro Kanda, Hirofumi Maruyama, Hiroyuki Ishiura, Shoji Tsuji, Ryosuke Takahashi, Akio Ikeda

    Movement disorders : official journal of the Movement Disorder Society   36 ( 10 )   2446 - 2448   2021年7月

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    記述言語:英語  

    DOI: 10.1002/mds.28718

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  • Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis. 国際誌

    Hitoshi Aizawa, Haruhisa Kato, Koji Oba, Takuya Kawahara, Yoshihiko Okubo, Tomoko Saito, Makiko Naito, Makoto Urushitani, Akira Tamaoka, Kiyotaka Nakamagoe, Kazuhiro Ishii, Takashi Kanda, Masahisa Katsuno, Naoki Atsuta, Yasushi Maeda, Makiko Nagai, Kazutoshi Nishiyama, Hiroyuki Ishiura, Tatsushi Toda, Akihiro Kawata, Koji Abe, Ichiro Yabe, Ikuko Takahashi-Iwata, Hidenao Sasaki, Hitoshi Warita, Masashi Aoki, Gen Sobue, Hidehiro Mizusawa, Yutaka Matsuyama, Tomohiro Haga, Shin Kwak

    Journal of neurology   269 ( 2 )   885 - 896   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

    DOI: 10.1007/s00415-021-10670-y

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  • A Case of Irreversible Corneal Edema Associated with Dentatorubropallidoluysian Atrophy Following Corneal Endothelial Transplantation

    Yumi Hashimoto, Jun Mitsui, Hiroyuki Ishiura, Takashi Matsukawa, Tatsushi Toda, Koji Kakisu, Yuichi Hori, Suguru Nakagawa, Tetsuya Toyono, Junko Yoshida, Tomohiko Usui, Satoru Yamagami, Makoto Aihara, Takashi Miyai

    SN Comprehensive Clinical Medicine   2021年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1007/s42399-021-00962-9

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    その他リンク: https://link.springer.com/article/10.1007/s42399-021-00962-9/fulltext.html

  • Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. 国際誌

    Manuela Wiessner, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S Müller, Rolf Stucka, Christian Beetz, Stephanie Efthymiou, Filippo M Santorelli, Ahmed A Alfares, Changlian Zhu, Anna Uhrova Meszarosova, Elham Alehabib, Somayeh Bakhtiari, Andreas R Janecke, Maria Gabriela Otero, Jin Yun Helen Chen, James T Peterson, Tim M Strom, Peter De Jonghe, Tine Deconinck, Willem De Ridder, Jonathan De Winter, Rossella Pasquariello, Ivana Ricca, Majid Alfadhel, Bart P van de Warrenburg, Ruben Portier, Carsten Bergmann, Saghar Ghasemi Firouzabadi, Sheng Chih Jin, Kaya Bilguvar, Sherifa Hamed, Mohammed Abdelhameed, Nourelhoda A Haridy, Shazia Maqbool, Fatima Rahman, Najwa Anwar, Jenny Carmichael, Alistair Pagnamenta, Nick W Wood, Frederic Tran Mau-Them, Tobias Haack, Maja Di Rocco, Isabella Ceccherini, Michele Iacomino, Federico Zara, Vincenzo Salpietro, Marcello Scala, Marta Rusmini, Yiran Xu, Yinghong Wang, Yasuhiro Suzuki, Kishin Koh, Haitian Nan, Hiroyuki Ishiura, Shoji Tsuji, Laëtitia Lambert, Emmanuelle Schmitt, Elodie Lacaze, Hanna Küpper, David Dredge, Cara Skraban, Amy Goldstein, Mary J H Willis, Katheryn Grand, John M Graham, Richard A Lewis, Francisca Millan, Özgür Duman, Nihal Dündar, Gökhan Uyanik, Ludger Schöls, Peter Nürnberg, Gudrun Nürnberg, Andrea Catala Bordes, Pavel Seeman, Martin Kuchar, Hossein Darvish, Adriana Rebelo, Filipa Bouçanova, Jean-Jacques Medard, Roman Chrast, Michaela Auer-Grumbach, Fowzan S Alkuraya, Hanan Shamseldin, Saeed Al Tala, Jamileh Rezazadeh Varaghchi, Maryam Najafi, Selina Deschner, Dieter Gläser, Wolfgang Hüttel, Michael C Kruer, Erik-Jan Kamsteeg, Yoshihisa Takiyama, Stephan Züchner, Jonathan Baets, Matthis Synofzik, Rebecca Schüle, Rita Horvath, Henry Houlden, Luca Bartesaghi, Hwei-Jen Lee, Konstantinos Ampatzis, Tyler Mark Pierson, Jan Senderek

    Brain : a journal of neurology   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

    DOI: 10.1093/brain/awab041

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  • 脳神経内科医を対象とした遺伝カウンセリング・ロールプレイの試み

    竹内 千仙, 神原 容子, 西郷 和真, 矢部 一郎, 石浦 浩之, 松川 敬志, 池川 敦子, 柴田 有花, 張 香理, 吉田 邦広

    日本遺伝カウンセリング学会誌   42 ( 1 )   143 - 152   2021年5月

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    記述言語:日本語   出版者・発行元:(一社)日本遺伝カウンセリング学会  

    脳神経内科領域には遺伝性疾患が多く、遺伝カウンセリングの重要性は広く認識されているものの、実際にその知識やスキルを十分に習得している脳神経内科医は少ない。われわれは第60回日本神経学会学術大会において、代表的な神経疾患についての遺伝カウンセリング教育コースを開催したのでその開催概要を報告し、参加者による評価を報告する。教育コースには27名の参加があり、参加者がクライエント役と遺伝カウンセリング担当者役を担い、ロールプレイを行った。終了後のアンケートでは、参加者の理解度・満足度ともに非常に高く、ロールプレイを行ったこと自体が高評価であった。教育コースの内容に対する否定的な意見はなく、継続を希望する声も多かった。脳神経内科医にとって、ロールプレイにより模擬的な遺伝カウンセリングを学ぶことは有効であり、今後の継続を予定している。(著者抄録)

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  • Adrenoleukodystrophy siblings with a novel ABCD1 missense variant presenting with phenotypic differences: a case report and literature review. 国際誌

    Yuka Shibata, Masaaki Matsushima, Takashi Matsukawa, Hiroyuki Ishiura, Shoji Tsuji, Ichiro Yabe

    Journal of human genetics   66 ( 5 )   535 - 537   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.

    DOI: 10.1038/s10038-020-00866-x

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  • Reliability and validity of Japanese version of Unified Multiple System Atrophy Rating Scale

    Ayaka Chikada, Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda, Katsuhisa Ogata, Jun Goto, Gregor K. Wenning, Shoji Tsuji

    Neurology and Clinical Neuroscience   9 ( 2 )   171 - 180   2021年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/ncn3.12477

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  • Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan. 国際誌

    Takaki Taniguchi, Masahiro Ando, Yuji Okamoto, Akiko Yoshimura, Yujiro Higuchi, Akihiro Hashiguchi, Kensuke Shiga, Arisa Hayashida, Taku Hatano, Hiroyuki Ishiura, Jun Mitsui, Nobutaka Hattori, Toshiki Mizuno, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima

    Clinical genetics   99 ( 3 )   359 - 375   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

    DOI: 10.1111/cge.13881

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  • Voriconazoleによる治療により症状が改善した侵襲性アスペルギルス症による眼窩尖端症候群の1例

    岩崎 奏子, 横山 敬士, 勝瀬 一登, 角元 利行, 岡本 耕, 篠原 孝幸, 鴨頭 輝, 宮崎 義継, 石浦 浩之, 戸田 達史

    日本内科学会関東地方会   666回   42 - 42   2021年2月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders. 国際誌

    Wai Yan Yau, Jana Vandrovcova, Roisin Sullivan, Zhongbo Chen, Anna Zecchinelli, Roberto Cilia, Stefano Duga, Malgorzata Murray, Susana Carmona, Viorica Chelban, Hiroyuki Ishiura, Shoji Tsuji, Zane Jaunmuktane, Chris Turner, Nicholas W Wood, Henry Houlden

    Movement disorders : official journal of the Movement Disorder Society   36 ( 1 )   251 - 255   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The objective of this study was to determine the prevalence of the GGC-repeat expansion in NOTCH2NLC in whites presenting with movement disorders. METHODS: We searched for the GGC-repeat expansion in NOTCH2NLC using repeat-primed polymerase chain reaction in 203 patients with essential tremor, 825 patients with PD, 194 patients with spinocerebellar ataxia, 207 patients with "possible" or "probable" MSA, and 336 patients with pathologically confirmed MSA. We also screened 30,008 patients enrolled in the 100,000 Genomes Project for the same mutation using ExpansionHunter, followed by repeat-primed polymerase chain reaction. All possible expansions were confirmed by Southern blotting and/or long-read sequencing. RESULTS: We identified 1 patient who carried the NOTCH2NLC mutation in the essential tremor cohort, and 1 patient presenting with recurrent encephalopathy and postural tremor/parkinsonism in the 100,000 Genomes Project. CONCLUSIONS: GGC-repeat expansion in NOTCH2NLC is rare in whites presenting with movement disorders. In addition, existing whole-genome sequencing data are useful in case ascertainment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

    DOI: 10.1002/mds.28302

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  • Cranial Nerve Involvement and Dysautonomia in Post-COVID-19 Guillain-Barré Syndrome

    Toshiyuki Kakumoto, Satoshi Kobayashi, Hayato Yuuki, Mitsuhiro Kainaga, Yuichiro Shirota, Masashi Hamada, Meiko Hashimoto Maeda, Akatsuki Kubota, Mizuho Kawai, Masaaki Saito, Hiroyuki Ishiura, Tatsushi Toda

    Internal Medicine   60 ( 21 )   3477 - 3480   2021年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Society of Internal Medicine  

    DOI: 10.2169/internalmedicine.7355-21

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  • Familial dementia with Lewy bodies with VPS13C mutations. 国際誌

    Ryota Kobayashi, Hiroya Naruse, Shingo Koyama, Shinobu Kawakatsu, Hiroshi Hayashi, Hiroyuki Ishiura, Jun Mitsui, Yasuyuki Ohta, Tatsushi Toda, Shoji Tsuji, Koichi Otani

    Parkinsonism & related disorders   81   31 - 33   2020年12月

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  • A Japanese family with primary familial brain calcification presenting with paroxysmal kinesigenic dyskinesia - A comprehensive mutational analysis. 査読 国際誌

    Akihiko Mitsutake, Takashi Matsukawa, Kristine Joyce L Porto, Tatsuya Sato, Junko Katsumata, Tomonari Seki, Risa Maekawa, Takuto Hideyama, Masaki Tanaka, Hiroyuki Ishiura, Tatsushi Toda, Shoji Tsuji, Yasushi Shiio

    Journal of the neurological sciences   418   117091 - 117091   2020年11月

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  • A novel multi‐exon deletion in the dysferlin gene of a limb‐girdle muscular dystrophy type 2B Filipino patient

    Kristine Joyce L. Porto, Jun Mitsui, Hiroyuki Ishiura, Akatsuki Kubota, Kathleen Jaye L. Luspian, Emmanuel Eduardo, Ludwig Damian, Tatsushi Toda, Shoji Tsuji

    Neurology and Clinical Neuroscience   8 ( 6 )   419 - 421   2020年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/ncn3.12453

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    その他リンク: https://pericles-gcp.literatumonline.com/doi/full-xml/10.1111/ncn3.12453

  • Novel variant of CSF1R in sporadic case with early‐onset cognitive impairment

    Takashi Matsukawa, Hiroshi Shoji, Yasutaka Urasaki, Hiroyuki Ishiura, Jun Mitsui, Shuichi Oguri, Shoji Tsuji, Tatsushi Toda

    Neurology and Clinical Neuroscience   8 ( 6 )   430 - 432   2020年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/ncn3.12452

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12452

  • A Japanese family of primary familial brain calcification with paroxysmal kinesigenic dyskinesia(和訳中)

    Mitsutake Akihiko, Matsukawa Takashi, Sato Tatsuya, Katsumata Junko, Seki Tomonari, Maekawa Risa, Hideyama Takuto, Tanaka Masaki, Ishiura Hiroyuki, Toda Tatsushi, Tsuji Shoji, Shiio Yasushi

    臨床神経学   60 ( Suppl. )   S315 - S315   2020年11月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance. 国際誌

    Jun Hosoe, Fuyuki Miya, Hiroko Kadowaki, Toyofumi Fujiwara, Ken Suzuki, Takashi Kato, Hironori Waki, Takayoshi Sasako, Katsuya Aizu, Natsumi Yamamura, Fusako Sasaki, Makoto Kurano, Kazuo Hara, Masaki Tanaka, Hiroyuki Ishiura, Shoji Tsuji, Kenjiro Honda, Jun Yoshimura, Shinichi Morishita, Fumiko Matsuzawa, Sei-Ichi Aikawa, Keith A Boroevich, Masaomi Nangaku, Yukinori Okada, Tatsuhiko Tsunoda, Nobuhiro Shojima, Toshimasa Yamauchi, Takashi Kadowaki

    Diabetes research and clinical practice   169   108461 - 108461   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants. METHODS: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data. RESULTS: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance. CONCLUSIONS: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy.

    DOI: 10.1016/j.diabres.2020.108461

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  • 臨床ゲノム情報を活用した診断支援システムの要素技術の検討 査読

    高野 良治, 宮本 青, 石井 雅通, 石浦 浩之, 辻 省次, 大江 和彦

    医療情報学   40 ( 2 )   83 - 95   2020年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.14948/jami.40.83

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  • Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia. 国際誌

    Yasuko Odake, Kishin Koh, Yoshihisa Takiyama, Hiroyuki Ishiura, Shoji Tsuji, Masahito Yamada, Mitsuhiro Yoshita

    Neurology. Genetics   6 ( 5 )   e514   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective: To establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC). Methods: Physical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out. Results: The 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s-30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis. Conclusions: Our study further broadens the clinical spectrum associated with ATP13A2 mutations.

    DOI: 10.1212/NXG.0000000000000514

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  • ATP1A3遺伝子p.D801N変異を有する小児交互性片麻痺成人例のてんかん重積に対する抗てんかん薬の検討

    海永 光洋, 佐藤 ももか, 吉田 千晴, 小巻 奨吾, 石浦 浩之, 作石 かおり, 岩田 淳, 戸田 達史

    神経治療学   37 ( 6 )   S235 - S235   2020年10月

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    記述言語:日本語   出版者・発行元:(一社)日本神経治療学会  

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  • Clinical Characteristics of Neuronal Intranuclear Inclusion Disease-Related Retinopathy With CGG Repeat Expansions in the NOTCH2NLC Gene

    Natsuko Nakamura, Kazushige Tsunoda, Akihiko Mitsutake, Shota Shibata, Tatsuo Mano, Yu Nagashima, Hiroyuki Ishiura, Atsushi Iwata, Tatsushi Toda, Shoji Tsuji, Hiromasa Sawamura

    Investigative ophthalmology &amp; visual science   61 ( 11 )   27   2020年9月

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    掲載種別:研究論文(学術雑誌)  

    Purpose: To report the ocular characteristics of neuronal intranuclear inclusion disease (NIID)-related retinopathy with expansion of the CGG repeats in the NOTCH2NLC gene. Methods: Seven patients from six families (aged 66-81 years) diagnosed with adult-onset NIID were studied. Ophthalmologic examinations, including the best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), and full-field electroretinography (ERGs), were performed. The expansion of the CGG repeats in the NOTCH2NLC gene was determined. Results: All patients had an expansion of the CGG repeats (length approximately from 330-520 bp) in the NOTCH2NLC gene. The most common symptoms of the five symptomatic cases were reduced BCVA and night blindness. The other two cases did not have any ocular symptoms. The decimal BCVA varied from 0.15 to 1.2. Goldmann perimetry was constricted in all four cases tested; physiological blind spot was enlarged in two of the cases. The FAF images showed an absence of autofluorescence (AF) around the optic disc in all cases and also showed mild hypo-AF or extinguished AF in the midperiphery. In all cases, the OCT images showed an absence of the ellipsoid zone of the photoreceptors in the peripapillary region, and hyperreflective dots were also present between the retinal ganglion cell layer and outer nuclear layer. The macular region was involved in the late stage of the retinopathy. The full-field ERGs showed rod-cone dysfunction. Conclusions: Patients with adult-onset NIID with CGG repeats expansions in the NOTCH2NLC gene had similar ophthalmologic features, including rod-cone dysfunction with progressive retinal degeneration in the peripapillary and midperipheral regions. The primary site is most likely the photoreceptors. Because the ocular symptoms are often overlooked due to dementia and occasionally precede the onset of dementia, detailed ophthalmological examinations are important for the early diagnosis of NIID-related retinopathy.

    DOI: 10.1167/iovs.61.11.27

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  • A novel mutation in ABCD1 gene in a Filipino patient with adult‐onset X‐linked ALD

    Kristine Joyce Porto, Takashi Matsukawa, Hiroyuki Ishiura, Jun Mitsui, Alexandria Matic, Justine Megan Yu, Jacqueline Dominguez, Ludwig Damian, Tatsushi Toda, Shoji Tsuji

    Neurology and Clinical Neuroscience   8 ( 5 )   329 - 331   2020年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/ncn3.12425

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12425

  • Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis. 査読 国際誌

    Hiroki Hongo, Satoru Miyawaki, Hideaki Imai, Masahiro Shimizu, Shinichi Yagi, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Wei Qu, Yu Teranishi, Atsushi Okano, Hideaki Ono, Hirofumi Nakatomi, Tsuneo Shimizu, Shinichi Morishita, Shoji Tsuji, Nobuhito Saito

    Scientific reports   10 ( 1 )   11942 - 11942   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between ICAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P = 1.5 × 10-28, odds ratio = 29.3, 95% confidence interval 15.31-56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis.

    DOI: 10.1038/s41598-020-68888-1

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  • Selective impairment of On-reading (Chinese-style pronunciation) in alexia with agraphia for kanji due to subcortical hemorrhage in the left posterior middle temporal gyrus 査読

    Mizuho Yoshida, Toshihiro Hayashi, Kurumi Fujii, Hiroyuki Ishiura, Shoji Tsuji, Yasuhisa Sakurai

    Neurocase   26 ( 4 )   220 - 226   2020年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Informa UK Limited  

    DOI: 10.1080/13554794.2020.1788608

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  • MYH11遺伝子に病的バリアントをもつ親の子どもに対する発症前診断の経験

    張 香理, 犬塚 亮, 武田 憲文, 石浦 浩之, 戸田 達史, 織田 克利

    日本遺伝カウンセリング学会誌   41 ( 2 )   118 - 118   2020年6月

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    記述言語:日本語   出版者・発行元:日本遺伝カウンセリング学会  

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  • Clinical features of inherited neuropathy with BSCL2 mutations in Japan. 査読 国際誌

    Satoshi Ishihara, Yuji Okamoto, Hajime Tanabe, Akiko Yoshimura, Yujiro Higuchi, Jun-Hui Yuan, Akihiro Hashiguchi, Hiroyuki Ishiura, Jun Mitsui, Shugo Suwazono, Yasushi Oya, Masayuki Sasaki, Masanori Nakagawa, Shoji Tsuji, Yusuke Ohya, Hiroshi Takashima

    Journal of the peripheral nervous system : JPNS   25 ( 2 )   125 - 131   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.

    DOI: 10.1111/jns.12369

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  • 臨床像が異なる副腎白質ジストロフィーの同胞をもつ女性に対する保因者診断の経験

    柴田 有花, 松島 理明, 加藤 ももこ, 松川 敬志, 石浦 浩之, 辻 省次, 矢部 一郎

    日本遺伝カウンセリング学会誌   41 ( 2 )   62 - 62   2020年6月

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    記述言語:日本語   出版者・発行元:日本遺伝カウンセリング学会  

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  • 痙性対麻痺に小脳性失調、軸索型ニューロパチー、認知機能低下を合併し、KIF1Aの新規変異を認めたAD-SPG30の親子例

    河合 三津保, 織茂 賢太, 岩田 信恵, 石浦 浩之, 三井 純, 中嶋 秀樹, 村井 弘之, 後藤 順

    臨床神経学   60 ( 5 )   380 - 380   2020年5月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 10年の経過で緩徐に増悪する反復発作性運動失調症を呈し、CACNA1A c.3695+1G>A変異を認めた61歳男性例

    三宅 亮, 勝又 淳子, 日野 理美, 佐藤 達哉, 坂内 太郎, 中元 ふみ子, 関 大成, 石浦 浩之, 三井 純, 辻 省次, 戸田 達史, 椎尾 康

    臨床神経学   60 ( 5 )   378 - 378   2020年5月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 痙性対麻痺に小脳性失調、軸索型ニューロパチー、認知機能低下を合併し、KIF1Aの新規変異を認めたAD-SPG30の親子例

    河合 三津保, 織茂 賢太, 岩田 信恵, 石浦 浩之, 三井 純, 中嶋 秀樹, 村井 弘之, 後藤 順

    臨床神経学   60 ( 5 )   380 - 380   2020年5月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy. 査読 国際誌

    Takashi Matsukawa, Tomotaka Yamamoto, Akira Honda, Takashi Toya, Hiroyuki Ishiura, Jun Mitsui, Masaki Tanaka, Akihito Hao, Akihito Shinohara, Mizuki Ogura, Keisuke Kataoka, Sachiko Seo, Keiki Kumano, Masataka Hosoi, Kensuke Narukawa, Megumi Yasunaga, Hiroaki Maki, Motoshi Ichikawa, Yasuhito Nannya, Yoichi Imai, Tsuyoshi Takahashi, Yuji Takahashi, Yuki Nagasako, Kyoko Yasaka, Kagari Koshi Mano, Miho Kawabe Matsukawa, Toji Miyagawa, Masashi Hamada, Kaori Sakuishi, Toshihiro Hayashi, Atsushi Iwata, Yasuo Terao, Jun Shimizu, Jun Goto, Harushi Mori, Akira Kunimatsu, Shigeki Aoki, Shin Hayashi, Fumihiko Nakamura, Syunya Arai, Kazunari Momma, Katsuhisa Ogata, Toshikazu Yoshida, Osamu Abe, Johji Inazawa, Tatsushi Toda, Mineo Kurokawa, Shoji Tsuji

    Brain communications   2 ( 1 )   fcz048   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press (OUP)  

    Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

    DOI: 10.1093/braincomms/fcz048

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  • VPS13D-related disorders presenting as a pure and complicated form of hereditary spastic paraplegia. 査読 国際誌

    Koh K, Ishiura H, Shimazaki H, Tsutsumiuchi M, Ichinose Y, Nan H, Hamada S, Ohtsuka T, Tsuji S, Takiyama Y

    Molecular genetics & genomic medicine   e1108   2019年12月

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    記述言語:英語  

    DOI: 10.1002/mgg3.1108

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  • Spastic Paraplegia Accompanied by Extrapyramidal Sign and Frontal Cognitive Dysfunction. 査読

    Ryo Sasaki, Yasuyuki Ohta, Kota Sato, Koh Tadokoro, Yoshiaki Takahashi, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Hiroyuki Ishiura, Shoji Tsuji, Koji Abe

    Internal medicine (Tokyo, Japan)   58 ( 21 )   3163 - 3165   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A complicated form of spastic paraplegia is a neurodegenerative disorder presenting as progressive spasticity in the bilateral lower limbs accompanied by some clinical features. The present case showed spastic paralysis and hyperreflexia in all extremities as well as lead pipe rigidity in the neck and bilateral upper extremities (R < L), decreased scores on frontal cognitive tests, a decreased accumulation of the right dorsal putamen on a DAT scan, and hypoperfusion of the bilateral frontal lobes on 99mTc-ECD single photon emission computed tomography (SPECT). The present case provides a new spectrum of spastic paraplegia based on the evidence of clinical scores and the findings of brain functional imaging.

    DOI: 10.2169/internalmedicine.2765-19

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  • UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes. 査読 国際誌

    Haitian Nan, Yuta Ichinose, Masaki Tanaka, Kishin Koh, Hiroyuki Ishiura, Jun Mitsui, Heisuke Mizukami, Masafumi Morimoto, Shun Hamada, Toshihisa Ohtsuka, Shoji Tsuji, Yoshihisa Takiyama

    Journal of human genetics   64 ( 11 )   1055 - 1065   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC). Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene. A mouse homolog of one UBAP1 frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80). All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes. Our study demonstrated that mutations in the UBAP1 gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.

    DOI: 10.1038/s10038-019-0670-9

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  • BAFMEにおける表現型-遺伝子型の関連性 EEG所見とリピート長(Phenotype-genotype association in BAFME: EEG findings vs. repeat length)

    Tojima Maya, Neshige Shuichiro, Hitomi Takefumi, Oi Kazuki, Kobayashi Katsuya, Matsuhashi Masao, Shimotake Akihiro, Matsumoto Riki, Kanda Masutaro, Ishiura Hiroyuki, Tsuji Shoji, Takahashi Ryosuke, Ikeda Akio

    臨床神経学   59 ( Suppl. )   S406 - S406   2019年11月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • 良性成人型家族性ミオクローヌスてんかんの進行におけるリピート配列の伸長と加齢の影響(Effect of expanded repeats and aging on disease progress in benign adult familial myoclonus epilepsy)

    Neshige Shuichiro, Hitomi Takefumi, Oi Kazuki, Kobayashi Katsuya, Matsuhashi Masao, Akihiro Shimotake, Matsumoto Riki, Kanda Masutaro, Maruyama Hirofumi, Ishiura Hiroyuki, Tsuji Shoji, Takahashi Ryosuke, Ikeda Akio

    臨床神経学   59 ( Suppl. )   S226 - S226   2019年11月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • Prominent Spasticity and Hyperreflexia of the Legs in a Nepalese Patient with Friedreich Ataxia. 査読

    Hiroya Naruse, Yuji Takahashi, Hiroyuki Ishiura, Takashi Matsukawa, Jun Mitsui, Yaeko Ichikawa, Masashi Hamada, Jun Shimizu, Jun Goto, Tatsushi Toda, Shoji Tsuji

    Internal medicine (Tokyo, Japan)   58 ( 19 )   2865 - 2869   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.

    DOI: 10.2169/internalmedicine.2953-19

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  • Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42. 査読 国際誌

    Shunta Hashiguchi, Hiroshi Doi, Misako Kunii, Yukihiro Nakamura, Misa Shimuta, Etsuko Suzuki, Shigeru Koyano, Masaki Okubo, Hitaru Kishida, Masaaki Shiina, Kazuhiro Ogata, Fumiko Hirashima, Yukichi Inoue, Shun Kubota, Noriko Hayashi, Haruko Nakamura, Keita Takahashi, Atsuko Katsumoto, Mikiko Tada, Kenichi Tanaka, Toshikuni Sasaoka, Satoko Miyatake, Noriko Miyake, Hirotomo Saitsu, Nozomu Sato, Kokoro Ozaki, Kiyobumi Ohta, Takanori Yokota, Hidehiro Mizusawa, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Shinichi Morishita, Shoji Tsuji, Hideyuki Takeuchi, Kinya Ishikawa, Naomichi Matsumoto, Taro Ishikawa, Fumiaki Tanaka

    Neurobiology of disease   130   104516 - 104516   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

    DOI: 10.1016/j.nbd.2019.104516

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  • Sporadic progressive myoclonic epilepsy with early‐onset dementia caused by a de novo mutation in PSEN1

    Tomoya Taminato, Manabu Araki, Noriko Sato, Hiroyuki Ishiura, Jun Mitsui, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Yuji Takahashi

    Neurology and Clinical Neuroscience   7 ( 5 )   294 - 296   2019年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/ncn3.12319

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12319

  • Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells. 査読 国際誌

    Shin-Ichiro Sekine, Masayuki Kaneko, Masaki Tanaka, Yuhei Ninomiya, Hisaka Kurita, Masatoshi Inden, Megumi Yamada, Yuichi Hayashi, Takashi Inuzuka, Jun Mitsui, Hiroyuki Ishiura, Atsushi Iwata, Hiroto Fujigasaki, Hisamitsu Tamaki, Ryusei Tamaki, Shinsuke Kito, Yoshiharu Taguchi, Kortaro Tanaka, Naoki Atsuta, Gen Sobue, Takayuki Kondo, Haruhisa Inoue, Shoji Tsuji, Isao Hozumi

    Scientific reports   9 ( 1 )   5698 - 5698   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457-1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457-1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.

    DOI: 10.1038/s41598-019-42115-y

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  • The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case. 査読 国際誌

    Yoshikawa K, Kuwahara M, Saigoh K, Ishiura H, Yamagishi Y, Hamano Y, Samukawa M, Suzuki H, Hirano M, Mitsui Y, Tsuji S, Kusunoki S

    eNeurologicalSci   14   34 - 37   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ensci.2018.11.026

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  • A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. 査読 国際誌

    Takuya Miyabayashi, Tatsuhiro Ochiai, Naoki Suzuki, Masashi Aoki, Takehiko Inui, Yukimune Okubo, Ryo Sato, Noriko Togashi, Hiroshi Takashima, Hiroyuki Ishiura, Shoji Tsuji, Kishin Koh, Yoshihisa Takiyama, Kazuhiro Haginoya

    Journal of human genetics   64 ( 2 )   171 - 176   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.

    DOI: 10.1038/s10038-018-0538-4

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  • Correction: PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. 査読 国際誌

    Kishin Koh, Yuta Ichinose, Hiroyuki Ishiura, Haitian Nan, Jun Mitsui, Junya Takahashi, Wakiro Sato, Yoshiaki Itoh, Kyoko Hoshino, Shoji Tsuji, Yoshihisa Takiyama

    Journal of human genetics   64 ( 1 )   61 - 63   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The originally published version of this article contained an error in Fig. 1 and Table 2. The correct figure and table of this article should have read as below. This has now been corrected in the PDF and HTML versions of the article. The authors apologize for any inconvenience caused.

    DOI: 10.1038/s10038-018-0533-9

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  • PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. 査読 国際誌

    Kishin Koh, Yuta Ichinose, Hiroyuki Ishiura, Haitian Nan, Jun Mitsui, Junya Takahashi, Wakiro Sato, Yoshiaki Itoh, Kyoko Hoshino, Shoji Tsuji, Yoshihisa Takiyama

    Journal of human genetics   64 ( 1 )   55 - 59   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PLA2G6-associated neurodegeneration (PLAN) comprises heterogeneous neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation 2B, and Parkinson disease 14 (PARK14). In addition, very recently, PLA2G6 mutations have been reported to represent a phenotype of hereditary spastic paraplegia (HSP). In this study, we screened 383 HSP families to clarify the frequency of PLA2G6 mutations in the Japan Spastic Paraplegia Research Consortium, and revealed the clinical characteristics of HSP with PLA2G6 mutations. We found three families with compound heterozygous mutations of the PLA2G6 gene, c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, and c.1187-2 A > G/c.1933C > T, and one family with a homozygous mutation of the PLA2G6 gene, c.1904G > A/c.1904G > A. All three families with compound heterozygous mutations presented a uniform phenotype of a complicated form of HSP with infantile/child-onset spastic paraplegia, cerebellar ataxia, and mental retardation. On the other hand, the family with a homozygous mutation presented a late-onset complicated form of HSP with parkinsonism. This study may extend the clinical and genetic findings for PLAN.

    DOI: 10.1038/s10038-018-0519-7

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  • Atypical Familial Amyotrophic Lateral Sclerosis with Slowly Progressing Lower Extremities-predominant Late-onset Muscular Weakness and Atrophy. 査読

    Jumpei Togawa, Takekazu Ohi, Jun-Hui Yuan, Hiroshi Takashima, Hirokazu Furuya, Shinji Takechi, Junko Fujitake, Saki Hayashi, Hiroyuki Ishiura, Hiroya Naruse, Jun Mitsui, Shoji Tsuji

    Internal medicine (Tokyo, Japan)   58 ( 13 )   1851 - 1858   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the progressive loss of the upper and lower motor neurons that progresses to paralysis of almost all skeletal muscles of the extremities, bulbar, and respiratory system. Although most ALS cases are sporadic, about 10% are dominantly inherited. We herein report an atypical phenotype of familial ALS (fALS). To elucidate the phenotype-genotype correlation of this atypical phenotype of fALS, clinical and genetic investigations were performed. Methods and Patients Five sibling patients (three men, two women) from a Japanese family and one healthy sibling (a woman) were clinically interviewed and examined. Genetic analyses, including genome-wide linkage analyses and whole-exome sequencing, were performed using genomic DNA extracted from the peripheral blood samples of these siblings. Results The clinical features of fALS are characterized by slow progression (mean duration of the disease±standard deviation [SD]: 19.6±3.9 years) and lower extremities-predominant late-onset muscular weakness (mean onset of muscular weakness±SD: 52.8±2.6 years). Genetic analyses revealed novel heterozygous missense mutations of c.2668C>T, p.R890C in the PLEC gene and c.421G>C, p.V141L in the ST3GAL6 gene in all affected siblings. Conclusion A new atypical fALS family with a benign clinical course is herein reported. We identified two candidate gene mutations of PLEC and ST3GAL6 linked to this phenotype.

    DOI: 10.2169/internalmedicine.2222-18

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  • An Autopsy Case of Familial Neuronal Intranuclear Inclusion Disease with Dementia and Neuropathy. 査読

    Nanaka Yamaguchi, Tatsuo Mano, Ryo Ohtomo, Hiroyuki Ishiura, M Asem Almansour, Harushi Mori, Junko Kanda, Yuichiro Shirota, Kenichiro Taira, Teppei Morikawa, Masako Ikemura, Yasuo Yanagi, Shigeo Murayama, Jun Shimizu, Yasuhisa Sakurai, Shoji Tsuji, Atsushi Iwata

    Internal medicine (Tokyo, Japan)   57 ( 23 )   3459 - 3462   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with marked variety in its clinical manifestations. While characteristic neuroimaging and skin biopsy findings are important clues to the diagnosis, autopsy studies are still important for confirming the exact disease features. We herein report the case of a patient who received an antemortem diagnosis of familial NIID with dementia-dominant phenotype that was later confirmed by an autopsy. Our report is the first to document a case of autopsy-confirmed NIID involving both cognitive impairment and sensorimotor neuropathy.

    DOI: 10.2169/internalmedicine.1141-18

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  • 成人発症型ALDに対するHSCT 脳障害の早期診断をもたらす背景因子(HSCT for adult-onset ALD: Background factors leading to early diagnosis of the brain involvement)

    Matsukawa Takashi, Mitsui Jun, Ishiura Hiroyuki, Yamamoto Tomotaka, Hao Akihito, Matsukawa Miho, Tanaka Masaki, Chang Hyangri, Miyagawa Toji, Hamada Masashi, Takahashi Yuji, Hayashi Toshihiro, Iwata Atsushi, Shimizu Jun, Goto Jun, Toda Tatsushi, Tsuji Shoji

    臨床神経学   58 ( Suppl. )   S371 - S371   2018年12月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy. 査読 国際誌

    Fumiko Kusunoki Nakamoto, Satoshi Okamoto, Jun Mitsui, Takefumi Sone, Mitsuru Ishikawa, Yorihiro Yamamoto, Yumi Kanegae, Yuhki Nakatake, Kent Imaizumi, Hiroyuki Ishiura, Shoji Tsuji, Hideyuki Okano

    Scientific reports   8 ( 1 )   14215 - 14215   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. We previously reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10, are associated with MSA. Here, we report functional deficiencies in mitochondrial respiration and the antioxidative system in induced pluripotent stem cell (iPSC)-derived neurons from an MSA patient with compound heterozygous COQ2 mutations. The functional deficiencies were rescued by site-specific CRISPR/Cas9-mediated gene corrections. We also report an increase in apoptosis of iPSC-derived neurons from MSA patients. Coenzyme Q10 reduced apoptosis of neurons from the MSA patient with compound heterozygous COQ2 mutations. Our results reveal that cellular dysfunctions attributable to decreased coenzyme Q10 levels are related to neuronal death in MSA, particularly in patients with COQ2 variants, and may contribute to the development of therapy using coenzyme Q10 supplementation.

    DOI: 10.1038/s41598-018-32573-1

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  • Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment. 査読 国際誌

    Kishin Koh, Hiroyuki Ishiura, Minako Beppu, Haruo Shimazaki, Yuta Ichinose, Jun Mitsui, Satoshi Kuwabara, Shoji Tsuji, Yoshihisa Takiyama

    Journal of human genetics   63 ( 9 )   1009 - 1013   2018年9月

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    記述言語:英語  

    Hereditary spastic paraplegias (HSPs) are characterized by various inherited disorders in which weakness and spasticity of the lower extremities are the predominant symptoms. Recently, HSP caused by ALDH18A1 mutations has been reported as SPG9 with autosomal dominant (SPG9A) and autosomal recessive (SPG9B) transmission. In this study, we obtained clinical and genetic findings in two Japanese families with SPG9B. One family had a novel compound heterozygous mutation (c.1321 C > T/c.1994G > A) in the ALDH18A1 gene. The other family had a homozygous mutation (c.383 G > A/c.383 G > A) in the ALDH18A1 gene. To date, only two SPG9B families with ALDH18A1 mutations have been reported. This is the first report of SPG9 in non-Caucasians. Furthermore, we found cerebellar ataxia in one family, although cerebellar ataxia has not been reported in SPG9B so far. SPG9B might involve a complicated HSP including cerebellar ataxia and cognitive impairment. This study expands the clinical and genetic spectrum of ALDH18A1-related disorders.

    DOI: 10.1038/s10038-018-0477-0

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  • JASPAC: Japan Spastic Paraplegia Research Consortium. 査読

    Koh K, Ishiura H, Tsuji S, Takiyama Y

    Brain sciences   8 ( 8 )   2018年8月

  • Ketotic hyperglycemia-related seizure with reversible white matter lesion: Metabolic implication of its reversibility based on magnetic resonance spectroscopy study. 査読 国際誌

    Satoshi Kodama, Tatsuo Mano, Toshiyuki Kakumoto, Hiroyuki Ishiura, Akifumi Hagiwara, Kouhei Kamiya, Toshihiro Hayashi, Shoji Tsuji

    Journal of the neurological sciences   390   20 - 21   2018年7月

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  • No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY. 査読 国際誌

    Yukio Horikawa, Kazuyoshi Hosomichi, Mayumi Enya, Hiroyuki Ishiura, Yutaka Suzuki, Shoji Tsuji, Sumio Sugano, Ituro Inoue, Jun Takeda

    Journal of human genetics   63 ( 7 )   821 - 829   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.

    DOI: 10.1038/s10038-018-0449-4

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  • 両側脊髄病変による痙性麻痺の亜急性進行を呈した遅発性Krabbe病の症例(A case of late-onset Krabbe disease which showed subacute progression of spastic paresis with bilateral spinal cord lesions) 査読

    Mitsutake Akihiko, Matsukawa Takashi, Ishiura Hiroyuki, Mitsui Jun, Taira Kenichiro, Tokushige Shin-ichi, Iwata Atsushi, Terao Yasuo, Shimizu Jun, Sakai Norio, Tsuji Shoji

    Neurology and Clinical Neuroscience   6 ( 4 )   104 - 106   2018年7月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

    16歳男。10ヵ月前から走行中に転倒するようになり、次第に歩行障害が進行した。末梢神経障害の所見はなかった。MRI T2強調画像で脳内包から腰髄にかけて両側錐体路に高信号病変を認めた。対称性錐体路病変は遅発性Krabbe病の特徴であり、白血球中galactocerebrosidase活性には著明な低値を認めた。遺伝子解析ではhomozygous c.1901T>C変異を認めた。以上の所見より、遅発性Krabbe病と確定診断した。

    DOI: 10.1111/ncn3.12188

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  • SLC4A4 compound heterozygous mutations in exon-intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner's syndrome: a case report. 査読 国際誌

    Shoko Horita, Enver Simsek, Tulay Simsek, Nilgun Yildirim, Hiroyuki Ishiura, Motonobu Nakamura, Nobuhiko Satoh, Atsushi Suzuki, Hiroyuki Tsukada, Tomohito Mizuno, George Seki, Shoji Tsuji, Masaomi Nangaku

    BMC medical genetics   19 ( 1 )   103 - 103   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Congenital NBCe1A deficiency with the SLC4A4 mutation causes severe proximal renal tubular acidosis, which often comprises extrarenal symptoms, such as intellectual disability and developmental delay, glaucoma, cataract and band keratopathy. To date, almost all mutations have been found to be homozygous mutations located in exons. CASE PRESENTATION: We performed direct nucleotide sequencing analysis of exons and exon-intron boundary regions of the SLC4A4 in a patient presenting with severe renal proximal tubule acidosis, glaucoma and intellectual disability and her parents without these signs. The examination revealed compound heterozygous mutations in exon-intron boundary regions, c.1076 + 3A > C and c.1772 - 2A > T, neither of which have been reported previously. While the former mutation was found in the mother, the latter was found in the father. The transcript of the SLC4A4 gene was almost undetectable, and the patient was also diagnosed with Turner's syndrome. CONCLUSIONS: We identified two novel SLC4A4 mutations, c.1076 + 3A > C and c.1772 - 2A > T. When presented in a compound heterozygous state, these mutations caused a phenotype of severe renal proximal tubular acidosis along with glaucoma and mental retardation. This is the first report of congenital proximal renal tubular acidosis carrying compound heterozygous SLC4A4 mutations in exon-intron boundary regions. We suggest that an mRNA surveillance mechanism, nonsense-mediated RNA decay, following aberrant splicing was the reason that the SLC4A4 transcript was almost undetectable in the proband.

    DOI: 10.1186/s12881-018-0612-y

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  • Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy. 査読 国際誌

    Yujiro Higuchi, Ryuta Okunushi, Taichi Hara, Akihiro Hashiguchi, Junhui Yuan, Akiko Yoshimura, Kei Murayama, Akira Ohtake, Masahiro Ando, Yu Hiramatsu, Satoshi Ishihara, Hajime Tanabe, Yuji Okamoto, Eiji Matsuura, Takehiro Ueda, Tatsushi Toda, Sumimasa Yamashita, Kenichiro Yamada, Takashi Koide, Hiroaki Yaguchi, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Ken Sato, Masanori Nakagawa, Masamitsu Yamaguchi, Shoji Tsuji, Hiroshi Takashima

    Brain : a journal of neurology   141 ( 6 )   1622 - 1636   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

    DOI: 10.1093/brain/awy104

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  • Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1. 査読

    Cen Z, Jiang Z, Chen Y, Zheng X, Xie F, Yang X, Lu X, Ouyang Z, Wu H, Chen S, Yin H, Qiu X, Wang S, Ding M, Tang Y, Yu F, Li C, Wang T, Ishiura H, Tsuji S, Jiao C, Liu C, Xiao J, Luo W

    Brain : a journal of neurology   141 ( 8 )   2280 - 2288   2018年6月

  • HIV Dementia with a Decreased Cardiac 123I-metaiodobenzylguanidine Uptake Masquerading as Dementia with Lewy Bodies. 査読

    Kurihara M, Sasaki T, Ishiura H, Tsuji S

    Internal medicine (Tokyo, Japan)   57 ( 20 )   3007 - 3010   2018年5月

  • Optineurin pathology in the spinal cord of amyotrophic lateral sclerosis/parkinsonism-dementia complex patients in Kii Peninsula, Japan. 査読 国際誌

    Satoru Morimoto, Hiroyuki Hatsuta, Rie Motoyama, Yasumasa Kokubo, Hiroyuki Ishiura, Shoji Tsuji, Shigeki Kuzuhara, Shigeo Murayama

    Brain pathology (Zurich, Switzerland)   28 ( 3 )   422 - 426   2018年5月

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    記述言語:英語  

    DOI: 10.1111/bpa.12558

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  • Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia 査読

    Masanori Kurihara, Hiroyuki Ishiura, Takuya Sasaki, Juuri Otsuka, Toshihiro Hayashi, Yasuo Terao, Takashi Matsukawa, Jun Mitsui, Juntaro Kaneko, Kazutoshi Nishiyama, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Shimizu, Shoji Tsuji

    Cerebellum   17 ( 2 )   237 - 242   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer New York LLC  

    Spinocerebellar ataxia 19/22 (SCA19/22) is a rare type of autosomal dominant SCA that was previously described in 11 families. We report the case of a 30-year-old Japanese man presenting with intellectual disability, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy, and electroencephalograms showed paroxysmal sharp waves during hyperventilation and photic stimulation. Trio whole-exome sequencing analysis of DNA samples from the patient and his parents revealed a de novo novel missense mutation (c.1150G&gt
    A, p.G384S) in KCND3, the causative gene of SCA19/22, substituting for evolutionally conserved glycine. The mutation was predicted to be functionally deleterious by bioinformatic analysis. Although pure cerebellar ataxia is the most common clinical feature in SCA19/22 families, extracerebellar symptoms including intellectual disability and myoclonus are reported in a limited number of families, suggesting a genotype–phenotype correlation for particular mutations. Although autosomal recessive diseases are more common in patients with early onset sporadic cerebellar ataxia, the present study emphasizes that such a possibility of de novo mutation should be considered.

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  • Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis. 査読 国際誌

    Genki Tohnai, Ryoichi Nakamura, Jun Sone, Masahiro Nakatochi, Daichi Yokoi, Masahisa Katsuno, Hazuki Watanabe, Hirohisa Watanabe, Mizuki Ito, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Osamu Onodera, Hiroya Naruse, Jun Mitsui, Yuji Takahashi, Jun Goto, Hiroyuki Ishiura, Shinichi Morishita, Jun Yoshimura, Koichiro Doi, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Naoki Atsuta, Gen Sobue

    Neurobiology of aging   64   158.e15-158.e19 - 158.e19   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.

    DOI: 10.1016/j.neurobiolaging.2017.12.005

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  • A Homozygous LAMA2 Mutation of c.818G>A Caused Partial Merosin Deficiency in a Japanese Patient. 査読

    Akatsuki Kubota, Hiroyuki Ishiura, Jun Mitsui, Kaori Sakuishi, Atsushi Iwata, Tomotaka Yamamoto, Ichizo Nishino, Shoji Tsuji, Jun Shimizu

    Internal medicine (Tokyo, Japan)   57 ( 6 )   877 - 882   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A complete loss of merosin, which is encoded by LAMA2, causes congenital muscular dystrophy with leukoencephalopathy. Partial merosin deficiency can be caused not only by primarily LAMA2 mutations, but also secondarily by dystroglycanopathy. Although it can be molecularly diagnosed based on a genetic analysis, this method is labor-intensive because of its huge genome size. A 26-year-old male patient presented with mild muscular weakness, joint contractures, and epilepsy. Double immunofluorescence staining of a muscle biopsy specimen showed mislocalization of merosin, and a genetic analysis revealed a homozygous c.818G>A (p.Arg273Lys) mutation in LAMA2. Double immunofluorescence staining and whole exome sequencing were useful for the diagnosis of partial merosin deficiency.

    DOI: 10.2169/internalmedicine.9588-17

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  • Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan 査読

    Hajime Tanabe, Yujiro Higuchi, Jun-Hui Yuan, Akihiro Hashiguchi, Akiko Yoshimura, Satoshi Ishihara, Satoshi Nozuma, Yuji Okamoto, Eiji Matsuura, Hiroyuki Ishiura, Jun Mitsui, Ryotaro Takashima, Norito Kokubun, Kengo Maeda, Yuri Asano, Yoko Sunami, Yu Kono, Yasunori Ishigaki, Shosaburo Yanamoto, Jiro Fukae, Hiroshi Kida, Mitsuya Morita, Shoji Tsuji, Hiroshi Takashima

    Journal of the Peripheral Nervous System   23 ( 1 )   40 - 48   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Inc.  

    Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

    DOI: 10.1111/jns.12252

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  • Authors’ reply to the Drs. Finsterer and Zarrouk-Mahjoub's comments for our case report 査読

    Eisuke Amiya, Hiroyuki Morita, Hiroyuki Ishiura, Shoji Tsuji, Issei Komuro

    International Journal of Cardiology   254   262   2018年3月

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    記述言語:英語   出版者・発行元:Elsevier Ireland Ltd  

    DOI: 10.1016/j.ijcard.2017.06.111

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  • Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing 査読

    Yosuke Eriguchi, Hitoshi Kuwabara, Aya Inai, Yuki Kawakubo, Fumichika Nishimura, Chihiro Kakiuchi, Mamoru Tochigi, Jun Ohashi, Naoto Aoki, Kayoko Kato, Hiroyuki Ishiura, Jun Mitsui, Shoji Tsuji, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Takafumi Shimada, Masaomi Furukawa, Tadashi Umekage, Tsukasa Sasaki, Kiyoto Kasai, Yukiko Kano

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   174 ( 7 )   712 - 723   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G &gt; A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

    DOI: 10.1002/ajmg.b.32559

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  • Structural Basis and Genotype-Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance 査読

    Jun Hosoe, Hiroko Kadowaki, Fuyuki Miya, Katsuya Aizu, Tomoyuki Kawamura, Ichiro Miyata, Kenichi Satomura, Takeru Ito, Kazuo Hara, Masaki Tanaka, Hiroyuki Ishiura, Shoji Tsuji, Ken Suzuki, Minaka Takakura, Keith A. Boroevich, Tatsuhiko Tsunoda, Toshimasa Yamauchi, Nobuhiro Shojima, Takashi Kadowaki

    DIABETES   66 ( 10 )   2713 - 2723   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER DIABETES ASSOC  

    The insulin receptor (INSR) gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the - cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 INSR missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance (P = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.

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  • repetitive CMAPを認め、神経筋接合部の微細構造を解析し得た抗LRP4抗体陽性重症筋無力症の一例 査読

    光武 明彦, 平 賢一郎, 荒川 晶, 佐藤 達哉, 勝又 淳子, 関 大成, 前川 理沙, 日出山 拓人, 石浦 浩之, 内尾 直裕, 清水 潤, 樋口 理, 松尾 秀徳, 椎尾 康

    神経免疫学   22 ( 1 )   156 - 156   2017年10月

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    記述言語:日本語   出版者・発行元:日本神経免疫学会  

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  • New familial amyotrophic lateral sclerosis with benign progression and myoclonus in lower extremities 査読

    Togawa J, Ohi T, Yuan JH, Takashima H, Furuya H, Takechi S, Fujitake J, Hayashi S, Ishiura H, Naruse H, Mitsui J, Tsuji S

    J. Neurol. Sci.   381 ( Supplement )   716   2017年10月

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    記述言語:英語   掲載種別:研究論文(国際会議プロシーディングス)  

    DOI: 10.1016/j.jns.2017.08.2017

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  • Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan 査読

    M. Ando, Y. Okamoto, A. Yoshimura, J. -H. Yuan, Y. Hiramatsu, Y. Higuchi, A. Hashiguchi, J. Mitsui, H. Ishiura, S. Fukumura, M. Matsushima, N. Ochi, J. Tsugawa, S. Morishita, S. Tsuji, H. Takashima

    EUROPEAN JOURNAL OF NEUROLOGY   24 ( 10 )   1274 - 1282   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Background and purpose: The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of Charcot-Marie-Tooth disease (CMT) type 2Z in 2016. We aimed to describe the clinical and mutational spectrum of patients with CMT harboring MORC2 mutations in Japan.
    Methods: We analyzed samples from 781 unrelated patients clinically diagnosed with CMT using deoxyribonucleic acid microarray or targeted resequencing by next-generation sequencing, and samples from 434 mutation-negative patients were subjected to whole-exome sequencing. We extracted MORC2 variants from these whole-exome sequencing data and classified them according to American College of Medical Genetics standards and guidelines.
    Results: We identified MORC2 variants in 13 patients. As the second most common causative gene of CMT type 2 after MFN2, MORC2 variants were detected in 2.7% of patients with CMT type 2. The mean age of onset was 10.3 +/- 8.7 years, and the inheritance pattern was mostly sporadic (11/13 patients, 84.6%). The clinical phenotype was typically length-dependent polyneuropathy, and electrophysiological studies revealed sensory-dominant axonal neuropathy. Mental retardation was identified in 4/13 patients (30.8%). p.Arg190Trp, as a mutational hotspot, was observed in eight unrelated families. We also identified two novel probably pathogenic variants, p.Cys345Tyr and p.Ala369Val, and one novel uncertain significance variant, p.Tyr332Cys.
    Conclusions: Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.

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  • Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology 査読

    Chiseko Ikenaga, Akatsuki Kubota, Masato Kadoya, Kenichiro Taira, Naohiro Uchio, Ayumi Hida, Meiko Hashimoto Maeda, Yu Nagashima, Hiroyuki Ishiura, Kenichi Kaida, Jun Goto, Shoji Tsuji, Jun Shimizu

    NEUROLOGY   89 ( 10 )   1060 - 1068   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective: To determine the clinical features of myositis patients with the histopathologic finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class 1 (CD8-MHC-1 complex), which is shared by polymyositis (PM) and inclusion body myositis (IBM), in relation to the p62 immunostaining pattern of muscle fibers.
    Methods: All 93 myositis patients with CD8-MHC-1 complex who were referred to our hospital from 1993 to 2015 were classified on the basis of the European Neuromuscular Center (ENMC) diagnostic criteria for IBM (Rose, 2013) or PM (Hoogendijk, 2004) and analyzed.
    Results: The 93 patients included were 17 patients with PM, 70 patients with IBM, and 6 patients who neither met the criteria for PM nor IBM in terms of muscle weakness distribution (unclassifiable group). For these PM, IBM, and unclassifiable patients, their mean ages at diagnosis were 63, 70, and 64 years; autoimmune disease was present in 7 (41%), 13 (19%), and 4 (67%); hepatitis C virus infection was detected in 0%, 13 (20%), and 2 (33%); and p62 was immunopositive in 0%, 66 (94%), and 2 (33%), respectively. Of the treated patients, 11 of 16 PM patients and 4 of 6 p62-immunonegative patients in the unclassifiable group showed responses to immunotherapy, whereas all 44 patients with IBM and 2 p62-immunopositive patients in the unclassifiable group were unresponsive to immunotherapy.
    Conclusions: CD8-MHC-1 complex is present in patients with PM, IBM, or unclassifiable group. The data may serve as an argument for a trial of immunosuppressive treatment in p62-immunonegative patients with unclassifiable myositis.

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  • Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants 査読

    A. Yoshimura, J. -H. Yuan, A. Hashiguchi, Y. Hiramatsu, M. Ando, Y. Higuchi, T. Nakamura, Y. Okamoto, K. Matsumura, T. Hamano, N. Sawaura, Y. Shimatani, S. Kumada, Y. Okumura, J. Miyahara, Y. Yamaguchi, S. Kitamura, K. Haginoya, J. Mitsui, H. Ishiura, S. Tsuji, H. Takashima

    CLINICAL GENETICS   92 ( 3 )   274 - 280   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    BackgroundMutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.
    Materials and MethodsFrom April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing.
    ResultsWe identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C&gt;T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C&gt;T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G&gt;A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy.
    ConclusionWe identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.

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  • Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study 査読

    Masahiro Ando, Akihiro Hashiguchi, Yuji Okamoto, Akiko Yoshimura, Yu Hiramatsu, Junhui Yuan, Yujiro Higuchi, Jun Mitsui, Hiroyuki Ishiura, Ayako Umemura, Koichi Maruyama, Takeshi Matsushige, Shinichi Morishita, Masanori Nakagawa, Shoji Tsuji, Hiroshi Takashima

    JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM   22 ( 3 )   191 - 199   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Charcot-Marie-Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1,334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole-exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 +/- 14 (range 0-59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co-occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is themost frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2-related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity.

    DOI: 10.1111/jns.12228

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  • Novel mutation in the membrane metalloendopeptidase gene in a patient with the autosomal recessive form of Charcot-Marie-Tooth disease 査読

    Ishiura Hiroyuki, Mitsui Jun, Yoshimura Jun, Doi Koichiro, Morishita Shinichi, Hamada Masashi, Goto Jun, Tsuji Shoji

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 4 )   124 - 126   2017年7月

  • 反復刺激試験でrepetitive CMAPを認め、先天性筋無力症と鑑別を要した抗LRP4抗体陽性重症筋無力症の1例 査読

    光武 明彦, 荒川 晶, 佐藤 達哉, 勝又 淳子, 関 大成, 前川 理沙, 日出山 拓人, 石浦 浩之, 樋口 理, 椎尾 康

    日本内科学会関東地方会   634回   42 - 42   2017年7月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Three-Year Follow-Up of High-Dose Ubiquinol Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous COQ2 Mutations 査読

    Jun Mitsui, Ken Koguchi, Toshimitsu Momose, Miwako Takahashi, Takashi Matsukawa, Tsutomu Yasuda, Shin-ichi Tokushige, Hiroyuki Ishiura, Jun Goto, Shigeaki Nakazaki, Tomoyoshi Kondo, Hidefumi Ito, Yorihiro Yamamoto, Shoji Tsuji

    CEREBELLUM   16 ( 3 )   664 - 672   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    We report a 3-year follow-up of high-dose ubiquinol supplementation in a case of familial multiple system atrophy (MSA) with compound heterozygous nonsense (R387X) and missense (V393A) mutations in COQ2. A high-dose ubiquinol supplementation substantially increased total coenzyme Q(10) levels in cerebrospinal fluid as well as in plasma. The patient was at the advanced stage of MSA, and the various scores of clinical rating scales remained stable without changes during the 3 years. The cerebral metabolic ratio of oxygen measured by O-15(2) PET, however, increased by approximately 30% after administration of ubiquinol, suggesting that ubiquinol can improve mitochondrial oxidative metabolism in the brain. It also suggests the therapeutic potential of ubiquinol for patients with MSA with COQ2 mutations. Further clinical trials of administration of high-dose ubiquinol to MSA patients are warranted.

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  • TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy 査読

    Toshio Ikeda, Akihiko Nakahara, Rie Nagano, Maiko Utoyama, Megumi Obara, Hiroshi Moritake, Tamayo Uechi, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Naoya Kenmochi, Shinichi Morishita, Ichizo Nishino, Shoji Tsuji, Hiroyuki Nunoi

    JOURNAL OF HUMAN GENETICS   62 ( 4 )   473 - 480   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.

    DOI: 10.1038/jhg.2016.149

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  • Authors' response to "Compound heterozygous Fukutin mutation-related non-compaction" by Finsterer and Zarrouk-Mahjoub 査読

    Eisuke Amiya, Hiroyuki Morita, Hiroyuki Ishiura, Shoji Tsuji, Issei Komuro

    INTERNATIONAL JOURNAL OF CARDIOLOGY   233   102 - 102   2017年4月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.ijcard.2017.01.107

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  • Novel GBE1 mutation in a Japanese family with adult polyglucosan body disease. 査読 国際誌

    Harigaya Y, Matsukawa T, Fujita Y, Mizushima K, Ishiura H, Mitsui J, Morishita S, Shoji M, Ikeda Y, Tsuji S

    Neurology. Genetics   3 ( 2 )   e138   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1212/NXG.0000000000000138

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  • Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype 査読

    Toru Yamashita, Jun Mitsui, Nobuyuki Shimozawa, Shigeo Takashima, Hiroshi Umemura, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Takashi Matsukawa, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Koji Abe

    JOURNAL OF THE NEUROLOGICAL SCIENCES   375   424 - 429   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T&gt;C (p.M1T), and a novel mutation, c920G&gt;A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems. (C) 2017 Elsevier B.V. All rights reserved.

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  • Slowly progressive D-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing 査読

    Takashi Matsukawa, Kagari Mano Koshi, Jun Mitsui, Taro Bannai, Miho Kawabe, Hiroyuki Ishiura, Yasuo Terao, Jun Shimizu, Keiko Murayama, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Jun Goto

    JOURNAL OF THE NEUROLOGICAL SCIENCES   372   6 - 10   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    D-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood. (C) 2016 Elsevier B.V. All rights reserved.

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  • Novel mutation in the SOD1 gene in a patient with early-onset, rapidly progressive amyotrophic lateral sclerosis. 査読

    kazaki M, Suzuki H, Takahashi Y, Ishiura H, Goto J, Hirano M, Saigoh K, Nakamura Y, Naruse H, Mitsui J, Tsuji S, Kusunoki S

    Neurol Clin Neurosci   5   189 - 191   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/ncn3.12153

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  • Fukutin gene mutations that cause left ventricular noncompaction 査読

    Eisuke Amiya, Hiroyuki Morita, Masaru Hatanoa, Daisuke Nitta, Yumiko Hosoya, Hisataka Maki, Yoshihiro Motozawa, Naoko Sato, Hiroyuki Ishiura, Satoe Numakura, Yukako Shintani, Koichiro Kinugawa, Norifumi Takeda, Jun Shimizu, Shoji Tsuji, Issei Komuro

    INTERNATIONAL JOURNAL OF CARDIOLOGY   222   727 - 729   2016年11月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.ijcard.2016.08.011

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  • Modeling neurological diseases with induced pluripotent cells reprogrammed from immortalized lymphoblastoid cell lines 査読

    Koki Fujimori, Toshiki Tezuka, Hiroyuki Ishiura, Jun Mitsui, Koichiro Doi, Jun Yoshimura, Hirobumi Tada, Takuya Matsumoto, Miho Isoda, Ryota Hashimoto, Nubutaka Hattori, Takuya Takahashi, Shinichi Morishita, Shoji Tsuji, Wado Akamatsu, Hideyuki Okano

    MOLECULAR BRAIN   9 ( 1 )   88   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Patient-specific induced pluripotent stem cells (iPSCs) facilitate understanding of the etiology of diseases, discovery of new drugs and development of novel therapeutic interventions. A frequently used starting source of cells for generating iPSCs has been dermal fibroblasts (DFs) isolated from skin biopsies. However, there are also numerous repositories containing lymphoblastoid B-cell lines (LCLs) generated from a variety of patients. To date, this rich bioresource of LCLs has been underused for generating iPSCs, and its use would greatly expand the range of targeted diseases that could be studied by using patient-specific iPSCs. However, it remains unclear whether patient's LCL-derived iPSCs (LiPSCs) can function as a disease model. Therefore, we generated Parkinson's disease patient-specific LiPSCs and evaluated their utility as tools for modeling neurological diseases. We established iPSCs from two LCL clones, which were derived from a healthy donor and a patient carrying PARK2 mutations, by using existing non-integrating episomal protocols. Whole genome sequencing (WGS) and comparative genomic hybridization (CGH) analyses showed that the appearance of somatic variations in the genomes of the iPSCs did not vary substantially according to the original cell types (LCLs, T-cells and fibroblasts). Furthermore, LiPSCs could be differentiated into functional neurons by using the direct neurosphere conversion method (dNS method), and they showed several Parkinson's disease phenotypes that were similar to those of DF-iPSCs. These data indicate that the global LCL repositories can be used as a resource for generating iPSCs and disease models. Thus, LCLs are the powerful tools for generating iPSCs and modeling neurological diseases.

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  • AgIn: measuring the landscape of CpG methylation of individual repetitive elements 査読

    Yuta Suzuki, Jonas Korlach, Stephen W. Turner, Tatsuya Tsukahara, Junko Taniguchi, Wei Qu, Kazuki Ichikawa, Jun Yoshimura, Hideaki Yurino, Yuji Takahashi, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Hiroyuki Takeda, Shinichi Morishita

    BIOINFORMATICS   32 ( 19 )   2911 - 2919   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Motivation: Determining the methylation state of regions with high copy numbers is challenging for second-generation sequencing, because the read length is insufficient to map reads uniquely, especially when repetitive regions are long and nearly identical to each other. Single-molecule real-time (SMRT) sequencing is a promising method for observing such regions, because it is not vulnerable to GC bias, it produces long read lengths, and its kinetic information is sensitive to DNA modifications.
    Results: We propose a novel linear-time algorithm that combines the kinetic information for neighboring CpG sites and increases the confidence in identifying the methylation states of those sites. Using a practical read coverage of similar to 30-fold from an inbred strain medaka (Oryzias latipes), we observed that both the sensitivity and precision of our method on individual CpG sites were -93.7%. We also observed a high correlation coefficient (R=0.884) between our method and bisulfite sequencing, and for 92.0% of CpG sites, methylation levels ranging over [0,1] were in concordance within an acceptable difference 0.25. Using this method, we characterized the landscape of the methylation status of repetitive elements, such as LINEs, in the human genome, thereby revealing the strong correlation between CpG density and hypomethylation and detecting hypomethylation hot spots of LTRs and LINEs. We uncovered the methylation states for nearly identical active transposons, two novel LINE insertions of identity similar to 99% and length 6050 base pairs (bp) in the human genome, and 16 Tol2 elements of identity &gt; 99.8% and length 4682 bp in the medaka genome.

    DOI: 10.1093/bioinformatics/btw360

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  • Novel COL6A2 mutation in a case of limb girdle muscular dystrophy phenotype with autosomal recessive inheritance 査読

    Mitsui Jun, Ishiura Hiroyuki, Yoshimura Jun, Doi Koichiro, Morishita Shinichi, Shoji Hiroshi, Arimori Yojiro, Matsumoto Takafumi, Shimizu Jun, Tsuji Shoji

    NEUROLOGY AND CLINICAL NEUROSCIENCE   4 ( 5 )   189 - 191   2016年9月

  • Plasma Coenzyme Q10 Levels in Patients With Multiple System Atrophy 査読

    Jun Mitsui, Takashi Matsukawa, Tsutomu Yasuda, Hiroyuki Ishiura, Shoji Tsuji

    JAMA NEUROLOGY   73 ( 8 )   977 - 980   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    IMPORTANCE Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA.
    OBJECTIVE To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls.
    DESIGN, SETTING, AND PARTICIPANTS We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level.
    MAIN OUTCOMES AND MEASURES Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype.
    RESULTS Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] mu g/mL; P = .01) (difference between medians: -0.14; 95% CI, -0.25 to -0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) mu g/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02).
    CONCLUSIONS AND RELEVANCE Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

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  • Human genetic variation database, a reference database of genetic variations in the Japanese population. 査読 国際誌

    Koichiro Higasa, Noriko Miyake, Jun Yoshimura, Kohji Okamura, Tetsuya Niihori, Hirotomo Saitsu, Koichiro Doi, Masakazu Shimizu, Kazuhiko Nakabayashi, Yoko Aoki, Yoshinori Tsurusaki, Shinichi Morishita, Takahisa Kawaguchi, Osuke Migita, Keiko Nakayama, Mitsuko Nakashima, Jun Mitsui, Maiko Narahara, Keiko Hayashi, Ryo Funayama, Daisuke Yamaguchi, Hiroyuki Ishiura, Wen-Ya Ko, Kenichiro Hata, Takeshi Nagashima, Ryo Yamada, Yoichi Matsubara, Akihiro Umezawa, Shoji Tsuji, Naomichi Matsumoto, Fumihiko Matsuda

    Journal of human genetics   61 ( 6 )   547 - 53   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the importance of constructing an ethnicity-specific reference genome for identifying rare variants. All the collected data were centralized to a newly developed database to serve as useful resources for exploring pathogenic variations. Public access to the database is available at http://www.genome.med.kyoto-u.ac.jp/SnpDB/.

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  • Exome sequencing reveals a novel missense mutation in the KIAA0196 gene in a Japanese patient with SPG8 査読

    Yuta Ichinose, Kishin Koh, Megumi Fukumoto, Nobuo Yamashiro, Fumikazu Kobayashi, Michiaki Miwa, Takamura Nagasaka, Kazumasa Shindo, Hiroyuki Ishiura, Shoji Tsuji, Yoshihisa Takiyama

    CLINICAL NEUROLOGY AND NEUROSURGERY   144   36 - 38   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Exome sequencing revealed a novel missense mutation (c.2152G &gt; A, p.E713K) in the KIAA0196 gene in a Japanese patient with SPG8. To date, only 10 mutations in the KIAA0196 gene have been reported in the world. We describe the clinical and genetic findings in our patient with SPG8, which is a rare dominant hereditary spastic paraplegia. Notably, our patient showed mild upper limb ataxia, which is a relatively atypical symptom of SPG8. Thus, our patient showed a wide clinical spectrum of SPG8. (C) 2016 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.clineuro.2016.02.031

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  • Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2 査読

    Yujiro Higuchi, Akihiro Hashiguchi, Junhui Yuan, Akiko Yoshimura, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Satoshi Ishihara, Hajime Tanabe, Satoshi Nozuma, Yuji Okamoto, Eiji Matsuura, Ryuichi Ohkubo, Saeko Inamizu, Wataru Shiraishi, Ryo Yamasaki, Yasumasa Ohyagi, Jun-ichi Kira, Yasushi Oya, Hayato Yabe, Noriko Nishikawa, Shinsuke Tobisawa, Nozomu Matsuda, Masayuki Masuda, Chiharu Kugimoto, Kazuhiro Fukushima, Satoshi Yano, Jun Yoshimura, Koichiro Doi, Masanori Nakagawa, Shinichi Morishita, Shoji Tsuji, Hiroshi Takashima

    ANNALS OF NEUROLOGY   79 ( 4 )   659 - 672   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    ObjectiveThe objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT.
    MethodsTo efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation.
    ResultsWe identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (A)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess A in Pittsburgh compound-B positron emission tomography imaging.
    InterpretationOur results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659-672

    DOI: 10.1002/ana.24612

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  • CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia 査読

    Kelly L. Williams, Simon Topp, Shu Yang, Bradley Smith, Jennifer A. Fifita, Sadaf T. Warraich, Katharine Y. Zhang, Natalie Farrawell, Caroline Vance, Xun Hu, Alessandra Chesi, Claire S. Leblond, Albert Lee, Stephanie L. Rayner, Vinod Sundaramoorthy, Carol Dobson-Stone, Mark P. Molloy, Marka van Blitterswijk, Dennis W. Dickson, Ronald C. Petersen, Neill R. Graff-Radford, Bradley F. Boeve, Melissa E. Murray, Cyril Pottier, Emily Don, Claire Winnick, Emily P. McCann, Alison Hogan, Hussein Daoud, Annie Levert, Patrick A. Dion, Jun Mitsui, Hiroyuki Ishiura, Yuji Takahashi, Jun Goto, Jason Kost, Cinzia Gellera, Athina Soragia Gkazi, Jack Miller, Joanne Stockton, William S. Brooks, Karyn Boundy, Meraida Polak, Jose Luis Munoz-Blanco, Jesus Esteban-Perez, Alberto Rabano, Orla Hardiman, Karen E. Morrison, Nicola Ticozzi, Vincenzo Silani, Jacqueline de Belleroche, Jonathan D. Glass, John B. J. Kwok, Gilles J. Guillemin, Roger S. Chung, Shoji Tsuji, Robert H. Brown, Alberto Garcia-Redondo, Rosa Rademakers, John E. Landers, Aaron D. Gitler, Guy A. Rouleau, Nicholas J. Cole, Justin J. Yerbury, Julie D. Atkin, Christopher E. Shaw, Garth A. Nicholson, Ian P. Blair

    NATURE COMMUNICATIONS   7   11253   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

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  • A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia A Broadened Spectrum of SCA34 査読

    Kokoro Ozaki, Hiroshi Doi, Jun Mitsui, Nozomu Sato, Yoichiro Iikuni, Takamasa Majima, Kiyomi Yamane, Takashi Irioka, Hiroyuki Ishiura, Koichiro Doi, Shinichi Morishita, Miwa Higashi, Teruhiko Sekiguchi, Kazuo Koyama, Naohisa Ueda, Yoshiharu Miura, Satoko Miyatake, Naomichi Matsumoto, Takanori Yokota, Fumiaki Tanaka, Shoji Tsuji, Hidehiro Mizusawa, Kinya Ishikawa

    JAMA NEUROLOGY   72 ( 7 )   797 - 805   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified.
    OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations.
    DESIGN, SETTING, AND PARTICIPANTS Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997.
    MAIN OUTCOMES AND MEASURES Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing.
    RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T&gt;G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G&gt;C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families.
    CONCLUSIONS AND RELEVANCE Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

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  • Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome. 査読

    Koh K, Kobayashi F, Miwa M, Shindo K, Isozaki E, Ishiura H, Tsuji S, Takiyama Y

    Journal of human genetics   60 ( 4 )   217 - 220   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Variants associated with Gaucher disease in multiple system atrophy 査読

    Jun Mitsui, Takashi Matsukawa, Hidenao Sasaki, Ichiro Yabe, Masaaki Matsushima, Alexandra Duerr, Alexis Brice, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Hiroyuki Ishiura, Tsutomu Yasuda, Hidetoshi Date, Budrul Ahsan, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Caroline M. Tanner, Walter A. Kukull, Mathew B. Stern, Virginia M. -Y. Lee, John Q. Trojanowski, Eliezer Masliah, Phillip A. Low, Paola Sandroni, Laurie J. Ozelius, Tatiana Foroud, Shoji Tsuji

    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY   2 ( 4 )   417 - 426   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 9 10(-3)). Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

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  • DNA Sequencing and Other Methods of Exonic and Genomic Analyses 査読

    Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji

    Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Fifth Edition   77 - 85   2014年11月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Elsevier Inc.  

    DNA sequencing technologies, and the application of these technologies for exploring molecular bases of diseases as well as for clinical sequencing, are reviewed in this chapter. The methods of DNA sequencing include: 1) the Maxam-Gilbert method
    2) the Sanger method
    and 3) next-generation sequencing (NGS) technologies. In addition, other technologies including fluorescence in situ hybridization (FISH) analysis, microarray-based comparative genomic hybridization (array CGH) analysis, polymerase chain reaction (PCR)-based methods (quantitative PCR analysis, multiplex ligation-dependent probe amplification (MLPA) analysis, PCR fragment analysis, and repeat-primed PCR analysis), and Southern blot hybridization analysis are also used to analyze alterations of structures of DNA molecules. Among these, in particular, NGS technologies are currently revolutionizing the field of molecular genetics research of diseases. Comprehensive genome sequence analyses employing NGS technologies have demonstrated excellent competence to identify molecular bases of diseases with Mendelian-trait as well as those with complex trait. NGS technologies are also being increasingly applied for clinical sequencing to provide molecular diagnoses of diseases.

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  • Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation 査読

    Haruo Shimazaki, Junko Honda, Tametou Naoi, Michito Namekawa, Imaharu Nakano, Masahide Yazaki, Katsuya Nakamura, Kunihiro Yoshida, Shu-ichi Ikeda, Hiroyuki Ishiura, Yoko Fukuda, Yuji Takahashi, Jun Goto, Shoji Tsuji, Yoshihisa Takiyama

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   85 ( 9 )   1024 - 1028   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ PUBLISHING GROUP  

    Background Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy.
    Methods This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample.
    Results We detected a homozygous missense mutation (c.4189T&gt;G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chediak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency.
    Conclusions We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.

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  • A Recurrent De Novo FAM111A Mutation Causes Kenny-Caffey Syndrome Type 2 査読

    Tsuyoshi Isojima, Koichiro Doi, Jun Mitsui, Yoichiro Oda, Etsuro Tokuhiro, Akihiro Yasoda, Tohru Yorifuji, Reiko Horikawa, Jun Yoshimura, Hiroyuki Ishiura, Shinichi Morishita, Shoji Tsuji, Sachiko Kitanaka

    JOURNAL OF BONE AND MINERAL RESEARCH   29 ( 4 )   992 - 998   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

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  • Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing 査読

    Koichiro Doi, Taku Monjo, Pham H. Hoang, Jun Yoshimura, Hideaki Yurino, Jun Mitsui, Hiroyuki Ishiura, Yuji Takahashi, Yaeko Ichikawa, Jun Goto, Shoji Tsuji, Shinichi Morishita

    BIOINFORMATICS   30 ( 6 )   815 - 822   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Motivation: Long expansions of short tandem repeats (STRs), i.e. DNA repeats of 2-6 nt, are associated with some genetic diseases. Cost-efficient high-throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100bp, the typical length of short reads.
    Results: We propose ab initio procedures for sensing and locating long STRs promptly by using the frequency distribution of all STRs and paired-end read information. We validated the reproducibility of this method using biological replicates and used it to locate an STR associated with a brain disease (SCA31). Subsequently, we sequenced this STR site in 11 SCA31 samples using SMRT TM sequencing (Pacific Biosciences), determined 2.3-3.1 kb sequences at nucleotide resolution and revealed that (TGGAA)- and (TAAAATAGAA)-repeat expansions determined the instability of the repeat expansions associated with SCA31. Our method could also identify common STRs, (AAAG)- and (AAAAG)-repeat expansions, which are remarkably expanded at four positions in an SCA31 sample. This is the first proposed method for rapidly finding disease-associated long STRs in personal genomes using hybrid sequencing of short and long reads.

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  • Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan 査読

    Megumi Yamada, Masaki Tanaka, Mari Takagi, Seiju Kobayashi, Yoshiharu Taguchi, Shutaro Takashima, Kortaro Tanaka, Tetsuo Touge, Hiroyuki Hatsuta, Shigeo Murayama, Yuichi Hayashi, Masayuki Kaneko, Hiroyuki Ishiura, Jun Mitsui, Naoki Atsuta, Gen Sobue, Nobuyuki Shimozawa, Takashi Inuzuka, Shoji Tsuji, Isao Hozumi

    NEUROLOGY   82 ( 8 )   705 - 712   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective:To investigate the clinical, genetic, and neuroradiologic presentations of idiopathic basal ganglia calcification (IBGC) in a nationwide study in Japan.Methods:We documented clinical and neuroimaging data of a total of 69 subjects including 23 subjects from 10 families and 46 subjects in sporadic cases of IBGC in Japan. Mutational analysis of SLC20A2 was performed.Results:Six new mutations in SLC20A2 were found in patients with IBGC: 4 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. Four of them were familial cases and 2 were sporadic cases in our survey. The frequency of families with mutations in SLC20A2 in Japan was 50%, which was as high as in a previous report on other regions. The clinical features varied widely among the patients with SLC20A2 mutations. However, 2 distinct families have the same mutation of S637R in SLC20A2 and they have similar characteristics in the clinical course, symptoms, neurologic findings, and neuroimaging. In our study, all the patients with SLC20A2 mutations showed calcification. In familial cases, there were symptomatic and asymptomatic patients in the same family.Conclusion:SLC20A2 mutations are a major cause of familial IBGC in Japan. The members in the families with the same mutation had similar patterns of calcification in the brain and the affected members showed similar clinical manifestations.

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  • Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12 査読

    Guida Landoure, Peng-Peng Zhu, Charles M. Lourenco, Janel O. Johnson, Camilo Toro, Katherine V. Bricceno, Carlo Rinaldi, Katherine G. Meilleur, Modibo Sangare, Oumarou Diallo, Tyler M. Pierson, Hiroyuki Ishiura, Shoji Tsuji, Nichole Hein, John K. Fink, Marion Stoll, Garth Nicholson, Michael A. Gonzalez, Fiorella Speziani, Alexandra Duerr, Giovanni Stevanin, Leslie G. Biesecker, John Accardi, Dennis M. D. Landis, William A. Gahl, Bryan J. Traynor, Wilson Marques, Stephan Zuechner, Craig Blackstone, Kenneth H. Fischbeck, Barrington G. Burnett

    HUMAN MUTATION   34 ( 10 )   1357 - 1360   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G&gt;C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain. Published 2013 Wiley Periodicals, Inc.

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  • Exome analysis reveals a Japanese family with spinocerebellar ataxia, autosomal recessive 1 査読

    Yaeko Ichikawa, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Shunsuke Kobayashi, Hiroshi Takuma, Ichiro Kanazawa, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Goto, Shoji Tsuji

    JOURNAL OF THE NEUROLOGICAL SCIENCES   331 ( 1-2 )   158 - 160   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Spinocerebellar ataxia autosomal recessive 1 (SCAR1/AOA2) is clinically characterized by an early-onset progressive cerebellar ataxia with axonal neuropathy, ocular motor apraxia, and elevation of serum alpha-fetoprotein level. The disorder is caused by mutations in senataxin (SETX) gene. Here, we report a Japanese SCAR1/AOA2 family with a homozygous nonsense mutation (p.Q1441X) of SETX that was identified by exome sequencing. The family was previously reported as early-onset ataxia of undetermined cause. The present study emphasized the role of whole exome-sequence analysis to establish the molecular diagnosis of neurodegenerative disease presenting with diverse clinical presentations. (C) 2013 Elsevier B.V. All rights reserved.

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  • [Present efforts in the medical genome center at the University of Tokyo Hospital]. 査読

    Mitsui J, Ishiura H, Tsuji S

    Brain and nerve = Shinkei kenkyu no shinpo   65 ( 3 )   247 - 255   2013年3月

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  • Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients 査読

    Atsushi Ishii, Yoshiaki Saito, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Hidee Arai, Sumimasa Yamashita, Sadami Kimura, Hirokazu Oguni, Shinichi Morishita, Shoji Tsuji, Masayuki Sasaki, Shinichi Hirose

    PLoS ONE   8 ( 2 )   e56120   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by transient repeated attacks of paresis and cognitive impairment. Recent studies from the U.S. and Europe have described ATP1A3 mutations in AHC. However, the genotype-phenotype relationship remains unclear. The purpose of this study was to identify the genetic abnormality in a Japanese cohort of AHC using exome analysis. Principal Findings: A total of 712,558 genetic single nucleotide variations in 8 patients with sporadic AHC were found. After a series of exclusions, mutations of three genes were regarded as candidate causes of AHC. Each patient harbored a heterozygous missense mutation of ATP1A3, which included G755C, E815K, C927Y and D801N. All mutations were at highly conserved amino acid residues and deduced to affect ATPase activity of the corresponding ATP pump, the product of ATP1A3. They were de novo mutations and not identified in 96 healthy volunteers. Using Sanger sequencing, E815K was found in two other sporadic cases of AHC. In this study, E815K was found in 5 of 10 patients (50%), a prevalence higher than that reported in two recent studies [19 of 82 (23%) and 7 of 24 (29%)]. Furthermore, the clinical data of the affected individuals indicated that E815K resulted in a severer phenotype compared with other ATP1A3 mutations. Interpretation: Heterozygous de novo mutations of ATP1A3 were identified in all Japanese patients with AHC examined in this study, confirming that ATP1A3 mutation is the cause of AHC. © 2013 Ishii et al.

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  • Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a mutation in TFG 査読

    Hiroyuki Ishiura, Shoji Tsuji

    Clinical Neurology   53 ( 11 )   1203 - 1205   2013年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Societas Neurologica Japonica  

    Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal dominant neurodegenerative disease characterized by proximal predominant weakness and muscle atrophy accompanied by distal sensory disturbance. Linkage analysis using 4 families identified a region on chromosome 3 showing a LOD score exceeding 4. Further refinement of candidate region was performed by haplotype analysis using high-density SNP data, resulting in a minimum candidate region spanning 3.3 Mb. Exome analysis of an HMSN-P patient revealed a mutation (c.854C&gt
    T, p.Pro285Leu) in TRK-fused gene (TFG). The identical mutation was found in the four families, which cosegregated with the disease. The mutation was neither found in Japanese control subjects nor public databases. Detailed haplotype analysis suggested two independent origins of the mutation. These findings indicate that the mutation in TFG causes HMSN-P.

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  • C9orf72 repeat expansionを伴った紀伊ALSの一自験例の臨床・疫学的特徴について 招待

    吉田宗平, 紀平為子, 尾野精一, 小久保康昌, 葛原茂樹, 石浦浩之, 辻省次

    厚生労働科学研究費補助金(難治性疾患克服研究事業)平成24年度(分担)研究報告書   2013年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55) 査読

    Haruo Shimazaki, Yoshihisa Takiyama, Hiroyuki Ishiura, Chika Sakai, Yuichi Matsushima, Hideyuki Hatakeyama, Junko Honda, Kumi Sakoe, Tametou Naoi, Michito Namekawa, Yoko Fukuda, Yuji Takahashi, Jun Goto, Shoji Tsuji, Yu-ichi Goto, Imaharu Nakano

    JOURNAL OF MEDICAL GENETICS   49 ( 12 )   777 - 784   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ PUBLISHING GROUP  

    Background Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy.
    Methods The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control.
    Results We identified a homozygous nonsense mutation (c.394C&gt;T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV.
    Conclusions This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

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  • CSF1R Mutations Identified in Three Families With Autosomal Dominantly Inherited Leukoencephalopathy 査読

    Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Koichiro Higasa, Jun Yoshimura, Taro L. Saito, Budrul Ahsan, Yuji Takahashi, Jun Goto, Atsushi Iwata, Yuki Niimi, Yuuichi Riku, Yoji Goto, Kazuo Mano, Mari Yoshida, Shinichi Morishita, Shoji Tsuji

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   159B ( 8 )   951 - 957   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Genetic and phenotypic heterogeneities are considerably high in adult-onset leukoencephalopathy, in which comprehensive mutational analyses of the candidate genes by conventional methods are too laborious. We applied exome sequencing to conduct a comprehensive mutational analysis of genes for autosomal dominant leukoencephalopathies. Genomic DNA samples from four patients of three families with autosomal dominantly inherited adult-onset leukodystrophy were subjected to exome sequencing. On the basis of the results, 21 patients with adult-onset sporadic leukodystrophy and one patient with pathologically proven HDLS were additionally screened for CSF1R mutations. Exome sequencing identified heterozygous CSF1R mutations (p.I794T and p.R777W) in two families. I794T has recently been reported as a causative mutation for hereditary diffuse leukoencephalopathy with spheroids (HDLS), and R777W is a novel mutation. Although mutational analysis of CSF1R in 21 sporadic cases revealed no mutations, another novel CSF1R mutation, p.C653Y, was identified in one patient with autopsy-proven HDSL. These variants were located in the PTK domain where the causative mutations cluster. Functional prediction of the mutant CSF1R was well as cross-species conservation of the affected amino acids supports the notion that these variants are pathogenic for HDLS. Exome sequencing is useful for a comprehensive mutational analysis of causative genes for hereditary leukoencephalopathies, and CSF1R should be considered a candidate gene for patients with autosomal dominant leukoencephalopathies. (C) 2012 Wiley Periodicals, Inc.

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  • Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population 査読

    Hiroya Naruse, Yuji Takahashi, Tameko Kihira, Sohei Yoshida, Yasumasa Kokubo, Shigeki Kuzuhara, Hiroyuki Ishiura, Masaharu Amagasa, Shigeo Murayama, Shoji Tsuji, Jun Goto

    AMYOTROPHIC LATERAL SCLEROSIS   13 ( 6 )   562 - 566   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INFORMA HEALTHCARE  

    Our objective was to elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS) with OPTN mutations in the Japanese population. Mutational analysis of OPTN was conducted in 18 FALS pedigrees in whom mutations in other causative genes have been excluded and in 218 SALS patients by direct nucleotide sequence analysis. Novel non-synonymous variants identified in ALS patients were further screened in 271 controls. Results showed that although no mutations were identified in the FALS pedigrees, a novel heterozygous non-synonymous variant c. 481G &gt; A (p.V161M) was identified in one SALS patient, who originated from the southernmost part of the Kii Peninsula. The mutation was not present in 271 controls. As the clinical feature, the patient carrying V161M showed predominantly upper motor neuron signs with slow progression. This study suggests that mutations in OPTN are not the main cause of ALS in the Japanese population.

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  • Adult-onset Alexander disease with an R66Q mutation in GFAP presented with severe vocal cord paralysis during sleep 査読

    Ayumi Hida, Hiroyuki Ishiura, Noritoshi Arai, Hisayo Fukuoka, Kanehiro Hasuo, Jun Goto, Yoshikazu Uesaka, Shoji Tsuji, Sousuke Takeuchi

    JOURNAL OF NEUROLOGY   259 ( 10 )   2234 - 2236   2012年10月

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    記述言語:英語   出版者・発行元:SPRINGER HEIDELBERG  

    DOI: 10.1007/s00415-012-6540-4

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  • Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study 査読

    Elisa Majounie, Alan E. Renton, Kin Mok, Elise G. P. Dopper, Adrian Waite, Sara Rollinson, Adrian Chio, Gabriella Restagno, Nayia Nicolaou, Javier Simon-Sanchez, John C. van Swieten, Yevgeniya Abramzon, Janel O. Johnson, Michael Sendtner, Roger Pamphlett, Richard W. Orrell, Simon Mead, Katie C. Sidle, Henry Houlden, Jonathan D. Rohrer, Karen E. Morrison, Hardev Pall, Kevin Talbot, Olaf Ansorge, Dena G. Hernandez, Sampath Arepalli, Mario Sabatelli, Gabriele Mora, Massimo Corbo, Fabio Giannini, Andrea Calvo, Elisabet Englund, Giuseppe Borghero, Gian Luca Foris, Anne M. Remes, Hannu Laaksovirta, Leo McCluskey, John Q. Trojanowski, Vivianna M. Van Deerlin, Gerard D. Schellenberg, Michael A. Nalls, Vivian E. Drory, Chin-Song Lu, Tu-Hsueh Yeh, Hiroyuki Ishiura, Yuji Takahashi, Shoji Tsuji, Isabelle Le Ber, Alexis Brice, Carsten Drepper, Nigel Williams, Janine Kirby, Pamela Shaw, John Hardy, Pentti J. Tienari, Peter Heutink, Huw R. Morris, Stuart Pickering-Brown, Bryan J. Traynor

    LANCET NEUROLOGY   11 ( 4 )   323 - 330   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
    Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.
    Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.
    Interpretation A common Mendelian genetic lesion in C9472 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.

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  • Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12 査読

    Gladys Montenegro, Adriana P. Rebelo, James Connell, Rachel Allison, Carla Babalini, Michela D'Aloia, Pasqua Montieri, Rebecca Schuele, Hiroyuki Ishiura, Justin Price, Alleene Strickland, Michael A. Gonzalez, Lisa Baumbach-Reardon, Tine Deconinck, Jia Huang, Giorgio Bernardi, Jeffery M. Vance, Mark T. Rogers, Shoji Tsuji, Peter De Jonghe, Margaret A. Pericak-Vance, Ludger Schoels, Antonio Orlacchio, Evan Reid, Stephan Zuechner

    JOURNAL OF CLINICAL INVESTIGATION   122 ( 2 )   538 - 544   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC CLINICAL INVESTIGATION INC  

    Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.

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  • Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease 査読

    Meiko Hashimoto Maeda, Jun Mitsui, Bing-Wen Soong, Yuji Takahashi, Hiroyuki Ishiura, Shin Hayashi, Yuichiro Shirota, Yaeko Ichikawa, Hideyuki Matsumoto, Makoto Arai, Tomoko Okamoto, Sahoko Miyama, Jun Shimizu, Johji Inazawa, Jun Goto, Shoji Tsuji

    ANNALS OF NEUROLOGY   71 ( 1 )   84 - 92   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: On the basis of the hypothesis that copy number mutations of the genes encoding myelin compact proteins are responsible for myelin disorders in humans, we have explored the possibility of copy number mutations in patients with Charcot-Marie-Tooth disease (CMT) whose responsible genes remain undefined. Methods: A family with 6 affected members in 3 consecutive generations, presenting with motor and sensory demyelinating polyneuropathy, was investigated. Characteristic clinical features in this pedigree include Adie pupils and substantial intrafamilial variability in the age at onset, electrophysiological findings, and clinical severity. Nucleotide sequence analyses of PMP22, MPZ, or GJB1 and gene dosage study of PMP22 did not reveal causative mutations. Hence, we applied a custom- designed array for comparative genomic hybridization ( CGH) analysis to conduct a comprehensive screening of copy number mutations involving any of the known causative genes for CMT other than PMP22. Results: The array CGH analyses revealed increased gene dosage involving the whole MPZ, and the flanking genes of SDHC and C1orf192. The gene dosage is estimated to be 5 copies. This mutation showed complete cosegregation with the disease phenotype in this pedigree. Interpretation: The increased gene dosage of MPZ and increased expression level of MPZ mRNA emphasize the important role of the dosage of the MPZ protein in the functional integrity of peripheral nerve myelin in humans, and provide a new insight into the pathogenic mechanisms underlying CMT.

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  • Hypertrophic Pachymeningitis and Tracheobronchial Stenosis in IgG4-related Disease: Case Presentation and Literature Review 査読

    Hiroyuki Yamashita, Yuko Takahashi, Hiroyuki Ishiura, Toshikazu Kano, Hiroshi Kaneko, Akio Mimori

    INTERNAL MEDICINE   51 ( 8 )   935 - 941   2012年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Immunoglobulin G4 (IgG4)-related disease is a distinctive mass-forming disorder with frequent systemic involvement, most commonly in the pancreas, salivary glands and lacrimal glands. A few cases of dural involvement and one case of central airway stenosis have also been described. We report here a rare case of IgG4-related disease with intracranial hypertrophic pachymeningitis and irregular tracheobronchial stenosis. We review four previously reported cases of IgG4-related pachymeningitis. We currently lack international standards for the diagnosis of extrapancreatic IgG4-related disease. Based on the findings of the present case and those reported previously, we discuss the distinctive features of IgG4-related pachymeningitis.

    DOI: 10.2169/internalmedicine.51.6604

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  • Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5 査読

    Takashi Matsukawa, Xuemin Wang, Rui Liu, Noel C. Wortham, Yuko Onuki, Akatsuki Kubota, Ayumi Hida, Hisatomo Kowa, Yoko Fukuda, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Shigeki Aoki, Shunya Takizawa, Jun Shimizu, Jun Goto, Christopher G. Proud, Shoji Tsuji

    NEUROGENETICS   12 ( 3 )   259 - 261   2011年8月

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    記述言語:英語   出版者・発行元:SPRINGER  

    DOI: 10.1007/s10048-011-0284-7

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  • Next-generation analysis on hereditary neurodegenerative disorders using next-generation sequencers 査読

    Hiroyuki Ishiura, Shoji Tsuji

    Clinical Neurology   51 ( 11 )   970 - 972   2011年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    With the throughput of next-generation sequencers, even whole genome analysis is a reality. Traditionally, it was important to collect as many samples as possible and to perform sequence analysis of many genes in candidate regions. There has been a paradigm shift in the era of next-generation sequencing
    to reveal the significance of raviants produced by next-generation sequencers rather than just to perform sequence analysis becomes the key to elucidate causes of disorders. We performed target capture and next-generation sequencing analyses of a small consanguineous family in which only two members were affected by posterior column ataxia with retinitis pigmentosa (PCARP). We successfully identified a causative mutation in FLVCR1 which cosegregated with the disease. The fact that we could identify the causative gene even from a small family means that the advent of next-generation sequencers has brought us to a next-generation analysis on hereditary disorders. In the near future, many causative genes of hereditary neurodegenerative disorders particularly with small number of affected members will be revealed, which must provide considerable insights into pathogenesis. Approaches utilizing bioinformatics to further narrow down the numerous variations produced by next-generation sequencers are demanded in order to study remaining small families, or sporadic diseases.

    DOI: 10.5692/clinicalneurol.51.970

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  • Dominant Mutations in RP1L1 Are Responsible for Occult Macular Dystrophy 査読

    Masakazu Akahori, Kazushige Tsunoda, Yozo Miyake, Yoko Fukuda, Hiroyuki Ishiura, Shoji Tsuji, Tomoaki Usui, Tetsuhisa Hatase, Makoto Nakamura, Hisao Ohde, Takeshi Itabashi, Haru Okamoto, Yuichiro Takada, Takeshi Iwata

    AMERICAN JOURNAL OF HUMAN GENETICS   87 ( 3 )   424 - 429   2010年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

    DOI: 10.1016/j.ajhg.2010.08.009

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  • Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing using next-generation sequencer 査読

    Jun Mitsui, Yoko Fukuda, Kyo Azuma, Hirokazu Tozaki, Hiroyuki Ishiura, Yuji Takahashi, Jun Goto, Shoji Tsuji

    JOURNAL OF HUMAN GENETICS   55 ( 7 )   448 - 455   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    We have recently found that multiple rare variants of the glucocerebrosidase gene (GBA) confer a robust risk for Parkinson disease, supporting the &apos;common disease-multiple rare variants&apos; hypothesis. To develop an efficient method of identifying rare variants in a large number of samples, we applied multiplexed resequencing using a next-generation sequencer to identification of rare variants of GBA. Sixteen sets of pooled DNAs from six pooled DNA samples were prepared. Each set of pooled DNAs was subjected to polymerase chain reaction to amplify the target gene (GBA) covering 6.5 kb, pooled into one tube with barcode indexing, and then subjected to extensive sequence analysis using the SOLiD System. Individual samples were also subjected to direct nucleotide sequence analysis. With the optimization of data processing, we were able to extract all the variants from 96 samples with acceptable rates of false-positive single-nucleotide variants. Journal of Human Genetics (2010) 55, 448-455; doi:10.1038/jhg.2010.46; published online 20 May 2010

    DOI: 10.1038/jhg.2010.46

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  • A Case of Atypical Amyloid Polyneuropathy with Predominant Upper-limb Involvement with the Diagnosis Unexpectedly Found at Lung Operation 査読

    Yuichiro Shirota, Atsushi Iwata, Hiroyuki Ishiura, Meiko Hashimoto, Jun Goto, Jun Shimizu, Ritsuko Hanajima, Jun Nakajima, Yutaka Takazawa, Shoji Tsuji

    INTERNAL MEDICINE   49 ( 15 )   1627 - 1631   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    We present a patient of familial amyloid polyneuropathy (FAP) with predominant upper-limb involvement, the pattern of which resembled a mononeuropathy multiplex pattern. Sural nerve biopsy failed to diagnose the disorder, but lung partial resection performed later for other diagnostic purposes suggested FAP. A rare mutation in the transthyretin gene (S50R) was subsequently confirmed. Diagnostic challenges of FAP with atypical clinical presentations, including difficulties in pathological diagnosis, are discussed with a review of the literature.

    DOI: 10.2169/internalmedicine.49.3663

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  • SNP Haplotype Mapping in a Small ALS Family 査読

    Katherine A. Dick Krueger, Shoji Tsuji, Yoko Fukuda, Yuji Takahashi, Jun Goto, Jun Mitsui, Hiroyuki Ishiura, Joline C. Dalton, Michael B. Miller, John W. Day, Laura P. W. Ranum

    PLOS ONE   4 ( 5 )   e5687   2009年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The identification of genes for monogenic disorders has proven to be highly effective for understanding disease mechanisms, pathways and gene function in humans. Nevertheless, while thousands of Mendelian disorders have not yet been mapped there has been a trend away from studying single-gene disorders. In part, this is due to the fact that many of the remaining single-gene families are not large enough to map the disease locus to a single site in the genome. New tools and approaches are needed to allow researchers to effectively tap into this genetic gold-mine. Towards this goal, we have used haploid cell lines to experimentally validate the use of high-density single nucleotide polymorphism (SNP) arrays to define genome-wide haplotypes and candidate regions, using a small amyotrophic lateral sclerosis (ALS) family as a prototype. Specifically, we used haploid-cell lines to determine if high-density SNP arrays accurately predict haplotypes across entire chromosomes and show that haplotype information significantly enhances the genetic information in small families. Panels of haploid-cell lines were generated and a 5 centimorgan (cM) short tandem repeat polymorphism (STRP) genome scan was performed. Experimentally derived haplotypes for entire chromosomes were used to directly identify regions of the genome identical-by-descent in 5 affected individuals. Comparisons between experimentally determined and in silico haplotypes predicted from SNP arrays demonstrate that SNP analysis of diploid DNA accurately predicted chromosomal haplotypes. These methods precisely identified 12 candidate intervals, which are shared by all 5 affected individuals. Our study illustrates how genetic information can be maximized using readily available tools as a first step in mapping single-gene disorders in small families.

    DOI: 10.1371/journal.pone.0005687

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  • γδT細胞浸潤による心筋障害を認めた拡張型心筋症の特異な1例

    石浦 浩之, 世古 義規, 武田 憲文, 石坂 信和, 大野 実, 平田 恭信, 永井 良三

    日本内科学会関東地方会   504回   24 - 24   2002年11月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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MISC

  • 遺伝性痙性対麻痺におけるATL1の新規de novo変異の同定と臨床像の検討

    中村歩美, 成瀬紘也, 光武明彦, 石浦浩之, 三井純, 張香理, 森下真一, 岩越美恵, 岩越美恵, 辻省次, 辻省次, 戸田達史

    日本神経学会学術大会プログラム・抄録集   64th   2023年

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  • BAFMEでの皮質興奮性における経時的進行の変性機構の解明:分子遺伝子学的・電気生理学的検討

    音成秀一郎, 音成秀一郎, 人見健文, 戸島麻耶, 小林勝哉, 石浦浩之, 石浦浩之, 池田昭夫

    臨床神経生理学(Web)   51 ( 2 )   2023年

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  • CGGリピート病の遺伝学的検査パイプラインの確立

    光武明彦, 松川敬志, 石浦浩之, 石浦浩之, 岩田信恵

    国際医療福祉大学学会誌   28   2023年

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  • 神経核内封入体病関連網膜症におけるリピート数と重症度の相関

    中村奈津子, 中村奈津子, 角田和繁, 光武明彦, 光武明彦, 柴田頌太, 前田明子, 濱田雅, 佐竹渉, 石浦浩之, 辻省次, 辻省次, 戸田達史

    日本網膜硝子体学会総会プログラム・講演抄録集   62nd   2023年

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  • 成人発症NOTCH2NLC関連神経核内封入体病における感覚障害・小脳性運動失調の検討

    舟川開, 栗原正典, 高橋健祐, 小松大樹, 波多野敬子, 井原涼子, 東原真奈, 仁科裕史, 徳丸阿耶, 原愛徒, 齊藤祐子, 光武明彦, 柴田頌太, 石浦浩之, 石浦浩之, 金丸和富, 村山繁雄, 村山繁雄, 村山繁雄, 岩田淳

    日本神経学会学術大会プログラム・抄録集   64th   2023年

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  • 右内頸動脈起始部高度狭窄により脳梗塞を伴わずに生じた左片側舞踏運動が右頸動脈内膜剥離術で改善した症例

    橋本優子, 原涼, 宮野涼至, 海永光洋, 角元利行, 小泉聡, 宮脇哲, 石浦浩之, 佐竹渉, 戸田達史

    日本内科学会関東支部関東地方会   678th   2022年

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  • BAFME 1型における皮質興奮性の進行における老化の影響

    音成秀一郎, 音成秀一郎, 人見健文, 戸島麻耶, 小林勝哉, 石浦浩之, 池田昭夫

    臨床神経生理学(Web)   50 ( 5 )   2022年

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  • 当院での経験から見た法的脳死判定における脳神経内科医の役割

    角元利行, 代田悠一郎, 矢野智香, 小玉聡, 間野達雄, 長島優, 前田明子, 石浦浩之, 佐竹渉, 戸田達史

    Journal of Japan Society of Neurological Emergencies & Critical Care (Web)   34 ( 1 )   2021年

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  • 急性脳症を呈し,内科的加療後に生体部分肝移植を行った成人発症2型シトルリン血症の52歳女性例

    横山敬士, 荒川晶, 勝瀬一登, 角元利行, 間野達雄, 赤松延久, 大宮謙一, 萱嶋信介, 石浦浩之, 佐竹渉, 戸田達史

    神経治療学(Web)   38 ( 6 )   2021年

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  • 多系統萎縮症における高解像度食道内圧検査を用いた食道運動障害についての報告

    瀬戸瑛子, 上羽瑠美, 角元利行, 松川敬志, 代田悠一郎, 久保田暁, 三井純, 石浦浩之, 佐藤拓, 後藤多嘉緒, 山内彰人, 戸田達史

    日本神経学会学術大会プログラム・抄録集   62nd   2021年

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  • 両側対立遺伝子でhuntingtinのCAG repeat異常伸長を認めたHuntington病の臨床的検討

    上田洲裕, 内上寛一, 松川敬志, 松川敬志, 久保田暁, 石浦浩之, 三井純, 高橋祐二, 後藤順, 辻省次, 辻省次, 戸田達史

    日本神経学会学術大会プログラム・抄録集   62nd   2021年

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  • 副腎白質ジストロフィーでの脳脊髄液中ミエリン塩基性蛋白測定の意義

    角元利行, 松川敬志, 松川敬志, 石浦浩之, 辻省次, 辻省次, 戸田達史

    日本神経学会学術大会プログラム・抄録集   62nd   2021年

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  • 抗TIF1-γ抗体陽性筋炎疑いで脳神経内科へコンサルテーションされた症例の現状把握

    前川裕貴, 前田明子, 横山敬士, 角元利行, 久保田暁, 石浦浩之, 戸田達史

    日本神経学会学術大会プログラム・抄録集   62nd   2021年

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  • 当科における家族性アミロイドポリニューロパチー(TTR I107V変異)の予後の検討

    大久保颯, 荒川晶, 成瀬紘也, 三井純, 石浦浩之, 作石かおり, 岩田淳, 佐竹渉, 辻省次, 戸田達史

    日本神経学会学術大会プログラム・抄録集   62nd   2021年

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  • 意思疎通不良があり当初過活動型せん妄が疑われたが,心原性脳塞栓による失構音であった1例

    岩崎奏子, 横山敬士, 勝瀬一登, 日野理美, 角元利行, 石浦浩之, 櫻井靖久, 戸田達史

    日本内科学会関東支部関東地方会   664th   2020年

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  • 10年の経過で緩徐に増悪する反復発作性運動失調症を呈し,CACNA1A c.3695+1G>A変異を認めた61歳男性例

    三宅亮, 勝又淳子, 日野理美, 佐藤達哉, 坂内太郎, 中元ふみ子, 関大成, 石浦浩之, 三井純, 辻省次, 戸田達史, 椎尾康

    臨床神経学(Web)   60 ( 5 )   2020年

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  • 痙性対麻痺に小脳性失調,軸索型ニューロパチー,認知機能低下を合併し,KIF1Aの新規変異を認めたAD-SPG30の親子例

    河合三津保, 織茂賢太, 岩田信恵, 石浦浩之, 三井純, 中嶋秀樹, 村井弘之, 後藤順

    臨床神経学(Web)   60 ( 5 )   2020年

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  • IBMPFD2家系の臨床的検討

    武田勇人, 三宅善嗣, 石井亜紀子, 保坂孝史, 奥根祥, 伊佐恵, 町田明, 成瀬紘也, 石浦浩之, 三井純, 三井純, 後藤順, 辻省次, 戸田達史, 斉藤史明, 川崎仁志, 幕内幹男, 玉岡晃

    日本神経学会学術大会プログラム・抄録集   61st   2020年

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  • ATP1A3遺伝子p.D801N変異を有する小児交互性片麻痺成人例のてんかん重積に対する抗てんかん薬の検討

    海永光洋, 佐藤ももか, 吉田千晴, 小巻奨吾, 石浦浩之, 作石かおり, 岩田淳, 戸田達史

    神経治療学(Web)   37 ( 6 )   2020年

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  • 遺伝性ニューロパチーの2つの新規遺伝子MMEとCOA7の同定

    樋口 雄二郎, 橋口 昭大, 袁 軍輝, 吉村 明子, 岡本 裕嗣, 松浦 英治, 矢部 勇, 上田 健博, 小出 隆司, 矢口 裕章, 三井 純, 石浦 浩之, 中川 正法, 森下 真一, 戸田 達史, 辻 省次, 高嶋 博

    臨床神経学   59 ( Suppl. )   S364 - S364   2019年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 見逃したくない治療可能な小脳性運動失調症 PEX10変異による小脳失調症

    山下 徹, 三井 純, 下澤 伸行, 高島 茂雄, 佐藤 恒太, 武本 麻美, 菱川 望, 太田 康之, 松川 敬志, 石浦 浩之, 吉村 淳, 土井 晃一郎, 森下 真一, 辻 省次, 阿部 康二

    臨床神経学   59 ( Suppl. )   S45 - S45   2019年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 遺伝性痙性対麻痺の新規原因遺伝子候補の抽出

    一瀬 佑太, 南 海天, 高 紀信, 田中 真生, 石浦 浩之, 三井 純, 下邨 華菜, 森本 昌史, 濱田 駿, 大塚 稔久, 辻 省次, 瀧山 嘉久

    臨床神経学   59 ( Suppl. )   S257 - S257   2019年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Neurodegeneration with brain iron accumulation(NBIA)様のMRI所見を呈したHuntington病の1例

    清水 崇宏, 松川 敬志, 阿部 有起, 須賀 裕樹, 富永 奈保美, 永井 真貴子, 飯塚 高浩, 石浦 浩之, 三井 純, 辻 省次, 花島 律子, 西山 和利

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   13回   106 - 106   2019年7月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

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  • 遺伝性筋疾患のクリニカルシークエンスにおいて2変異が検出された場合における変異のzygosity確認の意義

    佐藤 奈穂子, 石浦 浩之, 三井 純, 久保田 暁, 清水 潤, 森下 真一, 戸田 達史, 辻 省次

    日本遺伝カウンセリング学会誌   40 ( 2 )   92 - 92   2019年7月

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    記述言語:日本語   出版者・発行元:日本遺伝カウンセリング学会  

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  • 早期から幻覚、錐体路徴候を認めSNCA遺伝子のp.G51D変異を伴う家族性パーキンソン病の死亡時67歳女性剖検例

    宮崎 将行, 岡本 智子, 種井 善一, 佐野 輝典, 小松 奏子, 石浦 浩之, 三井 純, 辻 省次, 村山 繁雄, 長谷川 成人, 高橋 祐二, 齊藤 祐子

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   13回   105 - 105   2019年7月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

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  • Neurodegeneration with brain iron accumulation(NBIA)様のMRI所見を呈したHuntington病の1例

    清水 崇宏, 松川 敬志, 阿部 有起, 須賀 裕樹, 富永 奈保美, 永井 真貴子, 飯塚 高浩, 石浦 浩之, 三井 純, 辻 省次, 花島 律子, 西山 和利

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   13回   106 - 106   2019年7月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

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  • 診断と治療 良性成人型家族性ミオクローヌスてんかん(BAFME)の新知見

    石浦 浩之

    Epilepsy: てんかんの総合学術誌   13 ( 1 )   21 - 26   2019年5月

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    記述言語:日本語   出版者・発行元:(株)メディカルレビュー社  

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  • An autopsy case of late-onset slowly progressive spastic paraplegia with a large deletion mutation in KIAA0196

    Arakawa A, Kurihara M, Sano T, Morikawa T, Ikemura M, Ishiura H, Shimizu J, Murayama S, Saito Y, Toda T

    BRAIN PATHOLOGY   29   92 - 92   2019年2月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)  

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  • 神経内科疾患 筋萎縮性側索硬化症の遺伝子解析と臨床病型

    角元利行, 神崎真実, 上坂義和, 石浦浩之

    冲中記念成人病研究所年報   ( 45 )   2019年

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  • PLA2G6遺伝子変異は遺伝性痙性対麻痺を引き起こす

    高 紀信, 一瀬 佑太, 石浦 浩之, 三井 純, 高橋 純哉, 佐藤 和貴郎, 伊藤 義彰, 星野 恭子, 辻 省次, 瀧山 嘉久, JASPAC

    臨床神経学   58 ( Suppl. )   S292 - S292   2018年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 【リピート病の病態機構UPDATE-RNA毒性とRAN翻訳】新しいリピート病の同定と病態機序への考察 良性成人型家族性ミオクローヌスてんかんの原因の解明

    石浦 浩之

    医学のあゆみ   267 ( 11-12 )   809 - 813   2018年12月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

    これまで原因が明らかでなかった良性成人型家族性ミオクローヌスてんかん(BAFME)について遺伝学的解析を行い、わが国においてはほとんどの家系においてSAMD12のイントロン4にTTTCAおよびTTTTAリピート伸長変異が存在することを明らかにした。リピート伸長の長さはてんかんの発症年齢と逆相関した。患者剖検脳においてはTTTCAから転写されたUUUCAリピートからなるRNA凝集体(RNA foci)が検出された。2家系においては、SAMD12にリピート伸長変異を認めなかったが、それぞれTNRC6AとRAPGEF2のイントロンにやはりTTTCAおよびTTTTAリピート伸長変異を見出した。健常人においては、まれにTTTTAリピート伸長変異を認めるものの、TTTCAリピート伸長変異が見出されなかった。3遺伝子のイントロンに存在する同様のリピート伸長変異が同様の臨床病型を引き起こすことから、これらの遺伝子の機能そのものというより、TTTCAリピート伸長変異そのものがRNAを介して病態に関与しているという、てんかんにおけるあらたな病態機序を提唱した。(著者抄録)

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  • PLA2G6遺伝子変異は遺伝性痙性対麻痺を引き起こす

    高紀信, 一瀬佑太, 石浦浩之, 三井純, 三井純, 高橋純哉, 佐藤和貴郎, 伊藤義彰, 星野恭子, 辻省次, 辻省次, 瀧山嘉久

    日本神経学会学術大会プログラム・抄録集   59th ( Suppl. )   413 - S292   2018年12月

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  • HNRNPA1変異を有する家族性筋萎縮性側索硬化症の一家系

    武田勇人, 野原誠太郎, 石井亜紀子, 奥根祥, 遠坂直希, 三宅善嗣, 辻浩史, 冨所康志, 中馬越清隆, 石井一弘, 渡邊雅彦, 成瀬紘也, 石浦浩之, 三井純, 三井純, 後藤順, 辻省次, 玉岡晃

    日本神経学会学術大会プログラム・抄録集   59th ( Suppl. )   440 - S319   2018年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • HNRNPA1変異を有する家族性筋萎縮性側索硬化症の一家系

    武田 勇人, 野原 誠太郎, 石井 亜紀子, 奥根 祥, 遠坂 直希, 三宅 善嗣, 辻 浩史, 冨所 康志, 中馬越 清隆, 石井 一弘, 渡邊 雅彦, 成瀬 紘也, 石浦 浩之, 三井 純, 後藤 順, 辻 省次, 玉岡 晃

    臨床神経学   58 ( Suppl. )   S319 - S319   2018年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Japan Spastic Paraplegia Research Consortium 分かったこと、分からないこと

    高 紀信, 石浦 浩之, 一瀬 佑太, 田中 真生, 三井 純, 辻 省次, 瀧山 嘉久, JASPAC

    臨床神経学   58 ( Suppl. )   S76 - S76   2018年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 脳アミロイドアンギオパチーにおける皮質微小梗塞・白質病変の検討

    小林 敬, 栗原 正典, 神澤 彩, 織茂 賢太, 宮川 統爾, 石浦 浩之, 森 墾, 林 俊宏, 岩田 淳, 戸田 達史

    臨床神経学   58 ( Suppl. )   S451 - S451   2018年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • COA7は小脳失調を伴う軸索型ニューロパチーの新規原因遺伝子である

    樋口 雄二郎, 橋口 昭大, 袁 軍輝, 吉村 明子, 岡本 裕嗣, 松浦 英治, 上田 健博, 石浦 浩之, 三井 純, 戸田 達史, 辻 省次, 高嶋 博

    末梢神経   29 ( 2 )   308 - 308   2018年12月

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    記述言語:日本語   出版者・発行元:日本末梢神経学会  

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  • HSCT for adult-onset ALD: Background factors leading to early diagnosis of the brain involvement

    Matsukawa Takashi, Mitsui Jun, Ishiura Hiroyuki, Yamamoto Tomotaka, Hao Akihito, Matsukawa Miho, Tanaka Masaki, Chang Hyangri, Miyagawa Toji, Hamada Masashi, Takahashi Yuji, Hayashi Toshihiro, Iwata Atsushi, Shimizu Jun, Goto Jun, Toda Tatsushi, Tsuji Shoji

    臨床神経学   58 ( Suppl. )   S371 - S371   2018年12月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • 脳アミロイドアンギオパチーにおける皮質微小梗塞・白質病変の検討

    小林 敬, 栗原 正典, 神澤 彩, 織茂 賢太, 宮川 統爾, 石浦 浩之, 森 墾, 林 俊宏, 岩田 淳, 戸田 達史

    臨床神経学   58 ( Suppl. )   S451 - S451   2018年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 注目の遺伝子(第43回) SAMD12、TNRC6A、RAPGEF2

    石浦 浩之, 辻 省次

    分子精神医学   18 ( 4 )   247 - 249   2018年10月

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    記述言語:日本語   出版者・発行元:(株)先端医学社  

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  • 多数例のエクソーム解析データに基づいた新規アルツハイマー病関連遺伝子の同定

    田中 真生, 新見 淳, 石浦 浩之, 三井 純, 宮下 哲典, 桑野 良三, 池内 健, 辻 省次

    Dementia Japan   32 ( 3 )   449 - 449   2018年9月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • 良性成人型家族性ミオクローヌスてんかん(BAFME)における原因遺伝子のリピート数と神経生理学的所見の関係

    人見 健文, 音成 秀一郎, 小林 勝哉, 戸島 麻耶, 大井 和起, 下竹 昭寛, 松橋 眞生, 松本 理器, 神田 益太郎, 石浦 浩之, 辻 省次, 高橋 良輔, 池田 昭夫

    てんかん研究   36 ( 2 )   416 - 416   2018年9月

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    記述言語:日本語   出版者・発行元:(一社)日本てんかん学会  

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  • 【遺伝性痙性対麻痺の最前線】 [第2部]遺伝性痙性対麻痺の原因遺伝子

    石浦 浩之

    難病と在宅ケア   24 ( 5 )   6 - 9   2018年8月

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    記述言語:日本語   出版者・発行元:(株)日本プランニングセンター  

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  • ATP13A2遺伝子変異を認めた複合型遺伝性痙性対麻痺症例

    布村 仁一, 木村 珠喜, 高田 博仁, 小山 慶信, 今 清覚, 松永 宗雄, 瀧山 嘉久, 高 紀信, 石浦 浩之, 辻 省次

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   12回   117 - 117   2018年7月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

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  • 著明高TG血症の原因遺伝子 APOC2構造変異の探索

    高瀬 暁, 石浦 浩之, 田中 督記, 高梨 幹生, 蔵野 信, 岡崎 佐智子, 木村 武史, 飯塚 陽子, 岡島 史宜, 吉田 博, 原 眞純, 塚本 和久, 辻 省次, 門脇 孝, 岡崎 啓明

    日本動脈硬化学会総会プログラム・抄録集   50回   331 - 331   2018年6月

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    記述言語:日本語   出版者・発行元:(一社)日本動脈硬化学会  

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  • 著明高TG血症の原因遺伝子 APOC2構造変異の探索

    高瀬 暁, 石浦 浩之, 田中 督記, 高梨 幹生, 蔵野 信, 岡崎 佐智子, 木村 武史, 飯塚 陽子, 岡島 史宜, 吉田 博, 原 眞純, 塚本 和久, 辻 省次, 門脇 孝, 岡崎 啓明

    日本動脈硬化学会総会プログラム・抄録集   50回   331 - 331   2018年6月

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    記述言語:日本語   出版者・発行元:(一社)日本動脈硬化学会  

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  • 重症のインスリン抵抗性を引き起こすINSR変異の構造的基盤および遺伝型-表現型相関

    Hosoe Jun, Kadowaki Hiroko, Miya Fuyuki, Aizu Katsuya, Kawamura Tomoyuki, Miyata Ichiro, Satomura Kenichi, Ito Takeru, Hara Kazuo, Tanaka Masaki, Ishiura Hiroyuki, Tsuji Shoji, Suzuki Ken, Takakura Minaka, Boroevich Keith A., Tsunoda Tatsuhiko, Yamauchi Toshimasa, Shojima Nobuhiro, Kadowaki Takashi

    Diabetes : a journal of the American Diabetes Association   11 ( 3 )   23 - 33   2018年6月

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    記述言語:日本語   出版者・発行元:Blackwell Publishing  

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  • 家族性筋萎縮性側索硬化症の遺伝カウンセリング 他の難病をもつクライエントに対する一例

    張 香理, 佐藤 奈穂子, 石浦 浩之, 後藤 順, 南学 正臣, 戸田 達史, 辻 省次

    日本遺伝カウンセリング学会誌   39 ( 2 )   88 - 88   2018年5月

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    記述言語:日本語   出版者・発行元:日本遺伝カウンセリング学会  

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  • 自閉症状、多動、てんかん、痙性対麻痺及び感覚性ニューロパチーを呈し、KIF1A遺伝子に新規de novo変異を認めた18歳男性例

    栗原 正典, 坂内 太郎, 石浦 浩之, 林 俊宏, 清水 潤, 辻 省次, 戸田 達史

    臨床神経学   58 ( 4 )   251 - 251   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 著明高TG血症患者におけるhypoapoC-II構造変異

    高瀬 暁, 石浦 浩之, 田中 督記, 高梨 幹生, 蔵野 信, 岡崎 佐智子, 木村 武史, 李 騁騁, 飯塚 陽子, 岡島 史宜, 吉田 博, 澤野 文夫, 原 眞純, 大須賀 淳一, 島野 仁, 辻 省次, 石橋 俊, 門脇 孝, 岡崎 啓明

    糖尿病   61 ( Suppl.1 )   S - 313   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • 【ニューロジェネティクス新時代 次世代シークエンサーが拓く新しい世界】 筋疾患・神経疾患のジェネティクス 遺伝性痙性対麻痺

    石浦 浩之

    Clinical Neuroscience   36 ( 2 )   203 - 205   2018年2月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

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  • パーキンソン病の新規GBA変異の同定と患者由来リンパ芽球の機能解析

    鈴木康予, 近田彩香, 加藤君子, 山田憲一郎, 福士大輔, 石浦浩之, 出口一志, 三井純, 辻省次, 若松延昭

    日本分子生物学会年会プログラム・要旨集(Web)   41st   ROMBUNNO.2P‐0513 (WEB ONLY)   2018年

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    記述言語:日本語  

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  • 筋委縮性側索硬化症(ALS)の治療法を契機に遺伝子検査告知を希望した1例

    池川敦子, 西郷和真, 平野牧人, 木戸滋子, 青木由樹, 河合滋, 石浦浩之, 高橋祐二, 後藤純, 巽純子, 田村和朗, 辻省次, 楠進

    日本人類遺伝学会大会プログラム・抄録集   63rd   359   2018年

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  • 遺伝性筋疾患のクリニカルシークエンスにおける変異の解釈

    佐藤奈穂子, 石浦浩之, 三井純, 田中真生, 久保田暁, 清水潤, 森下真一, 戸田達史, 辻省次

    日本遺伝子診療学会大会プログラム・抄録集   25th   44   2018年

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    記述言語:日本語  

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  • 痙性対麻痺に対するITB療法の治療効果の検討

    一瀬 佑太, 高 紀信, 長坂 高村, 新藤 和雅, 石浦 浩之, 辻 省次, 瀧山 嘉久

    神経治療学   34 ( 6 )   S228 - S228   2017年11月

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    記述言語:日本語   出版者・発行元:日本神経治療学会  

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  • 前頭葉機能を中心とした認知機能障害とごく軽度の小脳性運動失調を認め、両側中小脳脚にMRI T2WI高信号を呈した76歳男性例

    瀬戸 瑛子, 鵜沼 敦, ムハッマド・アセム・アルマンスール, 石浦 浩之, 三井 純, 林 俊宏, 清水 潤, 辻 省次

    臨床神経学   57 ( 10 )   626 - 626   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 紀伊半島のALS/PDCに関する移住の研究(Immigration study on ALS/PDC of the Kii peninsula, Japan)

    小久保 康昌, 佐々木 良元, 森本 悟, 三室 マヤ, 石浦 浩之, 長谷川 成人, 吉田 眞理, 辻 省次, 葛原 茂樹

    Dementia Japan   31 ( 4 )   589 - 589   2017年10月

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    記述言語:英語   出版者・発行元:(一社)日本認知症学会  

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  • エクソーム解析データに基づく孤発性アルツハイマー病における疾患関連遺伝子の検討

    新見 淳, 田中 真生, 石浦 浩之, 三井 純, 宮下 哲典, 桑野 良三, 池内 健, 辻 省次

    Dementia Japan   31 ( 4 )   612 - 612   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • エクソーム解析データに基づくY染色体欠失の検出とアルツハイマー病との関連性の検討

    田中 真生, 石浦 浩之, 三井 純, 宮下 哲典, 桑野 良三, 池内 健, 辻 省次

    Dementia Japan   31 ( 4 )   612 - 612   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • 【一般臨床医に必要なてんかんの基礎知識とトピックス】 てんかんのトピックス 自己免疫性辺縁系脳炎

    松川 美穂, 石浦 浩之

    診断と治療   105 ( 7 )   918 - 922   2017年7月

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    記述言語:日本語   出版者・発行元:(株)診断と治療社  

    1 これまで原因不明とされていた辺縁系脳炎において、抗NMDA受容体抗体をはじめとした神経細胞表面抗原に対する自己抗体が関与していることが近年明らかとなった。2 自己免疫性辺縁系脳炎は、出現する自己抗体によって特異的な臨床的特徴を有しており、それぞれの特徴を理解することが重要である。3 神経細胞表面抗原に対する自己抗体による辺縁系脳炎は早期に治療を開始すれば症状が可逆的で予後良好な場合も多く、可能な限り早期に診断し治療を開始することが重要である。(著者抄録)

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    その他リンク: http://search.jamas.or.jp/link/ui/2017305637

  • 10代より意識消失発作を繰り返し、緩徐進行性の小脳性運動失調、複視、四肢筋力低下、認知機能低下を認めた53歳男性例

    井上 理美, 瀬戸 瑛子, 近田 彩香, 大友 岳, 田中 真生, 久保田 暁, 石浦 浩之, 林 俊宏, 清水 潤, 辻 省次, 村山 圭

    臨床神経学   57 ( 6 )   331 - 331   2017年6月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • C9orf72のGGGGCCリピートの異常伸長を認めた行動異型前頭側頭型認知症(byFTD)の一例

    渡邉 暁博, 荒畑 創, 成瀬 紘也, 井上 千尋, 三好 絢子, 河野 祐治, 笹ヶ迫 直一, 石浦 浩之, 辻 省次, 藤井 直樹

    臨床神経学   57 ( 6 )   317 - 317   2017年6月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Three-Year Follow-up of High-dose Ubiquinol Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous COQ2 Mutations

    J. Mitsui, K. Koguchi, T. Momose, M. Takahashi, T. Matsukawa, T. Yasuda, S-I. Tokushige, H. Ishiura, J. Goto, S. Nakazaki, T. Kondo, H. Ito, Y. Yamamoto, S. Tsuji

    MOVEMENT DISORDERS   32   2017年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY  

    Web of Science

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  • 外傷を契機に症状が顕在化した家族性筋萎縮性側索硬化症(SOD1L85F変異)の64歳男性例

    野原 誠太郎, 中馬越 清隆, 山口 哲人, 植松 洋, 成瀬 紘也, 石浦 浩之, 辻 省次, 玉岡 晃

    日本内科学会関東地方会   632回   39 - 39   2017年5月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • HSPD1遺伝子変異による遺伝性痙性対麻痺の一例

    中村 涼子, 松倉 幹, Chong Pin Fee, 吉良 龍太郎, 石浦 浩之, 辻 省次

    脳と発達   49 ( Suppl. )   S389 - S389   2017年5月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • 複雑型の臨床経過を示した純粋型遺伝性痙性対麻痺の遺伝子変異をもつ12歳女児例

    中村 涼子, 前田 謙一, 今城 透, 松倉 幹, チョン・ピンフィー, 石浦 浩之, 辻 省次, 吉良 龍太郎

    脳と発達   49 ( 3 )   215 - 215   2017年5月

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    記述言語:日本語   出版者・発行元:(一社)日本小児神経学会  

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  • 歯状核赤核・淡蒼球ルイ体萎縮症(DRPLA)と診断された女性と家族への支援 神経難病領域における認定遺伝カウンセラーの役割

    張 香理, 佐藤 奈穂子, 石浦 浩之, 岩田 淳, 後藤 順, 辻 省次

    日本遺伝カウンセリング学会誌   38 ( 2 )   147 - 147   2017年5月

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    記述言語:日本語   出版者・発行元:日本遺伝カウンセリング学会  

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  • 【最新遺伝医学研究と遺伝カウンセリング シリーズ2 最新精神・神経遺伝医学研究と遺伝カウンセリング】(第1章)総論 神経遺伝医学研究の歴史的背景と今後の課題

    辻 省次, 三井 純, 石浦 浩之

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    記述言語:日本語   出版者・発行元:(株)メディカルドゥ  

    遺伝性神経疾患の研究は先天代謝異常症の解析から始まり,連鎖解析とポジショナルクローニング法の確立,次世代シーケンサーの登場により大きく発展した。孤発性神経疾患の研究はゲノムワイド関連解析に基づく疾患感受性遺伝子の研究が精力的に行われてきている。疾患発症に対する影響度の大きい遺伝的要因の解明は困難を極めており,missing heritabilityとして研究上の大きな課題となっているが,common disease-multiple rare variant仮説に基づいた遺伝子探索が行われ,成果が得られはじめている。臨床遺伝学の観点からは,孤発性疾患であっても家族集積性が観察される疾患は数多く知られており,遺伝学の観点を重視した研究パラダイムが重要である。(著者抄録)

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  • 精神遅滞及び成人期発症の小脳性運動失調・体幹ミオクローヌスを呈し、KCND3遺伝子にde novo変異を認めた30歳男性例

    栗原 正典, 佐々木 拓也, 石浦 浩之, 大塚 十里, 林 俊宏, 清水 潤, 金子 淳太郎, 辻 省次

    臨床神経学   57 ( 4 )   193 - 193   2017年4月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 【最新遺伝医学研究と遺伝カウンセリング シリーズ2 最新精神・神経遺伝医学研究と遺伝カウンセリング】 (第1章)総論 次世代シーケンサー、次々世代シーケンサーとクリニカルシーケンシング

    石浦 浩之

    遺伝子医学MOOK   別冊 ( 最新精神・神経遺伝医学研究と遺伝カウンセリング )   45 - 50   2017年4月

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    記述言語:日本語   出版者・発行元:(株)メディカルドゥ  

    次世代シーケンサーの登場により全例のない規模でのシーケンシングが可能になり,エクソーム解析,全ゲノム配列解析も実用化の段階となっている。今後,いかに医療に応用していくかが課題となっている。次々世代シーケンサーと呼ばれる新規の手法も複数出現しており,今後の発展が期待される。これらの技術によりゲノム研究・ゲノム医療が発展していくことは間違いないが,それに伴った特有の問題も浮上しており,広く議論していくことが肝要である。(著者抄録)

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  • 同胞4症例に若年性認知症を認め、2症例にC9orf72遺伝子に6塩基反復配列の延長を認めた一家系

    井上 千尋, 渡邉 暁博, 成瀬 紘也, 石浦 浩之, 辻 省次

    臨床神経学   57 ( 3 )   137 - 137   2017年3月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • C9orf72のGGGGCCリピートの異常伸長を認めた行動異型前頭側頭型認知症(bvFTD)の一例

    渡邉暁博, 荒畑創, 成瀬紘也, 井上千尋, 三好絢子, 河野祐治, 笹ケ迫直一, 石浦浩之, 辻省次, 藤井直樹

    臨床神経学(Web)   57 ( 6 )   2017年

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  • 同胞4症例に若年性認知症を認め,2症例にC9orf72遺伝子に6塩基反復配列の延長を認めた一家系

    井上千尋, 渡邉暁博, 成瀬紘也, 石浦浩之, 辻省次

    臨床神経学(Web)   57 ( 3 )   2017年

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  • Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial 査読

    Abe, K., Aoki, M., Tsuji, S., Itoyama, Y., Sobue, G., Togo, M., Hamada, C., Tanaka, M., Akimoto, M., Nakamura, K., Takahashi, F., Kondo, K., Yoshino, H., Abe, K., Aoki, M., Tsuji, S., Itoyama, Y., Sobue, G., Togo, M., Hamada, C., Sasaki, H., Yabe, I., Doi, S., Warita, H., Imai, T., Ito, H., Fukuchi, M., Osumi, E., Wada, M., Nakano, I., Morita, M., Ogata, K., Maruki, Y., Ito, K., Kano, O., Yamazaki, M., Takahashi, Y., Ishiura, H., Ogino, M., Koike, R., Ishida, C., Uchiyama, T., Mizoguchi, K., Obi, T., Watanabe, H., Atsuta, N., Aiba, I., Taniguchi, A., Sawada, H., Hazama, T., Fujimura, H., Kusaka, H., Kunieda, T., Kikuchi, H., Matsuo, H., Ueyama, H., Uekawa, K., Tanaka, M., Akimoto, M., Ueda, M., Murakami, A., Sumii, R., Kudou, T., Nakamura, K., Morimoto, K., Yoneoka, T., Hirai, M., Sasaki, K., Terai, H., Natori, T., Matsui, H., Kotani, K., Yoshida, K., Iwasaki, T., Takahashi, F., Kondo, K., Yoshino, H.

    The Lancet Neurology   16 ( 7 )   505-512   2017年

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  • Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis 査読

    Abe, K., Aoki, M., Tsuji, S., Itoyama, Y., Sobue, G., Togo, M., Hamada, C., Sasaki, H., Yabe, I., Doi, S., Warita, H., Imai, T., Ito, H., Fukuchi, M., Osumi, E., Wada, M., Nakanoy, I., Morita, M., Ogata, K., Maruki, Y., Ito, K., Kano, O., Yamazaki, M., Takahashi, Y., Ishiura, H., Ogino, M., Koike, R., Ishida, C., Uchiyama, T., Mizoguchi, K., Obi, T., Watanabe, H., Atsuta, N., Aiba, I., Taniguchi, A., Sawada, H., Hazama, T., Fujimura, H., Kusaka, H., Kunieda, T., Kikuchi, H., Matsuo, H., Ueyama, H., Uekawa, K., Tanaka, M., Akimoto, M., Nakamura, K., Ueda, M., Kotani, K., Matsui, H., Yoneoka, T., Morimoto, K., Sasaki, K., Hirai, M., Murakami, A., Natori, T., Sumii, R., Terai, H., Kudou, T., Takahashi, F., Iwasaki, T., Kondo, K., Yoshino, H.

    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration   18   55-63   2017年

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  • A novel missense mutation in valosin-containing protein gene identified in a Japanese family with a pure form of hereditary spastic paraplegia. 査読

    Kakumoto, T, Kodama, S, Ishiura, H, Mitsui, J, Hayashi, T, Shimizu, J, Morishita, S, Tsuji, S

    XXIII World Congress of Neurology (WCN 2017)   2017年

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  • 運動失調症の医療基盤に関する調査研究 運動失調症の遺伝子学的研究および臨床的解析

    高嶋博, 崎山佑介, 樋口雄二郎, 安藤匡宏, 橋口昭大, 袁軍輝, 石原聡, 田邊肇, 吉村明子, 西郷隆二, 平松有, 田代雄一, 中村友紀, 岡本裕嗣, 石浦浩之, 三井純, 辻省次

    運動失調症の医療基盤に関する調査研究班 平成26-28年度 総合研究報告書(Web)   36‐41 (WEB ONLY)   2017年

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    記述言語:日本語  

    J-GLOBAL

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  • 運動失調症の医療基盤に関する調査研究 脊髄小脳失調症6型(SCA6),同34型(SCA34),同36型(SCA36)の診断基準,疾患頻度,重症度判定についての研究

    石川欽也, 大林正人, 佐藤望, 尾崎心, 曽我一將, 土井宏, 三井純, 飯國洋一郎, 馬嶋貴正, 山根清美, 入岡隆, 石浦浩之, 土井晃一郎, 森下真一, 東美和, 関口輝彦, 小山主夫, 上田直久, 三浦義治, 宮武聡子, 松本直通, 田中章景, 辻省次, 水澤英洋, 水澤英洋, 古屋徳郎, 飯田忠恒, 飯田忠恒, 山田哲夫, 山田哲夫, 安藤登, 太田浄文, 岡田(菅野)宏美, 岡田(菅野, 宏美, 田中伸哉, 新宅雅幸, 江石義信, 横田隆徳

    運動失調症の医療基盤に関する調査研究班 平成26-28年度 総合研究報告書(Web)   11‐17 (WEB ONLY)   2017年

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    記述言語:日本語  

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  • DNMT1 p.Y495H mutation is frequently associated with cerebellar ataxia compared with p.Y495C mutation. 査読

    Kanda, J, Nagashima, Y, Ishiura, H, Hayashi, T, Shimizu, J, Goto, J, Kanbayashi, T, Kira, J, Tsuji, S

    XXIII World Congress of Neurology (WCN 2017)   2017年

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  • Genetic anticipation and clinical features of 32 patients with benign adult familial myoclonic epilepsy (BAFME). 査読

    Matsukawa, M, Ishiura, H, Ichikawa, Y, Higashihara, M, Sakiyama, Y, Otsuka, M, Ueki, A, Kaida, K, Tanaka, M, Takahashi, Y, Mitsui, J, Matsukawa, T, Hanajima, R, Hayashi, T, Terao, Y, Inomata-Terada, S, Hamada, M, Shirota, Y, Kubota, A, Tsuji, S

    XXIII World Congress of Neurology (WCN 2017)   2017年

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  • Diagnostic role of aerobic exercise tests on cycle ergometry in clinical settings. 査読

    Kurihara, M, Sugiyama, Y, Tanaka, M, Ishiura, H, Kubota, A, Hayashi, T, Shimizu, J, Tsuji, S

    XXIII World Congress of Neurology (WCN 2017)   2017年

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  • ライソゾーム病・ペルオキシソーム病の調査研究 緩徐な経過を辿る成人例におけるエキソーム解析によるD‐二頭酵素欠損症の診断

    辻省次, 松川敬志, 三井純, 石浦浩之, 吉村淳, 土井晃一郎, 森下真一

    ライソゾーム病(ファブリ病含む)に関する調査研究 平成28年度 総括・分担研究年度終了報告書(Web)   68‐69 (WEB ONLY)   2017年

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    記述言語:日本語  

    J-GLOBAL

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  • ELOVL4における新規変異の同定とSCA34の臨床的スペクトラムの拡張

    尾崎 心, 土井 宏, 三井 純, 佐藤 望, 山根 清美, 入岡 隆, 石浦 浩之, 土井 晃一郎, 森下 真一, 小山 主夫, 三浦 義治, 松本 直通, 横田 隆徳, 田中 章景, 辻 省次, 水澤 英洋, 石川 欽也

    臨床神経学   56 ( Suppl. )   S81 - S81   2016年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 成人型Krabbe病の病初期における画像および電気生理学的所見についての検討

    光武 明彦, 平 賢一郎, 徳重 真一, 上田 順子, 松川 敬志, 石浦 浩之, 岩田 淳, 寺尾 安生, 清水 潤, 酒井 規夫, 辻 省次

    臨床神経学   56 ( Suppl. )   S494 - S494   2016年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 次世代シークエンサーを用いたミトコンドリア病の原因遺伝子の同定

    岡本 裕嗣, 吉村 明子, 平松 有, 袁 軍輝, 安藤 匡宏, 樋口 雄二郎, 橋口 昭大, 石浦 浩之, 三井 純, 辻 省次, 高嶋 博

    臨床神経学   56 ( Suppl. )   S497 - S497   2016年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 高血糖に伴う部分痙攣発作を来し、大脳白質にMRI T2WI低信号域を認めた59歳男性例

    角元 利行, 小玉 聡, 石浦 浩之, 間野 達雄, 林 俊宏, 辻 省次

    日本内科学会関東地方会   629回   58 - 58   2016年12月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 本邦における特発性基底核石灰化症(IBGC)の臨床的・遺伝学的検討(第2報)

    山田 恵, 田中 真生, 金子 雅幸, 二宮 勇平, 栗田 尚佳, 位田 雅俊, 林 祐一, 石浦 浩之, 三井 純, 岩田 淳, 犬塚 貴, 辻 省次, 保住 功

    臨床神経学   56 ( Suppl. )   S287 - S287   2016年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 先天性ミオパチー家系における臨床・分子遺伝学的検討

    佐藤 奈穂子, 石浦 浩之, 三井 純, 杉山 雄亮, 田中 真生, 清水 潤, 森下 真一, 後藤 順, 辻 省次

    臨床神経学   56 ( Suppl. )   S423 - S423   2016年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 我が国の常染色体劣性シャルコー・マリー・トゥース病(AR-CMT)

    橋口 昭大, 吉村 明子, 樋口 雄二郎, 中村 友紀, 岡本 裕嗣, 松浦 英治, 高嶋 博, 三井 純, 石浦 浩之, 辻 省次

    臨床神経学   56 ( Suppl. )   S463 - S463   2016年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • ゲノム情報の臨床活用に向けたゲノム変異とその意味情報の効率的な管理手法の提案

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    医療情報学連合大会論文集   36回 ( 2 )   934 - 935   2016年11月

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    川崎 怜子, 清田 正紘, 柴田 頌太, 新見 淳, 羽尾 曉人, 間野 達雄, 石浦 浩之, 林 俊宏, 辻 省次

    日本内科学会関東地方会   628回   42 - 42   2016年11月

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  • Hematopoietic Stem Cell Transplantation for Adolescent/Adult Cerebral and Olivo-Ponto-Cerebellar Adrenoleukodystrophy

    Takashi Matsukawa, Tomotaka Yamamoto, Takashi Toya, Akihito Shinohara, Yasuhito Nanya, Sachiko Seo, Keiki Kumano, Motoshi Ichikawa, Yuji Takahashi, Hiroyuki Ishiura, Jun Mitsui, Masaki Tanaka, Mineo Kurokawa, Shoji Tsuji

    ANNALS OF NEUROLOGY   80   S201 - S201   2016年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

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    石浦 浩之

    難病と在宅ケア   22 ( 4 )   23 - 26   2016年7月

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    記述言語:日本語   出版者・発行元:(株)日本プランニングセンター  

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    松川 敬志, 石浦 浩之, 三井 純, 辻 省次

    分子精神医学   16 ( 3 )   146 - 152   2016年7月

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    記述言語:日本語   出版者・発行元:(株)先端医学社  

    次世代シークエンサーを用いた解析技術は近年目覚ましい発達を遂げており、エクソーム解析、全ゲノムシークエンス、RNAシークエンスなどさまざまな解析に利用されている。現在広く用いられているエクソーム解析では、これまで多くの労力を要した白質脳症など既知の病因遺伝子が膨大で解析が難しい遺伝性疾患の網羅的な遺伝子変異解析にも非常に有用であり、エクソーム解析を用いてさまざまな病因遺伝子変異同定がなされている。ここでは次世代シークエンサーを用いた解析手法、それぞれのシークエンサーの特徴、原理などについて解説する。(著者抄録)

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    光武明彦, 平賢一郎, 上田順子, 松川敬志, 石浦浩之, 岩田淳, 辻省次, 酒井規夫

    臨床神経学(Web)   56 ( 7 )   512(J‐STAGE) - 512   2016年7月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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    高瀬 暁, 石浦 浩之, 蔵野 信, 高梨 幹生, 岡崎 佐智子, 飯塚 陽子, 吉田 博, 澤野 文夫, 原 眞純, 塚本 和久, 大須賀 淳一, 辻 省次, 石橋 俊, 門脇 孝, 岡崎 啓明

    日本動脈硬化学会総会プログラム・抄録集   48回   235 - 235   2016年6月

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    石浦 浩之

    神経内科   84 ( 6 )   585 - 589   2016年6月

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    高瀬暁, 石浦浩之, 蔵野信, 三井純, 高梨幹生, 平美乃, 久保田みどり, 岡崎佐智子, 飯塚陽子, 吉田博, 多田紀夫, 澤野文夫, 原眞純, 大須賀淳一, 島野仁, 辻省次, 石橋俊, 門脇孝, 岡崎啓明

    糖尿病(Web)   59 ( Suppl )   S.465(J‐STAGE) - 465   2016年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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    高瀬 暁, 石浦 浩之, 蔵野 信, 三井 純, 高梨 幹生, 平 美乃, 久保田 みどり, 岡崎 佐智子, 飯塚 陽子, 吉田 博, 多田 紀夫, 澤野 文夫, 原 眞純, 大須賀 淳一, 島野 仁, 辻 省次, 石橋 俊, 門脇 孝, 岡崎 啓明

    糖尿病   59 ( Suppl.1 )   S - 465   2016年4月

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    高次脳機能研究   36 ( 1 )   80 - 80   2016年3月

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    樋口 雄二郎, 橋口 昭大, 袁 軍輝, 石原 聡, 田邊 肇, 吉村 明子, 中村 友紀, 岡本 裕嗣, 石浦 浩之, 三井 純, 辻 省次, 高嶋 博

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    石原 聡, 田邊 肇, 吉村 明子, 樋口 雄二郎, 袁 軍輝, 橋口 昭大, 岡本 裕嗣, 石浦 浩之, 三井 純, 辻 省次, 高嶋 博

    臨床神経学   55 ( Suppl. )   S384 - S384   2015年12月

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    波多野 敬子, 伊達 英俊, 石浦 浩之, 三井 純, 後藤 順, 吉村 淳, 土井 晃一郎, 森下 真一, 辻 省次

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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    野妻 智嗣, 松浦 英治, 久保田 龍二, 児玉 大介, 松崎 敏男, 渡邊 修, 三井 純, 石浦 浩之, 山野 嘉久, 辻 省次, 出雲 周二, 高嶋 博

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    田邊 肇, 吉村 明子, 石原 聡, 樋口 雄二郎, 袁 軍輝, 橋口 昭大, 岡本 裕嗣, 石浦 浩之, 三井 純, 辻 省次, 高嶋 博

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    一瀬 佑太, 田中 真生, 三井 純, 山城 亘央, 新藤 和雅, 石浦 浩之, 後藤 順, 吉村 淳, 土井 晃一郎, 森下 真一, 瀧山 嘉久, 辻 省次

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    松川 敬志, 三井 純, 石浦 浩之, 辻 省次

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    石浦 浩之

    神経内科   82 ( 4 )   382 - 387   2015年4月

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    臨床神経学   54 ( Suppl. )   S47 - S47   2014年12月

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  • 常染色体劣性遺伝が疑われた遺伝性痙性対麻痺104例の遺伝子解析

    石浦 浩之, 高 紀信, 嶋崎 晴雄, 三井 純, 高橋 祐二, 後藤 順, 吉村 淳, 土井 晃一郎, 森下 真一, 新井 憲俊, 三方 崇嗣, 佐藤 裕康, 高嶋 博, 佐々木 彰一, 佐々木 秀直, 瀧山 嘉久, 辻 省次

    臨床神経学   54 ( Suppl. )   S47 - S47   2014年12月

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  • 思春期/成人大脳型副腎白質ジストロフィーに対する造血幹細胞移植の臨床的効果の検討

    松川 敬志, 山本 知孝, 篠原 明仁, 市川 幹, 高橋 祐二, 石浦 浩之, 三井 純, 田中 真生, 後藤 順, 黒川 峰夫, 辻 省次

    臨床神経学   54 ( Suppl. )   S52 - S52   2014年12月

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  • 本邦における特発性大脳基底核石灰化症の臨床的・遺伝学的検討

    山田 恵, 田中 真生, 高木 麻里, 小林 清樹, 田口 芳治, 高嶋 修太郎, 田中 耕太郎, 峠 哲男, 初田 裕幸, 村山 繁雄, 林 祐一, 金子 雅幸, 石浦 浩之, 三井 純, 熱田 直樹, 祖父江 元, 下澤 伸行, 犬塚 貴, 辻 省次, 保住 功

    臨床神経学   54 ( Suppl. )   S66 - S66   2014年12月

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  • Charcot-Marie-Tooth病におけるミエリン関連蛋白由来の新規原因遺伝子の探索

    田邊 肇, 石原 聡, 吉村 明子, 樋口 雄二郎, 袁 軍輝, 橋口 昭大, 岡本 裕嗣, 石浦 浩之, 三井 純, 辻 省次, 高嶋 博

    臨床神経学   54 ( Suppl. )   S266 - S266   2014年12月

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  • 複合Pick球を伴うFUS陽性FTLD-ALSの臨床病理学的検討

    中元 ふみ子, 高尾 昌樹, 林 俊宏, 石浦 浩之, 高橋 祐二, 辻 省次, 村山 繁雄

    臨床神経学   54 ( Suppl. )   S70 - S70   2014年12月

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  • 筋萎縮性側索硬化症の新規原因遺伝子ERBB4(ALS19)の同定

    高橋 祐二, 福田 陽子, 豊田 敦, 日笠 幸一郎, 吉村 淳, Kari Kurppa, 森豊 浩代子, Belzil Veronique V., 石浦 浩之, 三井 純, 祖父江 元, 西澤 正豊, 野元 正弘, Elenius Klaus, Rouleau Guy A., 藤山 秋佐夫, 森下 真一, 後藤 順, 辻 省次, Japanese Consortium for Amyotrophic Lateral Sclerosis Research

    臨床神経学   54 ( Suppl. )   S69 - S69   2014年12月

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  • 抗MuSK抗体陽性重症筋無力症の臨床的検討

    佐藤 奈穂子, 永迫 友規, 中元 ふみ子, 石浦 浩之, 清水 潤, 山本 知孝, 寺尾 安生, 辻 省次

    臨床神経学   54 ( Suppl. )   S108 - S108   2014年12月

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  • エクソーム解析によるHAM疾患感受性遺伝子の探索

    野妻 智嗣, 松浦 英治, 久保田 龍二, 児玉 大介, 松崎 敏男, 渡邊 修, 三井 純, 石浦 浩之, 高橋 祐二, 山野 嘉久, 森下 真一, 辻 省次, 出雲 周二, 高嶋 博

    臨床神経学   54 ( Suppl. )   S153 - S153   2014年12月

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  • Charcot-Marie-Tooth病におけるニューロフィラメント関連の新規原因遺伝子同定の試み

    石原 聡, 田邊 肇, 吉村 明子, 樋口 雄二郎, 袁 軍輝, 橋口 昭大, 岡本 裕嗣, 石浦 浩之, 三井 純, 辻 省次, 高嶋 博

    臨床神経学   54 ( Suppl. )   S266 - S266   2014年12月

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  • 【CT・MRI"戦略的"活用ガイド】 各科に直撃! よくある紹介疾患,紹介前にあるといい検査,紹介後にする検査 神経内科

    石浦 浩之

    Medicina   51 ( 11 )   319 - 324   2014年11月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

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  • 発作性四肢脱力を伴う片頭痛症例を有する片頭痛家系の病因遺伝子変異解析

    松川 敬志, 三井 純, 石浦 浩之, 高橋 祐二, 吉村 淳, 土井 晃一郎, 後藤 順, 森下 真一, 坂井 文彦, 辻 省次

    日本頭痛学会誌   41 ( 2 )   258 - 258   2014年11月

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  • 次世代シークエンサーを用いたHAM疾患感受性遺伝子の探索

    野妻 智嗣, 松浦 英治, 久保田 龍二, 児玉 大介, 松崎 敏男, 渡邊 修, 三井 純, 石浦 浩之, 高橋 祐二, 山野 嘉久, 森下 真一, 辻 省次, 出雲 周二, 高嶋 博

    NEUROINFECTION   19 ( 2 )   204 - 204   2014年8月

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  • KIAA0196遺伝子に新規ミスセンス変異を認めたSPG8の52歳男性例

    一瀬 佑太, 高 紀信, 福元 恵, 小林 史和, 三輪 道然, 石浦 浩之, 辻 省次, 瀧山 嘉久

    臨床神経学   54 ( 8 )   694 - 694   2014年8月

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  • 全ゲノム解析を用いたapoC-II低下症の原因遺伝子の探索

    高瀬 暁, 石浦 浩之, 三井 純, 藤田 逸人, 原 一雄, 高梨 幹生, 飯塚 陽子, 吉田 博, 大須賀 淳一, 石橋 俊, 辻 省次, 門脇 孝, 岡崎 啓明

    日本動脈硬化学会総会プログラム・抄録集   46回   256 - 256   2014年6月

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    記述言語:日本語   出版者・発行元:(一社)日本動脈硬化学会  

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  • 【次世代シーケンサーを用いた神経疾患のゲノム診断】 次世代シーケンサーによるゲノム解析

    石浦 浩之

    神経内科   80 ( 6 )   677 - 681   2014年6月

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  • ネブリン遺伝子の変異を認めたネマリンミオパチーの36歳女性例

    羽尾 暁人, 徳重 真一, 石浦 浩之, 三井 純, 寺尾 安生, 清水 潤, 後藤 順, 辻 省次

    臨床神経学   54 ( 5 )   458 - 458   2014年5月

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  • whole genome sequence解析を用いたapoC-II低下症の原因遺伝子変異同定の試み

    高瀬 暁, 石浦 浩之, 三井 純, 藤田 逸人, 原 一雄, 関谷 元博, 五十嵐 正樹, 高梨 幹生, 泉田 欣彦, 久保田 みどり, 升田 紫, 平 美乃, 岡崎 佐智子, 飯塚 陽子, 矢作 直也, 大橋 健, 吉田 博, 柳内 秀勝, 多田 紀夫, 後藤田 貴也, 大須賀 淳一, 石橋 俊, 辻 省次, 門脇 孝, 岡崎 啓明

    糖尿病   57 ( Suppl.1 )   S - 418   2014年4月

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  • 【神経症候群(第2版)-その他の神経疾患を含めて-】 変性疾患 脊髄小脳変性症 遺伝性痙性対麻痺 遺伝性痙性対麻痺の分子遺伝学と遺伝子診断

    石浦 浩之

    日本臨床   別冊 ( 神経症候群II )   427 - 432   2014年3月

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    記述言語:日本語   出版者・発行元:(株)日本臨床社  

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  • 【神経症候群(第2版)-その他の神経疾患を含めて-】 脱髄性疾患、遺伝性ニューロパチー 遺伝性ニューロパチー 近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)

    石浦 浩之

    日本臨床   別冊 ( 神経症候群II )   896 - 899   2014年3月

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    記述言語:日本語   出版者・発行元:(株)日本臨床社  

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  • Basic Neuroscience 生化学・分子生物学 近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)の分子病態

    石浦 浩之

    Annual Review神経   2014   37 - 42   2014年1月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

    本邦で多く報告されている,近位筋優位遺伝性運動感覚ニューロパチー(hereditary motor and sensory neuropathy with proximal dominant involvement:HMSN-P)は常染色体優性の近位筋優位の筋萎縮と筋力低下を特徴とする神経変性疾患である.次世代シーケンサーを用いた研究により,その原因遺伝子がTFGであることが明らかとなった.HMSN-P剖検例において,前角細胞を始めとした神経細胞においてTFGの細胞質内における異常凝集が認められた.TDP-43の細胞質内への凝集も認められ,培養細胞において変異TFGがTDP-43の局在を変化させること,TFGが細胞内で小胞輸送に関わることが報告され,TDP-43を介した運動神経変性のメカニズムがあるものと考えられた.HMSN-P研究により小胞輸送の障害と運動神経変性の関係に関する新たな知見が得られ,今後の研究の進展とともに,今後の治療のターゲットという意味でも非常に興味深い.(著者抄録)

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  • 神経内科学 HMSN(運動感覚ニューロパチー)の新規遺伝子同定

    石浦 浩之

    医学のあゆみ   248 ( 4 )   285 - 286   2014年1月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

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  • ニューロフィラメントに関連したCharcot‐Marie‐Tooth病の新規原因遺伝子同定の試み

    石原聡, 田邊肇, 吉村明子, 樋口雄二郎, 袁軍輝, 橋口昭大, 岡本裕嗣, 吉村淳, 土井晃一郎, 森下真一, 石浦浩之, 三井純, 辻省次, 高嶋博

    日本遺伝子診療学会大会プログラム・抄録集   21st   331   2014年

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  • 次世代シークエンサーによるHAM疾患感受性遺伝子の探索

    野妻智嗣, 松浦英治, 久保田龍二, 児玉大介, 松崎敏男, 渡邊修, 三井純, 石浦浩之, 高橋祐二, 山野嘉久, 森下真一, 辻省次, 出雲周二, 高嶋博

    日本HTLV‐1学会学術集会   1st   34   2014年

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  • パーキンソニズムを主徴とする遺伝性プリオン病:P105L

    輿かがり, 松川敬志, 三井純, 石浦浩之, 高橋祐二, 市川弥生子, 長島優, 寺尾安生, 清水潤, 濱田雅, 吉村淳, 土井晃一郎, 森下真一, 後藤順, 辻省次

    プリオン病のサーベイランスと感染予防に関する調査研究 平成25年度 総括・分担研究報告書   122   2014年

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  • 神経変性疾患に関する調査研究 筋萎縮性側索硬化症の新規病因遺伝子ERBB4(ALS19)の同定

    辻省次, 高橋祐二, 石浦浩之, 三井純, 後藤順

    神経変性疾患に関する調査研究 平成25年度 総括・分担研究報告書   167 - 168   2014年

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  • 三重県南部に多発する家族性認知症‐パーキンソン症候群 発症因子の探索と治療介入研究 紀伊筋萎縮性側索硬化症・パーキンソニズム認知症複合(ALS/PDC)の疾患遺伝子の探索

    辻省次, 石浦浩之, 三井純, AHSAN Budrul, 福田陽子, 後藤順, 小久保康昌, 葛原茂樹, 日笠幸一郎, 吉村淳, 土井晃一郎, 森下真一, 原賢寿, 西澤正豊, 豊田敦, 藤山秋佐夫

    三重県南部に多発する家族性認知症-パーキンソン症候群発症因子の探索と治療介入研究 平成25年度 総括・分担研究報告書   46 - 48   2014年

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  • Charcot‐Marie‐Tooth病におけるミエリン関連蛋白を中心とした新規遺伝子探索の試み

    田邊肇, 吉村明子, 石原聡, 野妻智嗣, 樋口雄二郎, 袁軍輝, 橋口昭大, 岡本裕嗣, 吉村淳, 土井晃一郎, 森下真一, 石浦浩之, 三井純, 辻省次, 高嶋博

    日本遺伝子診療学会大会プログラム・抄録集   21st   330   2014年

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  • 運動失調症の病態解明と治療法開発に関する研究 常染色体劣性遺伝が疑われた遺伝性痙性対麻痺88例のexome解析

    辻省次, 石浦浩之, 高紀信, 嶋崎晴雄, 三井純, 高橋祐二, 後藤順, 吉村淳, 土井晃一郎, 森下真一, 佐々木秀直, 瀧山嘉久

    運動失調症の病態解明と治療法開発に関する研究 平成25年度 総括・分担研究報告書   83 - 86   2014年

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  • 特発性両側性脳内石灰化症(ファール病を含む)のiPS細胞を活用した診断と治療法の確立 ファール病及び関連疾患における原因遺伝子の探索

    辻省次, 田中真生, 三井純, 石浦浩之, 初田裕幸, 村山繁雄

    特発性両側性脳内石灰化症(ファール病を含む)のiPS細胞を活用した診断と治療法の確立 平成25年度 総括・分担研究報告書   13 - 14   2014年

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  • 運動失調症の病態解明と治療法開発に関する研究 常染色体劣性遺伝性痙性対麻痺の新規原因遺伝子探索

    嶋崎晴雄, 本多純子, 直井為任, 滑川道人, 松浦徹, 石浦浩之, 三井純, 後藤順, 辻省次, 吉村淳, 土井晃一郎, 森下真一, 瀧山嘉久

    運動失調症の病態解明と治療法開発に関する研究 平成25年度 総括・分担研究報告書   78 - 82   2014年

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  • 遺伝性痙性対麻痺の最新情報 HSPの分子遺伝学と遺伝子診断

    石浦 浩之

    臨床神経学   54 ( 12 )   1016 - 1017   2014年

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

    遺伝性痙性対麻痺は下肢の痙性を主徴とする多様な神経変性疾患である。常染色体優性遺伝症例ではSPG4の頻度が多く、その他の病型を合わせ約60%の症例で変異が同定される。常染色体劣性遺伝症例では従来診断にいたる例は多くなかったが、次世代シーケンサーの登場により変異の同定率は4割を超える程に上昇した。一方、X染色体連鎖遺伝症例やミトコンドリア症例はまれである。非常に多くの遺伝子が一度に解析できる時代ではあるが、遺伝子診断を考える上で、家族歴と臨床型を鑑み、頻度の高い方から検討をおこなう鉄則には変化はない。遺伝子未同定家系、孤発例の遺伝学的基盤の解明は今後の大きな課題である。(著者抄録)

    DOI: 10.5692/clinicalneurol.54.1016

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  • 神経変性疾患に関する調査研究 パーキンソニズムを主症状とした遺伝性プリオン病(P105L)4家系の臨床及び分子遺伝学的研究

    辻省次, 輿かがり, 松川敬志, 三井純, 石浦浩之, 高橋祐二, 市川弥生子, 長島優, 寺尾安生, 清水潤, 濱田雅, 吉村淳, 土井晃一郎, 森下真一, 後藤順

    神経変性疾患に関する調査研究 平成25年度 総括・分担研究報告書   119 - 120   2014年

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    佐藤奈穂子, 石浦浩之, 三井純, 成瀬紘也, 前川理沙, 楯玄秀, 清水潤, 後藤順, 椎尾康, 辻省次

    日本遺伝子診療学会大会プログラム・抄録集   21st   267   2014年

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  • 筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 遺伝性筋ジストロフィー/ミオパチーの病因遺伝子の解明および病態機序の解明

    清水潤, 三井純, 石浦浩之, 福田陽子, 久保田暁, 後藤順, 辻省次

    筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 平成23-25年度 総括研究報告書   55 - 56   2014年

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  • エクソーム解析を用いたHAM疾患感受性遺伝子の探索

    野妻智嗣, 松浦英治, 久保田龍二, 児玉大介, 松崎敏男, 渡邊修, 三井純, 石浦浩之, 吉村淳, 土井晃一郎, 山野嘉久, 森下真一, 辻省次, 出雲周二, 高嶋博

    日本遺伝子診療学会大会プログラム・抄録集   21st   329   2014年

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  • Exome解析を用いた家族性ALSの分子疫学の解明

    成瀬紘也, 石浦浩之, 三井純, 高橋祐二, 吉村淳, 土井晃一郎, 森下真一, 後藤順, 辻省次

    日本遺伝子診療学会大会プログラム・抄録集   21st   331   2014年

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  • 常染色体劣性遺伝形式を示すspastic ataxiaの病因遺伝子の探索

    大崎雅央, 高橋祐二, 石浦浩之, 三井純, 松川敬志, 吉村淳, 土井晃一郎, 森下真一, 後藤順, 辻省次

    日本遺伝子診療学会大会プログラム・抄録集   21st   274   2014年

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  • 運動失調症の病態解明と治療法開発に関する研究 多系統萎縮症の疾患関連遺伝子の探索

    辻省次, 三井純, 松川敬志, 石浦浩之, 市川弥生子, AHSAN Budrul, 吉村淳, 土井晃一郎, 後藤順, 森下真一

    運動失調症の病態解明と治療法開発に関する研究 平成25年度 総括・分担研究報告書   143 - 148   2014年

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  • 網膜色素変性症を伴う常染色体劣性遺伝性痙性対麻痺5家系のエクソーム解析からDDHD1の変異が見出された

    石浦浩之, 高橋祐二, 三井純, 後藤順, 高紀信, 嶋崎晴雄, 吉村淳, 土井晃一郎, 森下真一, 新井憲俊, 金澤一郎, 三方崇嗣, 佐藤裕康, 高嶋博, 佐々木彰一, 山根清美, 佐々木秀直, 瀧山嘉久

    日本遺伝子診療学会大会プログラム・抄録集   21st   274   2014年

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  • 先天代謝異常症に対する移植療法の確立とガイドラインの作成に関する研究 成人大脳型副腎白質ジストロフィーに対する造血幹細胞移植の臨床的効果の検討

    辻省次, 松川敬志, 山本知孝, 篠原明仁, 熊野恵城, 市川幹, 高橋祐二, 石浦浩之, 三井純, 後藤順, 黒川峰夫

    先天代謝異常症に対する移植療法の確立とガイドラインの作成に関する研究 平成25年度 総括・分担研究報告書   79 - 80   2014年

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  • トリオのエクソーム解析によりATL1の新規de novo変異を見出した家族性痙性対麻痺家系

    高 紀信, 石浦 浩之, 三井 純, 森下 真一, 後藤 順, 辻 省次, 瀧山 嘉久

    臨床神経学   53 ( 12 )   1541 - 1541   2013年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 成人発症エオジン好性核内封入体病の家族例・孤発例における臨床像の検討

    間野 達雄, 大友 亮, 代田 悠一郎, 石浦 浩之, 岩田 淳, 寺尾 安生, 清水 潤, 後藤 順, 辻 省次

    臨床神経学   53 ( 12 )   1423 - 1423   2013年12月

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  • 【近位筋優位運動感覚ニューロパチー】 近位筋優位運動感覚ニューロパチーの病因遺伝子

    石浦 浩之

    神経内科   79 ( 6 )   746 - 750   2013年12月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

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  • 【てんかんと不随意運動】 進行性ミオクローヌスてんかんの分類と遺伝子異常

    石浦 浩之, 辻 省次

    神経内科   79 ( 6 )   699 - 705   2013年12月

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  • 小脳失調、末梢神経障害を伴った劣性遺伝性痙性対麻痺家系の遺伝子解析

    嶋崎 晴雄, 本多 純子, 直井 為任, 滑川 道人, 石浦 浩之, 福田 陽子, 高橋 祐二, 後藤 順, 辻 省次, 矢崎 正英, 中村 勝哉, 吉田 邦広, 池田 修一, 瀧山 嘉久, 中野 今治

    臨床神経学   53 ( 12 )   1540 - 1540   2013年12月

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  • 思春期/成人大脳型副腎白質ジストロフィーに対する造血幹細胞移植の臨床的効果の検討

    松川 敬志, 山本 知孝, 熊野 恵城, 市川 幹, 高橋 祐二, 石浦 浩之, 三井 純, 田中 真生, 後藤 順, 黒川 峰夫, 辻 省次

    臨床神経学   53 ( 12 )   1519 - 1519   2013年12月

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  • 原因未同定SCAの遺伝子探索

    尾崎 心, 石川 欽也, 太田 浄文, 佐藤 望, 三井 純, 石浦 浩之, 辻 省次, 水澤 英洋

    臨床神経学   53 ( 12 )   1496 - 1496   2013年12月

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  • 次世代シーケンサーを用いたミトコンドリア遺伝子の全塩基配列解析

    田中 真生, 石浦 浩之, 三井 純, Budrul Ahsan, 高橋 祐二, 後藤 順, 辻 省次

    臨床神経学   53 ( 12 )   1468 - 1468   2013年12月

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  • 【神経変性疾患-研究と診療の進歩】神経変性疾患の病態機序の解明 近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)とTRK-fused gene 運動ニューロン疾患の新しい病態機序

    藤田 浩司, 石浦 浩之, 梶 龍兒

    医学のあゆみ   247 ( 5 )   439 - 444   2013年11月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

    近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)は常染色体優性遺伝形式をとり、近位筋優位の筋力低下・萎縮、著明な線維束性収縮、感覚障害などを主徴とする緩徐進行性の疾患である。その原因遺伝子として2012年TRK-fused gene(TFG)のミスセンス変異p.Pro285Leuが報告された。病理所見では下位優位の運動ニューロン障害および感覚系障害を認め、興味深いことにTFGおよびユビキチン陽性の神経細胞質内封入体のみならず、筋萎縮性側索硬化症のマーカーとされるTAR DNA-binding protein 43 kDa(TDP-43)やoptineurinが陽性の封入体も伴う。また、変異TFGを過剰発現させた培養細胞では核外にTDP-43が蓄積する。TFGは細胞内の小胞輸送にかかわる蛋白であり、その変異に伴い、TFG自体の異常蓄積に加えてTDP-43など他の蛋白の輸送障害も生じると推測される。(著者抄録)

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  • 網羅的遺伝子診断による片麻痺性片頭痛の分子疫学の解明

    高橋 祐二, 石浦 浩之, 後藤 順, 辻 省次

    日本頭痛学会誌   40 ( 2 )   387 - 387   2013年11月

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  • 家族性に発症が認められ、小脳失調・ニューロパチー・感音性難聴を呈し、DNMT1変異が確認された53歳男性例

    上田 順子, 長島 優, 石浦 浩之, 林 俊宏, 寺尾 安生, 清水 潤, 辻 省次, 吉良 潤一

    臨床神経学   53 ( 10 )   878 - 878   2013年10月

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  • IDENTIFICATION OF ATP1A3 MUTATIONS BY EXOME SEQUENCING AS THE CAUSE OF ALTERNATING HEMIPLEGIA OF CHILDHOOD IN JAPAN

    A. Ishii, Y. Saito, J. Mitsui, H. Ishiura, J. Yoshimura, H. Arai, S. Yamashita, S. Kimura, H. Oguni, S. Morishita, S. Tsuji, M. Sasaki, S. Hirose

    EPILEPSIA   54   295 - 295   2013年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

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  • 【次世代シーケンサーによる神経変性疾患の解析と展望】東大病院ゲノム医学センターにおける取り組み パーキンソン病のパーソナルゲノム解析を中心に

    三井 純, 石浦 浩之, 辻 省次

    BRAIN and NERVE: 神経研究の進歩   65 ( 3 )   247 - 255   2013年3月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

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  • 経過約2年で進行する四肢体幹感覚障害・筋力低下を呈した、笑気吸入によるビタミンB12欠乏症の58歳男性例

    佐藤 大, 遠藤 聡, 間野 達雄, 石浦 浩之, 寺尾 安生, 清水 潤, 後藤 順, 辻 省次

    日本内科学会関東地方会   594回   51 - 51   2013年2月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 三重県南部に多発する家族性認知症‐パーキンソン症候群発症因子の探索と治療介入研究 紀伊筋萎縮性側索硬化症・パーキンソン認知症複合(ALS/PDC)の疾患遺伝子の探索

    石浦浩之, 三井純, AHSAN Budrul, 福田陽子, 後藤順, 辻省次, 小久保康昌, 葛原茂樹, 日笠幸一郎, 吉村淳, 土井晃一郎, 森下真一, 原賢寿, 西澤正豊, 桑野良三, 豊田敦, 藤山秋佐夫

    三重県南部に多発する家族性認知症-パーキンソン症候群発症因子の探索と治療介入研究 平成24年度 総括・分担研究報告書   45 - 47   2013年

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  • 運動失調症の病態解明と治療法開発に関する研究 原因未同定SCAの遺伝子探索

    水澤英洋, 石川欽也, 尾崎心, 太田浄文, 関口輝彦, 佐藤望, 三井純, 石浦浩之, 辻省次

    運動失調症の病態解明と治療法開発に関する研究 平成24年度 総括・分担研究報告書   185 - 190   2013年

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  • 神経・筋疾患診療における遺伝子検査の有用性

    市川弥生子, 石浦浩之, 三井純, 松川敬志, 田中真生, 高橋祐二, 後藤順, 辻省次

    日本遺伝子診療学会大会プログラム・抄録集   20th   91   2013年

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  • COQ2変異は家族性・孤発性多系統萎縮症と関連する

    三井純, 松川敬志, 石浦浩之, 福田陽子, 市川弥生子, 伊達英俊, AHSAN Budrul, 中原康雄, 百瀬義雄, 高橋祐二, 岩田淳, 後藤順, 辻省次

    日本人類遺伝学会大会プログラム・抄録集   58th   119   2013年

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  • 常染色体劣性遺伝が疑われた遺伝痙性対麻痺症例のexome解析

    石浦浩之, 高紀信, 嶋崎晴雄, 三井純, 高橋祐二, 吉村淳, 土井晃一郎, 森下真一, 後藤順, 瀧山嘉久, 辻省次

    日本人類遺伝学会大会プログラム・抄録集   58th   136   2013年

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  • 運動失調症の病態解明と治療法開発に関する研究 エクソーム解析を用いたATL1の新規de novo変異の検出

    瀧山嘉久, 高紀信, 森下真一, 石浦浩之, 三井純, 後藤順, 辻省次

    運動失調症の病態解明と治療法開発に関する研究 平成24年度 総括・分担研究報告書   191 - 195   2013年

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  • 先天代謝異常症に対する移植療法の確立とガイドラインの作成に関する研究 成人大脳型副腎白質ジストロフィーに対する造血幹細胞移植の臨床的効果の検討

    辻省次, 松川敬志, 山本知孝, 熊野恵城, 市川幹, 高橋祐二, 石浦浩之, 三井純, 後藤順, 黒川峰夫

    先天代謝異常症に対する移植療法の確立とガイドラインの作成に関する研究 平成24年度 総括・分担研究報告書   53 - 54   2013年

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  • 神経変性疾患に関する調査研究 HMSN‐P原因遺伝子であるTFGの培養細胞を用いた機能解析

    梶龍兒, 瓦井俊孝, 石浦浩之, 藤田浩司, 佐光亘, 森垣龍馬, 小泉英貴, 後藤惠, 田邉修, 和泉唯信, 辻省次

    神経変性疾患に関する調査研究 平成24年度 総括・分担研究報告書   178 - 181   2013年

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  • 次世代シークエンサーを用いたKenny‐Caffey症候群(KCS)2型の原因遺伝子の同定

    磯島豪, 土井晃一郎, 三井純, 小田洋一郎, 徳弘悦郎, 八十田明宏, 依藤亨, 堀川玲子, 吉村淳, 石浦浩之, 森下真一, 辻省次, 北中幸子

    日本人類遺伝学会大会プログラム・抄録集   58th   150   2013年

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  • 難病・がん等の疾患分野の医療の実用化研究事業の成果を基にした原因遺伝子変異データベースの構築

    松田文彦, 辻省次, 三井純, 石浦浩之, 後藤順

    難病・がん等の疾患分野の医療の実用化研究事業の成果を基にした原因遺伝子変異データベースの構築 平成24年度 総括・分担研究報告書   9 - 10   2013年

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  • 神経変性疾患に関する調査研究 本邦におけるC9ORF72変異の創始者効果と紀伊半島における集積について

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    神経変性疾患に関する調査研究 平成24年度 総括・分担研究報告書   176 - 177   2013年

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  • 三重県南部に多発する家族性認知症‐パーキンソン症候群発症因子の探索と治療介入研究 C9ORF72遺伝子の異常伸長を有する紀伊ALS2症例の臨床的特徴について

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    三重県南部に多発する家族性認知症-パーキンソン症候群発症因子の探索と治療介入研究 平成24年度 総括・分担研究報告書   24 - 26   2013年

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  • 次世代シークエンサーを用いたKenny‐Caffey症候群(KCS)2型の原因遺伝子の同定

    磯島豪, 土井晃一郎, 三井純, 小田洋一郎, 徳弘悦郎, 八十田明宏, 依藤亨, 堀川玲子, 吉村淳, 石浦浩之, 森下真一, 辻省次, 北中幸子

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  • トリオのエクソーム解析によりATL1の新規de novo変異を見出した家族性痙性対麻痺家系

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    日本神経学会学術大会プログラム・抄録集   54th   430   2013年

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  • 次世代シークエンサーを活用した眼咽頭遠位型ミオパチー(OPDM)病因遺伝子の探索

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    臨床神経学   52 ( 12 )   1403 - 1403   2012年12月

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  • 思春期/成人大脳型副腎白質ジストロフィーに対する造血幹細胞移植の臨床的効果に関する検討

    松川 敬志, 山本 知孝, 瀬尾 幸子, 熊野 恵城, 市川 幹, 高橋 祐二, 石浦 浩之, 三井 純, 後藤 順, 黒川 峰夫, 辻 省次

    臨床神経学   52 ( 12 )   1401 - 1401   2012年12月

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  • 家族性MSAおよびMSA・PD多発家系の全ゲノム解析

    三井 純, 石浦 浩之, 市川 弥生子, 日笠 幸一郎, 吉村 淳, 斉藤 太郎, 後藤 順, 森下 真一, 辻 省次

    臨床神経学   52 ( 12 )   1599 - 1599   2012年12月

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  • 視神経萎縮、末梢神経障害を伴う遺伝性痙性対麻痺家系の原因遺伝子同定

    嶋崎 晴雄, 石浦 浩之, 福田 陽子, 本多 純子, 迫江 公己, 直井 為任, 滑川 道人, 高橋 祐二, 後藤 順, 辻 省次, 後藤 雄一, 瀧山 嘉久, 中野 今治

    臨床神経学   52 ( 12 )   1400 - 1400   2012年12月

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  • 紀伊筋萎縮性側索硬化症・パーキンソニズム認知症複合(ALS/PDC)の全ゲノム配列解析による疾患遺伝子の探索

    石浦 浩之, 小久保 康昌, 三井 純, 福田 陽子, 日笠 幸一郎, 吉村 淳, 斉藤 太郎, 森下 真一, 豊田 敦, 原 賢寿, 西澤 正豊, 葛原 茂樹, 後藤 順, 辻 省次

    臨床神経学   52 ( 12 )   1549 - 1549   2012年12月

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  • エクソーム解析による常染色体劣性遺伝性家族性筋萎縮性側索硬化症の新規原因遺伝子探索

    高橋 祐二, 石浦 浩之, 三井 純, 福田 陽子, 高木 聡, 栗田 正, 日笠 幸一郎, 吉村 淳, 齋藤 太郎, 森下 真一, 後藤 順, 辻 省次

    臨床神経学   52 ( 12 )   1549 - 1549   2012年12月

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  • 紀伊半島の筋萎縮性側索硬化症/パーキンソン認知症複合(牟婁病:Kii ALS/PDC) 現状と課題

    小久保 康昌, 紀平 為子, 吉田 宗平, 岡本 和士, 広川 佳史, 白石 泰三, 富山 弘幸, 服部 信孝, 長谷川 成人, 森本 悟, 村山 繁雄, 石浦 浩之, 辻 省次, 葛原 茂樹

    臨床神経学   52 ( 12 )   1520 - 1520   2012年12月

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  • A four-generation Japanese family with autosomal dominant nemaline myopathy associated with dilated cardiomyopathy

    Y. Ichikawa, J. Goto, H. Ishiura, Y. Oya, H. Kowa, J. Shimizu, H. Date, S. Tsuji

    NEUROMUSCULAR DISORDERS   22 ( 9-10 )   845 - 845   2012年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.nmd.2012.06.142

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  • 下肢筋力低下で発症し、急性呼吸不全を呈したmultiminicore disease(MmD)の成人男性の1例

    榎本 雪, 蛯谷 征弘, 門脇 傑, 中村 耕一郎, 望月 仁志, 宇川 義一, 西野 一三, 埜中 征哉, 石浦 浩之, 三井 純, 辻 省次

    臨床神経学   52 ( 7 )   523 - 523   2012年7月

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  • 検査からみる神経疾患 Alexander病

    石浦 浩之, 後藤 順, 辻 省次

    Clinical Neuroscience   30 ( 4 )   470 - 471   2012年4月

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  • 本年の動向 神経変性疾患解明への次世代シーケンサーの応用

    辻 省次, 石浦 浩之, 三井 純

    Annual Review神経   2012   112 - 121   2012年1月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

    次世代シーケンサーの実用化により,疾患関連遺伝子の探索パラダイムが大きく変貌しつつある.これまでのゲノム解析研究は主として遺伝性疾患を対象としていたが,次世代シーケンサーの巨大な解析能力により,頻度の高い孤発性疾患の分子基盤の解明への応用,さらには診療への応用が期待されている.特に,孤発性疾患を対象とした研究では,これまでのcommon disease-common variants仮説から,common disease-multiple rare variants仮説へのパラダイムシフトが重要になってきている.診療への応用としては,同時に多数の遺伝子の解析ができることから,診断確定のために多数の遺伝子を解析する必要がある場合などへの応用が行われている.さらに,全ゲノムの情報(個人ゲノム)に基づいた,疾患の診断,治療,予防など,ヘルスケアの様々な分野において重要な役割をもつようになると予測される.(著者抄録)

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    三井純, 石浦浩之, 市川弥生子, 日笠幸一郎, 吉村淳, 斉藤太郎, 後藤順, 森下真一, 辻省次

    日本神経学会学術大会プログラム・抄録集   53rd   440   2012年

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  • 次世代シーケンサーを用いたヒトゲノム配列解析:SNV検出の問題点とその解決策

    AHSAN Budrul, 石浦浩之, 三井純, 辻省次

    日本人類遺伝学会大会プログラム・抄録集   57th   177   2012年

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  • 運動失調症の病態解明と治療法開発に関する研究 Exome解析にて同定されたSCAR1(AOA2)の本邦一家系に関する研究

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  • 次世代シークエンサーを活用した眼咽頭遠位型ミオパチー(OPDM)病因遺伝子の探索

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    日本神経学会学術大会プログラム・抄録集   53rd   231   2012年

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  • 牟婁病の実態の把握と治療指針作成 紀伊筋萎縮性側索硬化症・パーキンソニズム認知症複合(ALS/PDC)の疾患遺伝子の探索

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    牟婁病の実態の把握と治療指針作成 平成23年度 総括・分担研究報告書   31 - 33   2012年

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  • 運動失調症の病態解明と治療法開発に関する研究 家族性MSAおよびMSA・PD多発家系の全ゲノム解析

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  • 運動失調症の病態解明と治療法に開発する研究 脊髄小脳変性症および遺伝性痙性対麻痺の病態解明に向けたシーケンス拠点の整備

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  • エクソーム解析による常染色体劣性遺伝性家族性筋萎縮性側索硬化症の新規原因遺伝子探索

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    日本神経学会学術大会プログラム・抄録集   53rd   387   2012年

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  • 紀伊筋萎縮性側索硬化症・パーキンソニズム認知症複合(ALS/PDC)の全ゲノム配列解析による疾患遺伝子の探索

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    日本神経学会学術大会プログラム・抄録集   53rd   387   2012年

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  • 思春期/成人大脳型副腎白質ジストロフィーに対する造血幹細胞移植の臨床的効果に関する検討

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    日本神経学会学術大会プログラム・抄録集   53rd   229   2012年

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  • 運動失調症の病態解明と治療法開発に関する研究 視神経萎縮と末梢神経障害を伴ったARHSPの新規原因遺伝子の機能解析

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    運動失調症の病態解明と治療法開発に関する研究 平成23年度 総括・分担研究報告書   152 - 156   2012年

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  • 若年性アルツハイマー病の臨床的、遺伝学的背景の見当

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    臨床神経学   51 ( 12 )   1341 - 1341   2011年12月

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  • 家族性アミロイドポリニューロパチーIV型の臨床像と創始者ハプロタイプの検討

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    臨床神経学   51 ( 12 )   1456 - 1456   2011年12月

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  • 連鎖領域のcaptureと次世代シーケンサーによる解析に基づくposterior column ataxia with retinitis pigmentosaの原因遺伝子探索

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    臨床神経学   51 ( 12 )   1394 - 1394   2011年12月

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  • 視神経萎縮、末梢神経障害を伴う遺伝性痙性対麻痺症例の臨床像と、原因遺伝子検索

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    臨床神経学   51 ( 12 )   1394 - 1394   2011年12月

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  • 疾患と関連する稀で多様な変異の検出を目的としたpooled DNA解析

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    臨床神経学   51 ( 12 )   1428 - 1428   2011年12月

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  • オカルト黄斑ジストロフィー(Occult Macular Dystrophy)の原因遺伝子解明

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