Updated on 2025/06/17

写真a

 
Ishiura Hiroyuki
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
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Degree

  • PhD ( 2011.3   The University of Tokyo )

  • MD ( 2002.3   The University of Tokyo )

Research Interests

  • Next-generation sequencer

  • repeat expansion diseases

  • Neurogenetics

Research Areas

  • Life Science / Neurology  / Neurogenetics

Education

  • The University of Tokyo   大学院医学系研究科  

    2007.4 - 2011.3

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    Notes: 博士(医学)

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  • The University of Tokyo   医学部医学科  

    1996.4 - 2002.3

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    Notes: 学士(医学)

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Research History

  • Okayama University   Graduate School of Medicine, Dentistry and Pharmaceutical Sciences   Professor

    2022.11

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  • The University of Tokyo   Department of Neurology   Associate Professor/Senior Lecturer

    2020.4 - 2022.10

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    Country:Japan

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  • The University of Tokyo Hospital   Department of Neurology   Assistant Professor

    2012.4 - 2020.3

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  • Japan Society for Promotion of Science   Research Fellowships for Young Scientists

    2010.4 - 2012.3

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  • International Medical Center of Japan   Department of Neurology   resident

    2006.4 - 2007.3

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  • The University of Tokyo Hospital   Department of Neurology   resident

    2004.6 - 2006.3

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  • Kanto Chuo Hospital   Internal Medicine   resident

    2003.6 - 2004.5

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  • The University of Tokyo Hospital   Internal Medicine   resident

    2002.6 - 2003.5

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Committee Memberships

  • 日本神経学会   臨床神経学 編集副委員長  

    2025.5   

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  • Japanese Society of Neurological Therapeutics   Councilor  

    2023.11   

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  • The Japanese Society of Internal Medicine   Councilor  

    2023.4   

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    Committee type:Other

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  • 日本神経学会   代議員  

    2021.5   

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  • 日本人類遺伝学会   評議員  

    2019.11   

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  • 日本人類遺伝学会   臨床遺伝専門医  

       

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  • 日本神経学会   専門医、指導医  

       

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  • 日本内科学会   総合内科専門医  

       

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

       

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  • Human Genome Variation   Associate Editor  

       

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    Committee type:Other

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Papers

  • Two Cases of Autosomal Recessive Spinocerebellar Ataxia-8 Showing Two Novel Variants of SYNE1 in Japanese Families.

    Taijun Yunoki, Chika Matsuoka, Yosuke Osakada, Yusuke Fukui, Mami Takemoto, Ryuta Morihara, Toru Yamashita, Hiroyuki Ishiura

    Internal medicine (Tokyo, Japan)   2025.6

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    Autosomal recessive spinocerebellar ataxia-8 (SCAR8) is a neurodegenerative disorder caused by the biallelic pathogenic variants of SYNE1. It is characterized by slowly progressive cerebellar ataxia and atrophy. We identified two SCAR8 families using exome analyses and two novel variants, c.2127delG (p.Met709Ilefs) and c.15943G>T (p.Gly5315*), in SYNE1 (NM_182961.4). Pathogenic variants of SYNE1 cause various symptoms, including cerebellar ataxia, pyramidal tract disorders, and joint disorders, and the pathogenic variants discovered in this study were located in a region prone to cerebellar ataxia.

    DOI: 10.2169/internalmedicine.5602-25

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  • Recent progress in oculopharyngodistal myopathy research from clinical and genetic viewpoints. International journal

    Hiroyuki Ishiura

    Journal of neuromuscular diseases   22143602251319164 - 22143602251319164   2025.3

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    Oculopharyngodistal myopathy (OPDM) is a rare muscular disorder characterized by ocular symptoms, pharyngeal symptoms, facial weakness, and distal predominant limb muscle weakness. The cause of the disease was unknown for a long time. Recently, however, it has been reported that expansions of CGG or CCG repeats in LRP12, LOC642361/NUTM2B-AS1, GIPC1, NOTCH2NLC, RILPL1, and ABCD3 are the causes of the disease. Cases sometimes present with neurological symptoms, and the clinical spectrum of diseases caused by expansions of CGG or CCG repeats has been proposed to be called FNOP-spectrum disorder after the names of fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukoencephalopathy, and OPDM. In this article, the recent progress in the field of OPDM is reviewed, and remaining issues in OPDM are discussed.

    DOI: 10.1177/22143602251319164

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  • A Novel De Novo Variant in KCNH5 in a Patient with Refractory Epileptic Encephalopathy. Reviewed

    Akihiko Mitsutake, Takashi Matsukawa, Tatsuhiko Naito, Hiroyuki Ishiura, Jun Mitsui, Hiroaki Harada, Keishi Fujio, Jun Fujishiro, Harushi Mori, Shinichi Morishita, Shoji Tsuji, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2024.8

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    We herein report a novel de novo KCNH5 variant in a patient with refractory epileptic encephalopathy. The patient exhibited seizures at 1 year and 7 months old, which gradually worsened, leading to a bedridden status. Brain magnetic resonance imaging (MRI) showed cerebral atrophy and cerebellar hypoplasia. A trio whole-exome sequence analysis identified a de novo heterozygous c.640A>C, p.Lys214Gln variant in KCNH5 that was predicted to be deleterious. Recent studies have linked KCNH5 to various epileptic encephalopathies, with many patients showing normal MRI findings. The present case expands the clinical spectrum of the disease, as it is characterized by severe neurological prognosis, cerebral atrophy, and cerebellar hypoplasia.

    DOI: 10.2169/internalmedicine.3999-24

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  • Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis. Reviewed International journal

    Elisa Vegezzi, Hiroyuki Ishiura, D Cristopher Bragg, David Pellerin, Francesca Magrinelli, Riccardo Currò, Stefano Facchini, Arianna Tucci, John Hardy, Nutan Sharma, Matt C Danzi, Stephan Zuchner, Bernard Brais, Mary M Reilly, Shoji Tsuji, Henry Houlden, Andrea Cortese

    The Lancet. Neurology   23 ( 7 )   725 - 739   2024.7

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    Nucleotide repeat expansions in the human genome are a well-known cause of neurological disease. In the past decade, advances in DNA sequencing technologies have led to a better understanding of the role of non-coding DNA, that is, the DNA that is not transcribed into proteins. These techniques have also enabled the identification of pathogenic non-coding repeat expansions that cause neurological disorders. Mounting evidence shows that adult patients with familial or sporadic presentations of epilepsy, cognitive dysfunction, myopathy, neuropathy, ataxia, or movement disorders can be carriers of non-coding repeat expansions. The description of the clinical, epidemiological, and molecular features of these recently identified non-coding repeat expansion disorders should guide clinicians in the diagnosis and management of these patients, and help in the genetic counselling for patients and their families.

    DOI: 10.1016/S1474-4422(24)00167-4

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  • RFC1-related disorder presenting recurrent syncope. Reviewed International journal

    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   271 ( 7 )   4635 - 4638   2024.3

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    Authorship:Corresponding author   Language:English  

    DOI: 10.1007/s00415-024-12231-5

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  • SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis. Reviewed International journal

    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   11 ( 4 )   946 - 957   2024.2

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    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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  • Expanded clinical spectrum of oculopharyngodistal myopathy type 1 Reviewed

    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   2022.9

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1002/mus.27717

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  • Isolated Paravermal Hyperintensities in Neuronal Intranuclear Inclusion Disease. Reviewed International journal

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

    Neurology   98 ( 22 )   938 - 939   2022.3

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    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. International journal

    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   2021.7

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    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. International journal

    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   2021.3

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    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. International journal

    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   2021.3

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    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. International journal

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

    BMC neurology   21 ( 1 )   64 - 64   2021.2

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    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. International journal

    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   2021.1

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    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. International journal

    Hiroyuki Ishiura, Shoji Tsuji

    Current opinion in genetics & development   65   176 - 185   2020.12

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    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. International journal

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

    Amyotrophic lateral sclerosis & frontotemporal degeneration   22 ( 7-8 )   1 - 3   2020.9

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    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. Reviewed International journal

    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   2020.4

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    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. Reviewed International journal

    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   2020.3

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    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.

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

    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   2020.3

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    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.

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  • Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Reviewed International journal

    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   2019.8

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    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.

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  • Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS. Reviewed International journal

    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   2019.5

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    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.

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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. Reviewed International journal

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

    Neurogenetics   20 ( 2 )   65 - 71   2019.5

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    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. Reviewed International journal

    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   2019.4

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    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 Reviewed

    Hiroyuki Ishiura, Koichiro Doi, Jun Mitsui, Jun Yoshimura, Miho Kawabe Matsukawa, Asao Fujiyama, Yasuko Toyoshima, Akiyoshi Kakita, Hitoshi Takahashi, Yutaka Suzuki, Sumio Sugano, Wei Qu, Kazuki Ichikawa, Hideaki Yurino, Koichiro Higasa, Shota Shibata, Aki Mitsue, Masaki Tanaka, Yaeko Ichikawa, Yuji Takahashi, Hidetoshi Date, Takashi Matsukawa, Junko Kanda, Fumiko Kusunoki Nakamoto, Mana Higashihara, Koji Abe, Ryoko Koike, Mutsuo Sasagawa, Yasuko Kuroha, Naoya Hasegawa, Norio Kanesawa, Takayuki Kondo, Takefumi Hitomi, Masayoshi Tada, Hiroki Takano, Yutaka Saito, Kazuhiro Sanpei, Osamu Onodera, Masatoyo Nishizawa, Masayuki Nakamura, Takeshi Yasuda, Yoshio Sakiyama, Mieko Otsuka, Akira Ueki, Ken Ichi Kaida, Jun Shimizu, Ritsuko Hanajima, Toshihiro Hayashi, Yasuo Terao, Satomi Inomata-Terada, Masashi Hamada, Yuichiro Shirota, Akatsuki Kubota, Yoshikazu Ugawa, Kishin Koh, Yoshihisa Takiyama, Natsumi Ohsawa-Yoshida, Shoichi Ishiura, Ryo Yamasaki, Akira Tamaoka, Hiroshi Akiyama, Taisuke Otsuki, Akira Sano, Akio Ikeda, Jun Goto, Shinichi Morishita, Shoji Tsuji

    Nature Genetics   50 ( 4 )   581 - 590   2018.4

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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 Reviewed

    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   2018.1

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    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 Reviewed

    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   2017.6

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  • Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum. Reviewed International journal

    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   2016.2

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    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.

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

    Hiroyuki Ishiura, Shoji Tsuji

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

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

    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   2014.3

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

    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   2013.11

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

    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   2013.7

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

    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   2012.9

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

    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   2012.8

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

    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   2012.8

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

    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   2011.5

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

    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   2010.1

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

    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   2008.12

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

    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   2008.10

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

    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   2008.5

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  • Spearmint extract Neumentix downregulates amyloid-β accumulation by promoting phagocytosis in APP23 mice. International journal

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

    Brain research   1863   149752 - 149752   2025.6

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    In recent years, many researchers have focused on natural compounds that can effectively delay symptoms of Alzheimer's disease (AD). The spearmint extract Neumentix, which is rich in phenolic compounds, has been shown to reduce inflammatory responses and oxidative stress in mice. However, the effect of Neumentix on AD has not been thoroughly studied. In this study, APP23 transgenic female and male mice were administered Neumentix orally from 4 to 18 months of age at a dosage of 2.65 g/kg/day (containing 0.41 g/kg/day of rosmarinic acid). The impact was evaluated by behavioral tests and histological analyses and compared with APP23 mice to which Neumentix was not administered. The results showed that Neumentix administration increased the survival rate of APP23 mice and effectively reduced Aβ accumulation by enhancing its phagocytosis by microglial cells. These findings suggest that Neumentix is a potential natural nutritional treatment for improving the progression of AD.

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  • [Genetics of Motor Neuron Diseases and Hereditary Spastic Paraplegia].

    Hiroyuki Ishiura

    Brain and nerve = Shinkei kenkyu no shinpo   77 ( 5 )   481 - 491   2025.5

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    Motor neuron diseases encompass a range of phenotypes, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and spinal muscular atrophy (SMA). Related conditions include spinal and bulbar muscular atrophy (SBMA) and hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). Hereditary spastic paraplegia (HSP)-a group of disorders primarily affecting the corticospinal tract-also exhibits diverse clinical manifestations. This review summarizes the genetic basis of these diseases, along with their clinical characteristics, diagnostic approaches, and disease-specific therapies.

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  • Authors' response to "If Status Epilepticus Disappears with Tocilizumab, Paucisymptomatic SARS-CoV-2 Infection Should be Suspected.".

    Yumiko Nakamura, Masayuki Ueda, Satoshi Kodama, Tomohiko Kimura, Yuichiro Shirota, Masashi Hamada, Hiroyuki Ishiura, Takahiro Iizuka, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2025.4

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  • Clinical, neuroimaging and genetic findings in the Japanese case series of CLCN2-related leukoencephalopathy. International journal

    Kenta Orimo, Takashi Matsukawa, Akihiko Mitsutake, Takusei Cho, Hiroya Naruse, Yoshio Sakiyama, Kensho Sumi, Naohiro Uchio, Akane Satake, Yoshihisa Takiyama, Takuya Matsushita, Yosuke Omae, Yosuke Kawai, Katsushi Tokunaga, Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji, Tatsushi Toda

    Journal of the neurological sciences   472   123486 - 123486   2025.4

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    Biallelic loss-of-function variants in CLCN2 lead to CLCN2-related leukoencephalopathy (CC2L), also called leukoencephalopathy with ataxia (LKPAT). CC2L is characterized clinically by a spectrum of clinical presentations including childhood- to adult-onset mild ataxia, spasticity, cognitive decline, and vision loss as well as typical MRI findings of symmetrical high signal intensities on the DWIs/T2WIs of the middle cerebellar peduncles (MCPs). We searched for pathogenic variants of CLCN2 in a case series of undiagnosed leukoencephalopathy accompanied by MCP signs, which led to the identification of four Japanese patients with CC2L. All the patients carried at least one allele of c.61dupC (p.Leu21Profs*27) in CLCN2, including compound heterozygosity with either the novel pathogenic variant c.983 + 2 T > A or the previously reported pathogenic variant c.1828C > T (p.Arg610*). Of note, all the four previously reported cases from Japan also harbored c.61dupC, and no reports of this variant have been documented from outside Japan. The allele frequency of c.61dupC in the Japanese population is 0.002152, raising the possibility of a relatively high prevalence of CC2L in Japan. Patients in this study developed symptoms after the age of 30, and demonstrated neurological signs including cerebellar ataxia, pyramidal signs, and mild cognitive impairment, consistent with previous reports. One male patient had two children, supporting preserved fertility, and another patient had calcifications in the cerebral and cerebellar surfaces. These findings provide valuable insights into the broader clinical and genetic spectra of CC2L in the Japanese population, and emphasize the importance of considering this disease in the differential diagnoses of leukoencephalopathy with MCP signs.

    DOI: 10.1016/j.jns.2025.123486

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  • In-frame deletion variant of ABCD1 in a sporadic case of adrenoleukodystrophy. International journal

    Takashi Matsukawa, Atsushi Sudo, Toshiyuki Kakumoto, Akihito Hao, Mitsuhiro Kainaga, Hyangri Chang, Tatsuo Mano, Hiroyuki Ishiura, Jun Mitsui, Toshihiro Hayashi, Shinichi Morishita, Shoji Tsuji, Tatsushi Toda

    Human genome variation   12 ( 1 )   5 - 5   2025.2

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    Adrenoleukodystrophy (ALD), an X-linked leukodystrophy caused by pathogenic variants in ABCD1, exhibits a broad range of phenotypes from childhood-onset cerebral forms to adult-onset adrenomyeloneuropathy (AMN). We report a rare in-frame ABCD1 deletion c.1469_71delTGG (p.Val490del) in a man with AMN. Although this variant has been interpreted as 'uncertain significance' in ClinVar, biochemical analysis along with clinical evaluation confirmed the pathogenicity of this variant, underscoring the importance of functional assessment of in-frame deletions.

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  • Clinical and Genetic Analyses of SPG7 in Japanese Patients with Undiagnosed Ataxia.

    Akihiko Mitsutake, Takashi Matsukawa, Rimi Hino, Go Fujino, Yuto Sakai, Jun Mitsui, Hiroyuki Ishiura, Nobue K Iwata, Shoji Tsuji, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2025.2

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    Objective Spastic paraplegia 7 (SPG7) is an autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in SPG7. It is predominantly characterized by adult-onset slowly progressive spastic paraparesis. While SPG7 presenting with ataxia with or without spasticity is relatively common in Europe and North America, it is considered rare in Japan. This study aimed to identify SPG7 patients among those with undiagnosed ataxia within the Japanese population. Methods We retrospectively selected 351 patients with undiagnosed ataxia, excluding those with secondary and common spinocerebellar ataxia. Whole-exome sequence analysis was conducted, and homozygosity of the identified variants was confirmed using droplet digital polymerase chain reaction (ddPCR). Results Among the 351 patients, 2 were diagnosed with SPG7, and homozygosity was confirmed by ddPCR. Both patients carried homozygous pathogenic variants in SPG7: c.1948G>A, p.Asp650Asn, and c.1192C>T, p.Arg398Ter (NM_003119.4). Clinically, both patients presented with progressive ataxia. In addition, Patient 1 exhibited partial ophthalmoplegia and spastic paraparesis, whereas Patient 2 demonstrated cerebellar ataxia without spasticity. Conclusion The rarity of SPG7 in Japan may be attributed to variation in the minor allele frequency of the c.1529C>T, p.Ala510Val variant, which is more prevalent in Europe and North America than in other areas.

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  • The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model. International journal

    Yuting Bian, Yusuke Fukui, Ricardo Satoshi Ota-Elliott, Xinran Hu, Hongming Sun, Zhihong Bian, Yun Zhai, Haibo Yu, Xiao Hu, Hangping An, Hongzhi Liu, Ryuta Morihara, Hiroyuki Ishiura, Toru Yamashita

    Neuroscience research   2025.1

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    The disruption of transactive response DNA binding protein 43 kDa (TDP-43) shuttling leads to the depletion of nuclear localization and the cytoplasmic accumulation of TDP-43. We aimed to evaluate the mechanism underlying the behavior of TDP-43 in ischemic stroke. Adult male C57BL/6 J mice were subjected to 30 or 60 min of transient middle cerebral artery occlusion (tMCAO), and examined at 1, 6, and 24 h post reperfusion. Immunostaining was used to evaluate the expression of TDP-43, G3BP1, HDAC6, and RAD23B. The total and cytoplasmic number of TDP-43-positive cells increased compared with sham operation group and peaked at 6 h post reperfusion after tMCAO. The elevated expression of G3BP1 protein peaked at 6 h after reperfusion and decreased at 24 h after reperfusion in ischemic mice brains. We also observed an increase of expression level of HDAC6 and the number of RAD23B-positive cells increased after tMCAO. RAD23B was colocalized with TDP-43 24 h after tMCAO. We proposed that the formation of stress granules might be involved in the mislocalization of TDP-43, based on an evaluation of G3BP1 and HDAC6. Subsequently, RAD23B, may also contribute to the downstream degradation of mislocalized TDP-43 in mice tMCAO model.

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  • Guidelines for presymptomatic genetic testing for adult-onset hereditary neuromuscular diseases in Japan

    Yuka Shibata, Hyangri Chang, Katsuya Nakamura, Shinichiro Yamada, Masaaki Matsushima, Kazumasa Saigoh, Hiroyuki Ishiura, Yoshiki Sekijima, Hirofumi Maruyama, Takeshi Ikeuchi, Kazuko Hasegawa, Masashi Aoki, Masahisa Katsuno, Tatsushi Toda, Ichiro Yabe

    Rinsho Shinkeigaku   2025

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    DOI: 10.5692/clinicalneurol.cn-002049

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  • A Japanese Family with a Novel Pathogenic Variant in KIF1A Presenting with Spastic Paraparesis, Cerebellar Ataxia, and Intellectual Disability. International journal

    Akihiko Mitsutake, Mizuho Kawai, Kenta Orimo, Takashi Matsukawa, Hiroyuki Ishiura, Jun Mitsui, Hideki Nakajima, Hiroyuki Murai, Shoji Tsuji, Jun Goto, Nobue K Iwata

    Cerebellum (London, England)   24 ( 1 )   20 - 20   2024.12

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    Variants in KIF1A are associated with hereditary spastic paraplegia (SPG30), which can manifest in both pure and complex forms. We describe a Japanese family with a novel KIF1A variant presenting with a complex form of SPG30. Patient 1, a 69-year-old woman, experienced progressive gait disturbance due to spastic paraparesis and cerebellar atrophy, and intellectual disability. Patient 2, the daughter of Patient 1, exhibited similar symptoms with more severe dysarthria. Patients 1 and 2 shared a heterozygous c.173 C > G (p.Ser58Trp) variant in the motor domain of KIF1A (NM_001244008.2), which is classified as likely pathogenic. This family highlights the role of autosomal dominant inheritance in a complex form of SPG30, expanding the understanding of its genetic basis and clinical presentation.

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  • A Case of Wilson's Disease Preceded by Schizophrenia-like Symptoms with Frontal-dominant Leukoencephalopathy.

    Ryoji Miyano, Akihiko Mitsutake, Takashi Matsukawa, Satomi Obata, Hiroaki Koyama, Yudai Nakai, Hiroyuki Ishiura, Akatsuki Kubota, Jun Shimizu, Kaori Sakuishi, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2024.12

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    We herein report a 26-year-old man diagnosed with Wilson's disease (WD), initially treated for schizophrenia for 11 years. At 26 years old, he was admitted because of status epilepticus. Brain magnetic resonance imaging revealed frontal-dominant leukoencephalopathy with cystic changes and basal ganglia atrophy. The diagnosis of WD was confirmed based on neuropsychiatric symptoms, Kayser-Fleischer rings, abnormal copper metabolism, and a genetic analysis of ATP7B. Psychotic symptoms in WD can precede neurological manifestations, and extrapyramidal signs may be mistaken for drug-induced Parkinsonism. WD should be considered in patients presenting with progressive Parkinsonism preceded by schizophrenia-like psychiatric symptoms.

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  • Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis. International journal

    So Okubo, Hiroya Naruse, Hiroyuki Ishiura, Atsushi Sudo, Kayoko Esaki, Jun Mitsui, Takashi Matsukawa, Wataru Satake, Peter Greimel, Nanoka Shingai, Yasushi Oya, Takeo Yoshikawa, Shoji Tsuji, Tatsushi Toda

    Journal of neurology   272 ( 1 )   36 - 36   2024.12

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    INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1, encoding a subunit of serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), and have recently been associated with juvenile ALS. SPTLC1 variants associated with ALS cause elevated levels of sphinganines and ceramides. Reports on ALS associated with SPTLC1 remain limited. This study aimed to investigate the frequency of SPTLC1 variants in ALS and relevant clinical characteristics. METHODS: We analyzed whole-exome and whole-genome sequence data from 40 probands with familial ALS and 413 patients with sporadic ALS without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis and droplet digital PCR (ddPCR) were used to assess splicing and mosaicism, respectively. Plasma sphingolipid levels were quantified to analyze biochemical consequences. RESULTS: The heterozygous c.58G>A, p.Ala20Thr variant was identified in a 21-year-old Japanese female patient presenting with symmetric weakness which slowly progressed over 15 years. RT-PCR analysis showed no splice defects. Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents. ddPCR revealed that the asymptomatic father harbored a mosaic variant with 17% relative mutant allele abundance in peripheral blood leukocytes. CONCLUSIONS: We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism. Lipid analysis results are consistent with previous findings on SPTLC1-associated ALS. Further studies are necessary to determine the clinical effect of mosaic variants of SPTLC1.

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  • Subacute Upper Motor Neuron Dysfunction Possibly Associated with the Anti-GM1 Autoantibody: A Case Report.

    So Okubo, Meiko Maeda, Kazuto Katsuse, Hiroyuki Ishiura, Yuichiro Shirota, Masashi Hamada, Wataru Satake, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2024.11

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    Anti-GM1 antibodies are associated with Guillain-Barré syndrome (GBS), primarily peripheral neuropathy. However, there are cases of anti-GM1 IgG antibody-positive GBS with upper motor neuron (UMN) signs. We herein report a case of gastrointestinal infection followed by subacute gait disturbance with predominant signs of UMN on a neurological examination. The serum and cerebrospinal fluid tests were positive for anti-GM1 and anti-asialo-GM1 IgG antibodies. An electrophysiological evaluation revealed normal nerve conduction and prolonged central motor conduction times. No MRI abnormalities were observed. The symptoms improved with treatment, which was accompanied by decreased antibody titers. This case highlights the fact that anti-GM1 IgG-associated disorders may present with predominant UMN involvement.

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  • Clinical phenotypes and CSF phospho-tau in NOTCH2NLC-related neuronal intranuclear inclusion disease(タイトル和訳中)

    Kurihara Masanori, Sengoku Renpei, Morimoto Satoru, Mitsutake Akihiko, Ishiura Hiroyuki, Higashihara Mana, Tokumaru Aya Midori, Kanemaru Kazutomi, Saito Yuko, Murayama Shigeo, Iwata Atsushi

    臨床神経学   64 ( Suppl. )   S265 - S265   2024.10

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  • Clinical and genetic analysis of Japanese patients with SPG7(タイトル和訳中)

    Mitsutake Akihiko, Hino Rimi, Sakai Yuto, Matsukawa Takashi, Mitsui Jun, Ishiura Hiroyuki, Iwata Nobue K., Tsuji Shoji, Toda Tatsushi

    臨床神経学   64 ( Suppl. )   S372 - S372   2024.10

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  • 当院における2家系のSCAR8の検討

    柚木 太淳, 松岡 千加, 小坂田 陽介, 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   64 ( 10 )   751 - 751   2024.10

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  • ATXN2遺伝子のCAGリピートをホモ接合性に有し同胞と臨床病型が異なりパーキンソニズムと痙性を呈した症例

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

    臨床神経学   64 ( 10 )   755 - 755   2024.10

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  • 髄液中抗MOG抗体を指標にIVIGによる維持療法を行った再発性MOGADの一例

    池上 憲, 佐々木 諒, 石田 将大, 樹下 明典, 平 祐貴, 小坂田 陽介, 武本 麻美, 森原 隆太, 柚木 太淳, 山下 徹, 石浦 浩之

    神経免疫学   29 ( 1 )   262 - 262   2024.10

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  • レカネマブ治療に伴うAPOE遺伝子型検査の実際

    森原 隆太, 小坂田 陽介, 池上 憲, 平 祐貴, 石田 将大, 樹下 明典, 柚木 太淳, 武本 麻美, 野村 恵美, 河野 智仁, 松岡 千加, 山下 徹, 加藤 芙美乃, 深野 智華, 平沢 晃, 石浦 浩之

    Dementia Japan   38 ( 4 )   681 - 681   2024.10

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  • Hyperdense Vessel Sign in Brain Computed Tomography as an Early Indication of Reversible Cerebral Vasoconstriction Syndrome: A Case Report.

    Akihiko Mitsutake, Tatsuo Mano, Mizuho Kawai, Ryo Kurokawa, Hiroyuki Ishiura, Kaori Sakuishi, Harushi Mori, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2024.9

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    We herein report a case of reversible cerebral vasoconstriction syndrome (RCVS) with an unusual presentation of hyperdense blood vessels. A 53-year-old woman developed thunderclap headache. Brain computed tomography (CT) showed hyperdensity of the anterior cerebral artery. Brain magnetic resonance imaging revealed cerebral infarctions in the left anterior cerebral artery (ACA) territory and cerebellum. The left ACA presented with a hyperintense vessel sign, although magnetic resonance angiography (MRA) appeared normal. One week later, stenotic changes were confirmed using MRA. The vasoconstriction disappeared on day 20, and the patient was diagnosed with RCVS. CT-defined hyperdense vessel signs can be observed at an early stage of RCVS, leading to ischemic events.

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  • Association study of GBA1 variants with MSA based on comprehensive sequence analysis -Pitfalls in short-read sequence analysis depending on the human reference genome- Reviewed International journal

    Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Masaki Tanaka, Junko Nomoto, Hiroyuki Ishiura, Yosuke Omae, Yosuke Kawai, Katsushi Tokunaga, Hatsue Ishibashi-Ueda, Tsutomu Tomita, Michio Noguchi, Ayako Takahashi, Yu-ichi Goto, Sumiko Yoshida, Kotaro Hattori, Ryo Matsumura, Aritoshi Iida, Yutaka Maruoka, Hiroyuki Gatanaga, Akihiko Shimomura, Masaya Sugiyama, Satoshi Suzuki, Kengo Miyo, Yoichi Matsubara, Akihiro Umezawa, Kenichiro Hata, Tadashi Kaname, Kouichi Ozaki, Haruhiko Tokuda, Hiroshi Watanabe, Shumpei Niida, Eisei Noiri, Koji Kitajima, Yosuke Omae, Reiko Miyahara, Hideyuki Shimanuki, Yosuke Kawai, Katsushi Tokunaga, Tatsushi Toda, Shoji Tsuji

    Journal of Human Genetics   2024.7

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    Abstract

    Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar ataxia. To elucidate variants associated with MSA, we have been conducting short-read-based whole-genome sequence analysis. In the process of the association studies, we initially focused on GBA1, a previously proposed susceptibility gene for MSA, to evaluate whether GBA1 variants can be efficiently identified despite its extraordinarily high homology with its pseudogene, GBA1LP. To accomplish this, we conducted a short-read whole-genome sequence analysis with alignment to GRCh38 as well as Sanger sequence analysis and compared the results. We identified five variants with inconsistencies between the two pipelines, of which three variants (p.L483P, p.A495P–p.V499V, p.L483_M489delinsW) were the results of misalignment due to minor alleles in GBA1P1 registered in GRCh38. The miscalling events in these variants were resolved by alignment to GRCh37 as the reference genome, where the major alleles are registered. In addition, a structural variant was not properly identified either by short-read or by Sanger sequence analyses. Having accomplished correct variant calling, we identified three variants pathogenic for Gaucher disease (p.S310G, p.L483P, and p.L483_M489delinsW). Of these variants, the allele frequency of p.L483P (0.003) in the MSA cases was higher than that (0.0011) in controls. The meta-analysis incorporating a previous report demonstrated a significant association of p.L483P with MSA with an odds ratio of 2.92 (95% CI; 1.08 – 7.90, p = 0.0353).

    DOI: 10.1038/s10038-024-01266-1

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    Other Link: https://www.nature.com/articles/s10038-024-01266-1

  • A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes. Reviewed International journal

    Hiroya Naruse, Chifumi Iseki, Jun Mitsui, Jun Miki, Hikaru Nagasawa, Katsuro Kurokawa, Ryota Kobayashi, Hiroyasu Sato, Jun Goto, Wataru Satake, Hiroyuki Ishiura, Shoji Tsuji, Yasuyuki Ohta, Tatsushi Toda

    Amyotrophic lateral sclerosis & frontotemporal degeneration   1 - 4   2024.7

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    Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.

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  • Treatment of cryptogenic new-onset refractory status epilepticus (C-NORSE) with tocilizumab: A case report. Reviewed

    Yumiko Nakamura, Masayuki Ueda, Satoshi Kodama, Tomohiko Kimura, Yuichiro Shirota, Masashi Hamada, Hiroyuki Ishiura, Takahiro Iizuka, Tatsushi Toda

    Internal medicine (Tokyo, Japan)   2024.4

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    A 35-year-old woman with no prior history of epilepsy developed status epilepticus (SE), which was highly resistant to multiple antiseizure medications and sedatives. The etiology of SE was not identified despite extensive investigation, and the patient was diagnosed with cryptogenic new-onset refractory status epilepticus (C-NORSE). Although first-line immunotherapies such as high-dose corticosteroids and plasma exchange were ineffective, the patient manifested a resolution of SE after the administration of tocilizumab, which inhibits interleukin-6. Non-antibody-mediated inflammation has been hypothesized to be a probable pathophysiology of C-NORSE in recent studies, and tocilizumab may be a plausible second-line treatment.

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  • Protective effect of scallop-derived plasmalogen against vascular dysfunction, via the pSTAT3/PIM1/NFATc1 axis, in a novel mouse model of Alzheimer's disease with cerebral hypoperfusion. Reviewed International journal

    Yun Zhai, Ryuta Morihara, Tian Feng, Xinran Hu, Yusuke Fukui, Zhihong Bian, Yuting Bian, Haibo Yu, Hongming Sun, Mami Takemoto, Yumiko Nakano, Taijun Yunoki, Ying Tang, Hiroyuki Ishiura, Toru Yamashita

    Brain research   1828   148790 - 148790   2024.4

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    A strong relationship between Alzheimer's disease (AD) and vascular dysfunction has been the focus of increasing attention in aging societies. In the present study, we examined the long-term effect of scallop-derived plasmalogen (sPlas) on vascular remodeling-related proteins in the brain of an AD with cerebral hypoperfusion (HP) mouse model. We demonstrated, for the first time, that cerebral HP activated the axis of the receptor for advanced glycation endproducts (RAGE)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/provirus integration site for Moloney murine leukemia virus 1 (PIM1)/nuclear factor of activated T cells 1 (NFATc1), accounting for such cerebral vascular remodeling. Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD.

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  • Neuroprotective effect of, a flavonoid, sudachitin in mice stroke model. Reviewed International journal

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

    Brain research   1827   148745 - 148745   2024.3

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    A flavonoid, sudachitin, has been reported to show some beneficial health effects, including as an anti-inflammatory in LPS-stimulated macrophages, as well as improving glucose and lipid metabolism in mice fed a high-fat diet. In this study, we investigated the neuroprotective effect of sudachitin in the transient middle cerebral artery occlusion (tMCAO) mouse model. After daily pre-treatment of vehicle or sudachitin (5 or 50 mg/kg) for 14 days, mice (n = 76) were subjected to a sham operation or tMCAO for 45 min, and on the following days, they were treated daily with vehicle or sudachitin. The administration of sudachitin significantly reduced (p < 0.05) cerebral infarct volume and attenuated apoptosis, 5 days after tMCAO. Neurological impairment improved, the expression of an oxidative stress marker, 4-HNE, decreased, and the Sirt1/PGC-1α pathway was activated 5 days after tMCAO in the sudachitin-treated group. This is the first report to demonstrate the neuroprotective effect of sudachitin in cerebral ischemia/reperfusion injury mice model, probably by activating the Sirt1/PGC-1α axis. Sudachitin may be a promising supplement or therapeutic agent for reducing injury caused by ischemic strokes.

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  • Proximal sensory neuropathy and cerebellar ataxia as presenting symptoms of NOTCH2NLC-related neuronal intranuclear inclusion disease. Reviewed International journal

    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   458   122915 - 122915   2024.2

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  • CGG repeat expansion in LOC642361/NUTM2B-AS1 typically presents as oculopharyngodistal myopathy. Reviewed International journal

    Yan Shi, Chunyan Cao, Yiheng Zeng, Yuanliang Ding, Long Chen, Fuze Zheng, Xuejiao Chen, Fanggui Zhou, Xiefeng Yang, Jinjing Li, Liuqing Xu, Guorong Xu, Minting Lin, Hiroyuki Ishiura, Shoji Tsuji, Ning Wang, Zhiqiang Wang, Wan-Jin Chen, Kang Yang

    Journal of genetics and genomics = Yi chuan xue bao   51 ( 2 )   184 - 196   2024.2

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    CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy. However, since only three patients from a single family were reported, it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1. Here, using repeat-primed-polymerase chain reaction and long-read sequencing, we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1, typically presenting with oculopharyngodistal myopathy. The CGG repeat expansions range from 161 to 669 repeat units. Most of the patients present with ptosis, restricted eye movements, dysphagia, dysarthria, and diffuse limb muscle weakness. Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging. Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles. Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity, suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis. Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.

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  • The Japan MSA registry: A multicenter cohort study of multiple system atrophy Reviewed

    Ayaka Chikada, Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda, Hidehiro Mizusawa, Yuji Takahashi, Masahisa Katsuno, Kazuhiro Hara, Osamu Onodera, Tomohiko Ishihara, Masayoshi Tada, Satoshi Kuwabara, Atsuhiko Sugiyama, Yoshitaka Yamanaka, Ryosuke Takahashi, Nobukatsu Sawamoto, Yusuke Sakato, Tomoyuki Ishimoto, Ritsuko Hanajima, Yasuhiro Watanabe, Hiroshi Takigawa, Tadashi Adachi, Koji Abe, Toru Yamashita, Hiroshi Takashima, Keiko Higashi, Junichi Kira, Ichiro Yabe, Masaaki Matsushima, Katsuhisa Ogata, Kinya Ishikawa, Yoichiro Nishida, Taro Ishiguro, Kokoro Ozaki, Tetsuya Nagata, Shoji Tsuji

    Neurology and Clinical Neuroscience   2024

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    DOI: 10.1111/ncn3.12809

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  • A novel de novo disease-causing variant in ATL1 in a pediatric patient with spastic paraplegia

    Ayumi Nakamura, Hiroya Naruse, Akihiko Mitsutake, Jun Mitsui, Shinichi Morishita, Mie Iwakoshi, Hiroyuki Ishiura, Shoji Tsuji, Tatsushi Toda

    Neurology and Clinical Neuroscience   2024

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    DOI: 10.1111/ncn3.12860

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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 Reviewed

    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   2023.12

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

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

    Internal medicine (Tokyo, Japan)   63 ( 12 )   1807 - 1812   2023.11

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

    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   2023.10

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    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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  • 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   2023.9

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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   2023.9

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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   2023.9

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  • 当院で経験した脊髄小脳変性症7型2家系の臨床的検討

    吉田 千晴, 小松 大樹, 馬場 智也, 後藤 良司, 首藤 篤史, 松川 敬志, 石浦 浩之, 三井 純, 中森 知毅, 市川 弥生子, 後藤 順, 中村 奈津子, 角田 和繁, 小畑 亮, 澤村 裕正, 戸田 達史

    臨床神経学   63 ( Suppl. )   S298 - S298   2023.9

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

    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)   63 ( 7 )   999 - 1004   2023.8

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    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. Reviewed

    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)   63 ( 6 )   861 - 865   2023.8

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    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 Reviewed International journal

    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   2023.7

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    DOI: 10.1016/j.jns.2023.120732

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

    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)   63 ( 4 )   565 - 569   2023.6

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    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. Reviewed International journal

    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   2023.6

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    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.

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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. Reviewed International journal

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

    Epilepsia   64 Suppl 1   S31-S38   2023.6

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    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. Reviewed International journal

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

    Annals of clinical and translational neurology   10 ( 7 )   1230 - 1238   2023.5

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    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. Reviewed International journal

    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   2023.5

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    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.

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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. Reviewed International journal

    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   2023.5

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    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.

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  • Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy. International journal

    Yasuo Nakahara, Jun Mitsui, Hidetoshi Date, Kristine Joyce Porto, Yasuhiro Hayashi, Atsushi Yamashita, Yoshio Kusakabe, Takashi Matsukawa, Hiroyuki Ishiura, Tsutomu Yasuda, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yoshio Momose, Yuji Takahashi, Tatsushi Toda, Rikifumi Ohta, Jun Yoshimura, Shinichi Morishita, Emil K Gustavsson, Darren Christy, Melissa Maczis, Matthew J Farrer, Han-Joon Kim, Sung-Sup Park, Beomseok Jeon, Jin Zhang, Weihong Gu, Sonja W Scholz, Andrew B Singleton, Henry Houlden, Ichiro Yabe, Hidenao Sasaki, Masaaki Matsushima, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, 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, Ken Yamamoto, Mihoko Shimada, Taku Miyagawa, Yosuke Kawai, Nao Nishida, Katsushi Tokunaga, Alexandra Dürr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wüllner, Caroline M Tanner, Walter A Kukull, Virginia M-Y Lee, Eliezer Masliah, Phillip A Low, Paola Sandroni, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji

    medRxiv : the preprint server for health sciences   2023.5

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    To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.

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  • A case of intravascular lymphoma presenting with a lesion in the splenium of the corpus callosum. Reviewed International journal

    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   2023.5

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    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.

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

    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   2023.5

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    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.

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  • Favorable outcome of hematopoietic stem cell transplantation in late-onset Krabbe disease. Reviewed International journal

    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   2023.4

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    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.

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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. Invited Reviewed International journal

    Hiroyuki Ishiura, Shoji Tsuji, Tatsushi Toda

    Journal of human genetics   68 ( 3 )   169 - 174   2023.3

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    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.

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

    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   2023.2

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    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. Reviewed International journal

    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   2023.1

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    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.

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

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

    Internal Medicine   63 ( 2 )   333 - 336   2023

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    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.

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  • A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis. Reviewed International journal

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

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

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    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.

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

    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   100 ( 10 )   10.1212/WNL.0000000000201647 - 10.1212/WNL.0000000000201647   2022.12

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    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.

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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. Reviewed International journal

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

    Neurology   99 ( 22 )   e2437-e2442   2022.11

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    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.

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  • Valosin-containing protein Asp395Gly mutation in a patient with frontotemporal dementia: a case report. Reviewed International journal

    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   2022.11

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    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.

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

    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   2022.10

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    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.

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

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

    Cerebellum (London, England)   2022.10

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    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.

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

    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   2022.10

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    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.

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  • Clinical and Genetic Features of Multiplex Families with Multiple System Atrophy and Parkinson's Disease. Reviewed International journal

    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)   2022.9

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    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.

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

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

    Internal medicine (Tokyo, Japan)   62 ( 7 )   1073 - 1076   2022.8

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    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.

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  • Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations. Reviewed International journal

    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   2022.7

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    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.

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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 Reviewed

    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   2022.7

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    DOI: 10.1111/ncn3.12607

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  • Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible. Reviewed International journal

    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 )   2022.6

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    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.

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

    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   2022.5

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    DOI: 10.1002/ajmg.a.62774

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

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

    Movement Disorders   2022.5

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    DOI: 10.1002/mds.29048

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  • Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan. Reviewed International journal

    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   2022.5

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    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.

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

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

    Clinical rheumatology   2022.3

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    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.

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  • Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes. Reviewed International journal

    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   2022.3

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    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.

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  • Muscle Transcriptomics Shows Overexpression of Cadherin 1 in Inclusion Body Myositis. Reviewed International journal

    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   2022.3

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    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.

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  • Family with congenital contractural arachnodactyly due to a novel multiexon deletion of the FBN2 gene. Reviewed International journal

    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   2022.2

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    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.

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  • An immigrant family with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. Reviewed International journal

    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   2022.2

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    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.

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  • An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families. Reviewed International journal

    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   2022.1

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    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.

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

    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   2022.1

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    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.

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  • Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy. Reviewed International journal

    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

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    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.

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  • DMD exon 2 duplication due to a complex genomic rearrangement is associated with a somatic mosaicism. Reviewed International journal

    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   2021.12

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    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 Reviewed

    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   2021.12

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    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. Reviewed International journal

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

    Cerebellum (London, England)   2021.11

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    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.

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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   2021.11

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    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.

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

    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   2021.10

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    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.

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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   2021.10

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    DOI: 10.1111/ncn3.12552

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  • Clinical Impact of Copy Number Variation on the Genetic Diagnosis of Syndromic Aortopathies. International journal

    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   2021.7

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

    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   2021.7

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  • 腰曲がりで発症し、筋逸脱酵素上昇・筋MRI所見から当初筋疾患も疑った運動ニューロン疾患の1例

    水上 颯, 大久保 颯, 内上 寛一, 清水 潤, 濱田 雅, 石浦 浩之, 佐竹 渉, 戸田 達史

    日本内科学会関東地方会   670回   40 - 40   2021.7

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  • Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis. International journal

    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   2021.6

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    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.

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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   2021.6

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    DOI: 10.1007/s42399-021-00962-9

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  • Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. International journal

    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   2021.5

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    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.

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

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

    Journal of human genetics   66 ( 5 )   535 - 537   2021.5

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    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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  • 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   2021.5

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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   2021.3

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    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. International journal

    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   2021.3

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    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   2021.2

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  • Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders. International journal

    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   2021.1

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    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

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    DOI: 10.2169/internalmedicine.7355-21

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  • Chédiak–Higashi syndrome presenting as a hereditary spastic paraplegia

    Kishin Koh, Mai Tsuchiya, Hiroyuki Ishiura, Haruo Shimazaki, Takeshi Nakamura, Hideo Hara, Kohei Suzuyama, Makio Takahashi, Shoji Tsuji, Yoshihisa Takiyama, Japan Spastic Paraplegia Research Consortium

    Journal of Human Genetics   2021

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    DOI: 10.1038/s10038-021-00977-z

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  • Familial dementia with Lewy bodies with VPS13C mutations. International journal

    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   2020.12

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  • A Japanese family with primary familial brain calcification presenting with paroxysmal kinesigenic dyskinesia - A comprehensive mutational analysis. Reviewed International journal

    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   2020.11

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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   2020.11

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    DOI: 10.1111/ncn3.12453

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  • 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   2020.11

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    DOI: 10.1111/ncn3.12452

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  • 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   2020.11

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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. International journal

    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   2020.11

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    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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  • Rapid Prototyping of Genomic Diagnostic Platform for Clinical Decision Support Reviewed

    Takano R, Miyamoto S, Ishii M, Ishiura H, Tsuji S, Ohe K

    An Official Journal of the Japan Association for Medical Informatics   40 ( 2 )   83 - 95   2020.10

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    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. International journal

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

    Neurology. Genetics   6 ( 5 )   e514   2020.10

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    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.

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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   2020.9

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    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   2020.9

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    DOI: 10.1111/ncn3.12425

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  • Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis. Reviewed International journal

    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   2020.7

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    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.

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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 Reviewed

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

    Neurocase   26 ( 4 )   220 - 226   2020.7

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    DOI: 10.1080/13554794.2020.1788608

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  • A novel mutation in the GBA2 gene in a Japanese patient with SPG46: A case report

    Keiko Nakamura-Shindo, Kenjiro Ono, Kishin Koh, Hiroyuki Ishiura, Shoji Tsuji, Yoshihisa Takiyama, Masahito Yamada

    eNeurologicalSci   19   2020.6

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    DOI: 10.1016/j.ensci.2020.100238

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  • Clinical features of inherited neuropathy with BSCL2 mutations in Japan. Reviewed International journal

    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   2020.6

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    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.

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  • Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy. Reviewed International journal

    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

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    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.

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  • VPS13D-related disorders presenting as a pure and complicated form of hereditary spastic paraplegia. Reviewed International journal

    Kishin Koh, Hiroyuki Ishiura, Haruo Shimazaki, Michiko Tsutsumiuchi, Yuta Ichinose, Haitian Nan, Shun Hamada, Toshihisa Ohtsuka, Shoji Tsuji, Yoshihisa Takiyama

    Molecular genetics & genomic medicine   e1108   2019.12

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    BACKGROUND: Alterations of vacuolar protein sorting-associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D-related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia. METHODS: We applied whole-exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents. Then, we screened the candidate genes in 664 Japanese families with HSP in Japan. RESULTS: We first found a compound heterozygote VPS13D mutation and a heterozygote ABHD4 variation in a sporadic patient with spastic paraplegia. Then, we found three patients with VPS13D mutations in two Japanese HSP families. The three patients with homozygous mutations (p.Thr1118Met/p.Thr1118Met and p.Thr2945Ala/p.Thr2945Ala) in the VPS13D showed an adult onset pure form of HSP. Meanwhile, the patient with a compound heterozygous mutation (p.Ser405Arg/p.Arg3141Ter) in the VPS13D showed a childhood onset complicated form of HSP associated with cerebellar ataxia, cervical dystonia, cataracts, and chorioretinal dystrophy. CONCLUSION: In the present study, we found four patients in three Japanese families with novel VPS13D mutations, which may broaden the clinical and genetic findings for VPS13D-related disorders.

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

    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   2019.11

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    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.

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  • UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes. Reviewed International journal

    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   2019.11

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    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.

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

    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   2019.10

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    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.

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  • Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42. Reviewed International journal

    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   2019.10

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    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.

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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   2019.9

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    DOI: 10.1111/ncn3.12319

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  • Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells. Reviewed International journal

    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   2019.4

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    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.

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  • The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case. Reviewed International journal

    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   2019.3

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    Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of KIF1A reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease. Results: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel de novo mutation (c.254C > A, p.A85D) in the motor domain of KIF1A.

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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. Reviewed International journal

    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   2019.2

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    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.

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  • Correction: PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. Reviewed International journal

    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   2019.1

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    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.

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  • PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. Reviewed International journal

    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   2019.1

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    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.

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

    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

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    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.

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

    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   2018.12

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    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.

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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   2018.12

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  • The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy. Reviewed International journal

    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   2018.9

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    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.

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  • Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment. Reviewed International journal

    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   2018.9

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    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.

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  • JASPAC: Japan Spastic Paraplegia Research Consortium. Reviewed

    Koh K, Ishiura H, Tsuji S, Takiyama Y

    Brain sciences   8 ( 8 )   2018.8

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

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

    Journal of the neurological sciences   390   20 - 21   2018.7

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  • No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY. Reviewed International journal

    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   2018.7

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    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.

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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) Reviewed

    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   2018.7

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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. Reviewed International journal

    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   2018.6

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    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.

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  • Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy. Reviewed International journal

    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   2018.6

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    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.

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

    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   2018.6

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

    Kurihara M, Sasaki T, Ishiura H, Tsuji S

    Internal medicine (Tokyo, Japan)   57 ( 20 )   3007 - 3010   2018.5

  • Optineurin pathology in the spinal cord of amyotrophic lateral sclerosis/parkinsonism-dementia complex patients in Kii Peninsula, Japan. Reviewed International journal

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

    Brain pathology (Zurich, Switzerland)   28 ( 3 )   422 - 426   2018.5

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

    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   2018.4

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    DOI: 10.1007/s12311-017-0883-4

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  • Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis. Reviewed International journal

    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   2018.4

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    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.

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

    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   2018.3

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    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.

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

    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   2018.3

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    DOI: 10.1111/jns.12252

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

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

    International Journal of Cardiology   254   262   2018.3

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    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 Reviewed

    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   2017.10

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

    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   2017.10

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

    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   2017.10

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

    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   2017.10

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

    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   2017.9

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

    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   2017.9

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    DOI: 10.1111/cge.13002

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

    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   2017.9

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

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

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 4 )   124 - 126   2017.7

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

    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   2017.6

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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 Reviewed

    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   2017.4

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

    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   2017.4

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

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

    INTERNATIONAL JOURNAL OF CARDIOLOGY   233   102 - 102   2017.4

  • Novel GBE1 mutation in a Japanese family with adult polyglucosan body disease. Reviewed International journal

    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   2017.4

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

    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   2017.1

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

    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

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  • Fukutin gene mutations that cause left ventricular noncompaction Reviewed

    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   2016.11

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

    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   2016.10

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    DOI: 10.1186/s13041-016-0267-6

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

    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   2016.10

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

    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   2016.9

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

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

    JAMA NEUROLOGY   73 ( 8 )   977 - 980   2016.8

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    DOI: 10.1001/jamaneurol.2016.1325

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  • Human genetic variation database, a reference database of genetic variations in the Japanese population. Reviewed International journal

    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   2016.6

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    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 Reviewed

    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   2016.5

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

    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   2016.4

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  • CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia Reviewed

    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   2016.4

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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 Reviewed

    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   2015.7

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    DOI: 10.1001/jamaneurol.2015.0610

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  • Novel mutations in the PNPLA6 gene in Boucher-Neuhauser syndrome Reviewed

    Kishin Koh, Fumikazu Kobayashi, Michiaki Miwa, Kazumasa Shindo, Eiji Isozaki, Hiroyuki Ishiura, Shoji Tsuji, Yoshihisa Takiyama

    JOURNAL OF HUMAN GENETICS   60 ( 4 )   217 - 220   2015.4

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    DOI: 10.1038/jhg.2015.3

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  • Variants associated with Gaucher disease in multiple system atrophy Reviewed

    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   2015.4

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    DOI: 10.1002/acn3.185

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

    Jun Mitsui, Hiroyuki Ishiura, Shoji Tsuji

    Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Fifth Edition   77 - 85   2014.11

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    DOI: 10.1016/B978-0-12-410529-4.00006-1

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

    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   2014.9

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    DOI: 10.1136/jnnp-2013-306981

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

    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   2014.4

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    DOI: 10.1002/jbmr.2091

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

    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   2014.3

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    DOI: 10.1093/bioinformatics/btt647

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

    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   2014.2

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    DOI: 10.1212/WNL.0000000000000143

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

    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   2013.10

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    DOI: 10.1002/humu.22378

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

    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   2013.8

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    DOI: 10.1016/j.jns.2013.05.018

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

    Mitsui J, Ishiura H, Tsuji S

    Brain and nerve = Shinkei kenkyu no shinpo   65 ( 3 )   247 - 255   2013.3

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

    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   2013.2

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    DOI: 10.1371/journal.pone.0056120

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

    Hiroyuki Ishiura, Shoji Tsuji

    Clinical Neurology   53 ( 11 )   1203 - 1205   2013

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    DOI: 10.5692/clinicalneurol.53.1203

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

    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   2012.12

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    DOI: 10.1136/jmedgenet-2012-101212

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

    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   2012.12

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    DOI: 10.1002/ajmg.b.32100

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

    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   2012.10

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    DOI: 10.3109/17482968.2012.684213

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

    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   2012.10

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

    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   2012.4

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    DOI: 10.1016/S1474-4422(12)70043-1

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  • Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12 Reviewed

    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   2012.2

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    DOI: 10.1172/JCI60560

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  • Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease Reviewed

    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   2012.1

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    DOI: 10.1002/ana.22658

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  • Hypertrophic Pachymeningitis and Tracheobronchial Stenosis in IgG4-related Disease: Case Presentation and Literature Review Reviewed

    Hiroyuki Yamashita, Yuko Takahashi, Hiroyuki Ishiura, Toshikazu Kano, Hiroshi Kaneko, Akio Mimori

    INTERNAL MEDICINE   51 ( 8 )   935 - 941   2012

  • Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5 Reviewed

    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   2011.8

  • Next-generation analysis on hereditary neurodegenerative disorders using next-generation sequencers Reviewed

    Hiroyuki Ishiura, Shoji Tsuji

    Clinical Neurology   51 ( 11 )   970 - 972   2011

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    DOI: 10.5692/clinicalneurol.51.970

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  • Dominant Mutations in RP1L1 Are Responsible for Occult Macular Dystrophy Reviewed

    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   2010.9

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    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 Reviewed

    Jun Mitsui, Yoko Fukuda, Kyo Azuma, Hirokazu Tozaki, Hiroyuki Ishiura, Yuji Takahashi, Jun Goto, Shoji Tsuji

    JOURNAL OF HUMAN GENETICS   55 ( 7 )   448 - 455   2010.7

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    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 Reviewed

    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

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    DOI: 10.2169/internalmedicine.49.3663

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  • SNP Haplotype Mapping in a Small ALS Family Reviewed

    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   2009.5

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MISC

  • Spearmint extract Neumentix promotes the phagocytosis of Aβ by microglia in APP23 mice

    胡欣冉, 山下徹, 石浦浩之, 森原隆太, 福井裕介, 卞宇てい

    日本脳血管・認知症学会総会プログラム・抄録集   14th   2024

  • Mislocalized TAR DNA-binding protein-43 in mice stroke model

    卞宇てい, 福井裕介, 森原隆太, 石浦浩之, 山下徹

    日本脳血管・認知症学会総会プログラム・抄録集   14th   2024

  • 当科で経験した遺伝性プリオン病症例の検討

    平佑貴, 柚木太淳, 中野由美子, 松岡千加, 小坂田陽介, 河野智仁, 武本麻美, 森原隆太, 山下徹, 石浦浩之

    日本神経学会学術大会プログラム・抄録集   65th   2024

  • 当院における髄液IL-6高値患者の検討

    柚木太淳, 河野智仁, 平佑貴, 小坂田陽介, 中野由美子, 武本麻美, 森原隆太, 山下徹, 石浦浩之

    日本神経学会学術大会プログラム・抄録集   65th   2024

  • TARDBP遺伝子変異を認めた家族性ALSの家系の3症例の臨床経過の検討

    河野智仁, 柚木太淳, 成瀬紘也, 中野由美子, 平佑貴, 松岡千加, 小坂田陽介, 野村恵美, 武本麻美, 森原隆太, 山下徹, 石浦浩之

    日本神経学会学術大会プログラム・抄録集   65th   2024

  • 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

  • 脳低灌流アルツハイマー病マウスにおけるホタテ由来プラズマローゲンの脳血管保護効果

    福井裕介, ZHAI Yun, FENG Tian, 森原隆太, 石浦浩之, 山下徹

    日本脳サプリメント学会(Web)   5th   2023

  • 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(Web)   63 ( 9 )   2023

  • Exogenous amyloid-β oligomers exacerbate cognitive deficits and activated necroptosis in APP23 mice

    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(Web)   35 ( 1 )   2023

  • 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

  • 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

  • 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

  • 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

  • 緩徐進行性の筋力低下,呼吸不全を呈し,特徴的な筋萎縮と筋面像所見を認め,既知のTTN遺伝子変異を持つHMERFの36歳男性例.

    坪山耀子, 成瀬紘也, 光武明彦, 坂井悠人, 石浦浩之, 三井純, 後藤順, 岩田信恵

    臨床神経学(Web)   63 ( 3 )   2023

  • 脳血栓回収療法がpost-stroke dementiaをひきおこすのか?

    小坂田陽介, 森原隆太, 角田慶一郎, 久我純弘, 阿部康二, 大西英之, 石浦浩之, 山下徹

    日本脳血管・認知症学会総会プログラム・抄録集   13th   2023

  • 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

  • A role of aging in the progression of cortical excitability in BAFME type 1

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    臨床神経生理学(Web)   50 ( 5 )   2022

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    日本神経学会学術大会プログラム・抄録集   62nd   2021

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    日本神経学会学術大会プログラム・抄録集   62nd   2021

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    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

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    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

  • 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

  • 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

  • 遺伝性痙性対麻痺の病態と治療

    一瀬佑太, 高紀信, 南海天, 石浦浩之, 三井純, 戸田達史, 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   62nd   2021

  • 診療科の特徴を生かした遺伝性疾患の診療・遺伝カウンセリング体制の創設

    佐藤奈穂子, 白井晴巳, 近田彩香, 堀内惠美子, 石浦浩之, 三井純, 辻省次, 辻省次, 戸田達史, 橋田秀司

    日本人類遺伝学会大会(CD-ROM)   66th   2021

  • 側弯症手術での運動誘発電位の導出に苦慮したCharcot-Marie-Tooth diseaseの一例

    田島将太郎, 持田智之, 秋田萌, 真崎桂, 谷口優樹, 成瀬紘也, 石浦浩之, 矢冨裕, 代田悠一郎

    臨床神経生理学(Web)   49 ( 5 )   2021

  • Do eye movements “age” earlier in progeria?

    Yasuo Terao, Shun-ichi Matsuda, Hiroyuki Ishiura, Shoji Tsuji, Tomotaka Yamamoto, Hideki Fukuda, Yoshikazu Ugawa

    Clinical Neurophysiology   131 ( 8 )   1835 - 1836   2020.8

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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

  • 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

  • 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

  • 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

  • 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

  • 2型糖尿病発症の高リスク疾患関連遺伝子バリアントを有する日本人の臨床像

    市川弥生子, 宮崎泰, 炭谷由計, 茂呂直紀, 渋谷裕彦, 永井健太郎, 石本麻衣, 徳重真一, 内堀歩, 石浦浩之, 三井純, 三井純, 辻省次, 辻省次, 戸田達史, 安田和基, 千葉厚郎, 市川弥生子

    日本人類遺伝学会大会(CD-ROM)   65th   2020

  • 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   2019.11

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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   2019.11

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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   2019.11

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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   2019.7

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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   2019.7

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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

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    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   2019.7

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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   2019.7

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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   2019.5

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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   2019.2

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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

  • HNRNPA1変異を有する家族性筋萎縮性側索硬化症の一家系

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    臨床神経学   58 ( Suppl. )   S319 - S319   2018.12

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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   2018.12

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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   2018.12

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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, YUAN Junhui, 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, 戸田達史, 辻省次, 高嶋博

    末梢神経   29 ( 2 )   308 - 308   2018.12

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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   2018.12

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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   2018.12

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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   2018.12

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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   2018.12

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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   2018.12

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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   2018.12

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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   2018.10

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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, 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, 辻省次

    Dementia Japan   32 ( 3 )   449 - 449   2018.9

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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   2018.9

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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   2018.8

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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   2018.7

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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   2018.6

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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   2018.6

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

    Diabetes : a journal of the American Diabetes Association   11 ( 3 )   23 - 33   2018.6

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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   2018.5

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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   2018.4

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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   2018.4

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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   2018.2

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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

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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

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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

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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   2017.11

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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   2017.10

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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   2017.10

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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   2017.10

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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   2017.10

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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   2017.7

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    Other Link: 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   2017.6

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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   2017.6

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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   2017.6

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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   2017.5

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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   2017.5

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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   2017.5

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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   2017.5

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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

    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 )   22 - 27   2017.4

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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   2017.4

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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   2017.4

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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   2017.3

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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

  • 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

  • Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial Reviewed

    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

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  • Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis Reviewed

    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

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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. Reviewed

    Kakumoto, T, Kodama, S, Ishiura, H, Mitsui, J, Hayashi, T, Shimizu, J, Morishita, S, Tsuji, S

    XXIII World Congress of Neurology (WCN 2017)   2017

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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

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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

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  • DNMT1 p.Y495H mutation is frequently associated with cerebellar ataxia compared with p.Y495C mutation. Reviewed

    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

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  • Genetic anticipation and clinical features of 32 patients with benign adult familial myoclonic epilepsy (BAFME). Reviewed

    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

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  • Diagnostic role of aerobic exercise tests on cycle ergometry in clinical settings. Reviewed

    Kurihara, M, Sugiyama, Y, Tanaka, M, Ishiura, H, Kubota, A, Hayashi, T, Shimizu, J, Tsuji, S

    XXIII World Congress of Neurology (WCN 2017)   2017

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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

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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   2016.12

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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   2016.12

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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   2016.12

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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   2016.12

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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   2016.12

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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   2016.12

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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   2016.12

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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

    高野 良治, 近藤 裕治, 北島 正人, 宮本 青, 安藝 理彦, 石浦 浩之, 辻 省次, 石井 雅通, 大江 和彦

    医療情報学連合大会論文集   36回 ( 2 )   934 - 935   2016.11

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  • 延髄最後野の病変により、嘔吐・吃逆を呈した視神経脊髄炎の81歳女性例

    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   2016.11

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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   2016.10

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  • 【SCD・MSA病型の新研究】 (第5部)遺伝型の最新研究進歩

    石浦 浩之

    難病と在宅ケア   22 ( 4 )   23 - 26   2016.7

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  • 【精神神経疾患における全エクソーム/全ゲノム解析の現状と展望】 次世代シークエンサーによるパーソナルゲノム解析の基礎

    松川 敬志, 石浦 浩之, 三井 純, 辻 省次

    分子精神医学   16 ( 3 )   146 - 152   2016.7

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  • 経過1年で緩徐進行性痙性対麻痺を呈し両側錐体路にT2高信号病変を認めた遅発型Krabbe病の一例

    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   2016.7

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  • 経過1年で緩徐進行性痙性対麻痺を呈し両側錐体路にT2高信号病変を認めた遅発型Krabbe病の一例

    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   56 ( 7 )   512 - 512   2016.7

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  • 軽度の嚥下障害と歩行障害で発症し、MRIで延髄・頸髄に著明な萎縮を認めた、成人発症アレキサンダー病の1例

    海永 光洋, 高橋 朗子, 大友 岳, 間野 達雄, 三井 純, 松川 敬志, 石浦 浩之, 林 俊宏, 清水 潤, 辻 省次

    日本内科学会関東地方会   625回   23 - 23   2016.7

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  • 新規構造変異によるapoC-II低下症(hypoapoC-II)

    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   2016.6

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  • 【ビッグデータ解析に基づく臨床研究】 ゲノムビッグデータの解析

    石浦 浩之

    神経内科   84 ( 6 )   585 - 589   2016.6

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  • apoC‐II低下症(hypoapoC‐II)に見出された新たな構造変異

    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   2016.4

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  • apoC-II低下症(hypoapoC-II)に見出された新たな構造変異

    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   2016.4

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  • 音読みが訓読み、熟字訓より障害された左中側頭回・角回皮質下出血による漢字の失読失書

    吉田 瑞, 林 俊宏, 藤井 くるみ, 石浦 浩之, 辻 省次, 櫻井 靖久

    高次脳機能研究   36 ( 1 )   80 - 80   2016.3

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  • 小児期より軽度知的障害を伴い、20歳代より錐体外路障害、知的機能低下が緩徐に進行し、POLR1C遺伝子変異を認めた57歳男性例

    神澤 彩, 内尾 直裕, 大塚 十里, 石浦 浩之, 清水 潤, 辻 省次

    臨床神経学   56 ( 3 )   214 - 214   2016.3

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  • ライソゾーム病(ファブリー病含む)に関する調査研究 副腎白質ジストロフィーの多彩な表現型を規定する遺伝的修飾因子の探索研究

    辻省次, 松川敬志, 三井純, 石浦浩之, AHSAN Budrul, 吉村淳, 土井晃一郎, 鈴木康之, 下澤伸行, 小野寺理, 西澤正豊, 森下真一

    ライソゾーム病(ファブリ病含む)に関する調査研究班 平成27年度 総括・分担研究年度終了報告書   84‐85   2016

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  • 運動失調症の医療基盤に関する調査研究 ELOVL4遺伝子異常によるSCA34

    石川欽也, 尾崎心, 土井宏, 三井純, 佐藤望, 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, 横田隆徳, 田中章景, 辻省次, 水澤英洋, 水澤英洋

    運動失調症の医療基盤に関する調査研究 平成27年度 総括・分担研究報告書   52‐54   2016

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  • 神経変性疾患領域における基盤的調査研究 次世代シーケンサーを用いた網羅的な遺伝子解析の診療への応用

    田中真生, 石浦浩之, 三井純, 森下真一, 辻省次

    神経変性疾患領域における基盤的調査研究 平成27年度 総括・分担研究報告書   145‐147   2016

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  • 筋萎縮性側索硬化症患者における次世代シーケンサーデータを用いた構造変異解析

    田中 真生, 高橋 祐二, 成瀬 紘也, 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

    臨床神経学   55 ( Suppl. )   S237 - S237   2015.12

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  • 痙性失調症を呈した新規PLA2G6変異の一卵性双生児例

    高 紀信, 星野 恭子, 泉 鉉吉, 石浦 浩之, 辻 省次, 瀧山 嘉久

    臨床神経学   55 ( Suppl. )   S223 - S223   2015.12

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  • エクソーム解析による常染色体劣性遺伝型CMTの新規原因遺伝子の同定

    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

    臨床神経学   55 ( Suppl. )   S384 - S384   2015.12

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  • BSCL2変異を認めた遺伝性ニューロパチーの臨床的特徴

    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   2015.12

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  • 歯状核赤核・淡蒼球ルイ体萎縮症遺伝子発現細胞系のRNAseqによる検討

    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

    臨床神経学   55 ( Suppl. )   S320 - S320   2015.12

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  • エクソーム関連解析による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, 山野 嘉久, 辻 省次, 出雲 周二, 高嶋 博

    臨床神経学   55 ( Suppl. )   S240 - S240   2015.12

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  • Charcot-Marie-Tooth病2F/hereditary motor neuropathy 2Bの臨床的検討

    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

    臨床神経学   55 ( Suppl. )   S384 - S384   2015.12

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  • 原因遺伝子未同定の遺伝性痙性対麻痺家系における新規原因遺伝子の探索

    川辺 美穂, 石浦 浩之, 三井 純, 鵜沼 敦, 岩田 淳, 吉村 淳, 土井 晃一郎, 森下 真一, 後藤 順, 辻 省次

    臨床神経学   55 ( Suppl. )   S441 - S441   2015.12

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  • 家族性パーキンソン病11家系における原因遺伝子の検索

    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

    臨床神経学   55 ( Suppl. )   S433 - S433   2015.12

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  • 白質変性症と非アルツハイマー型認知症 成人発症Vanishing white matter disease(VWMD)

    松川 敬志, 三井 純, 石浦 浩之, 辻 省次

    Dementia Japan   29 ( 3 )   297 - 297   2015.9

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  • 幼少時より緩徐進行性の体幹失調・末梢神経障害・錐体路徴候を呈しPLA2G6遺伝子変異を認めた29歳男性例

    池永 知誓子, 佐々木 拓也, 松川 敬志, 石浦 浩之, 三井 純, 寺尾 安生, 後藤 順, 辻 省次

    臨床神経学   55 ( 8 )   608 - 608   2015.8

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  • 【筋萎縮性側索硬化症(ALS)の分子遺伝学update】 ALSとC9orf72

    石浦 浩之

    神経内科   82 ( 4 )   382 - 387   2015.4

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  • 神経変性疾患領域における基盤的調査研究 クリニカルシーケンシングの応用と課題

    辻省次, 石浦浩之, 三井純, 後藤順

    神経変性疾患領域における基盤的調査研究 平成26年度 総括・分担研究報告書   147‐148   2015

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  • シャルコー・マリー・トゥース病の診療向上に関するエビデンスを構築する研究 Charcot‐Marie‐Tooth病の包括的遺伝子診断

    高嶋博, 橋口昭大, 樋口雄二郎, 岡本裕嗣, 石浦浩之, 三井純, 辻省次, 中川正法

    シャルコー・マリー・トゥース病の診療向上に関するエビデンスを構築する研究 平成26年度 委託業務成果報告書   12‐14   2015

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  • 運動失調症の医療基盤に関する調査研究 エクソーム解析による常染色体劣性遺伝型小脳失調症の新規原因遺伝子の同定~軸索型ニューロパチーを伴う小脳失調症の二家系~

    高嶋博, 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

    運動失調症の医療基盤に関する調査研究 平成26年度 総括・分担研究報告書   47‐51   2015

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  • 幼少時より緩徐進行性の体幹失調・失梢神経障害・錐体路微候を呈しPLA2G6遺伝子変異を認めた29歳男性例

    池永知誓子, 佐々木拓也, 松川敬志, 石浦浩之, 三井純, 寺尾安生, 後藤順, 辻省次

    臨床神経学(Web)   55 ( 8 )   608(J‐STAGE)   2015

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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変異の高感度定量的解析

    田中 真生, 石浦 浩之, 三井 純, 後藤 順, 辻 省次

    臨床神経学   54 ( Suppl. )   S34 - S34   2014.12

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  • 多系統萎縮症の疾患関連遺伝子の探索

    三井 純, 松川 敬志, 石浦 浩之, 市川 弥生子, 後藤 順, 村山 繁雄, 高嶋 博, 佐々木 秀直, 辻 省次, JAMSAC

    臨床神経学   54 ( Suppl. )   S47 - S47   2014.12

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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   2014.12

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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   2014.12

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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   2014.12

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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   2014.12

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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   2014.12

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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   2014.12

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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   2014.12

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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   2014.12

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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   2014.12

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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   2014.11

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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   2014.11

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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   2014.8

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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   2014.8

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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   2014.6

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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   2014.6

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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   2014.5

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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   2014.4

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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   2014.3

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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   2014.3

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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   2014.1

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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   2014.1

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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

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  • Molecular genetics and gene analysis of hereditary spastic paraplegia

    Hiroyuki Ishiura

    Clinical Neurology   54 ( 12 )   1016 - 1017   2014

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    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

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  • 46,XY gonadal dysgenesisを佯うminifascicular neuropathyにおける新規遺伝子変異の同定

    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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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   2013.12

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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   2013.12

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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   2013.12

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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   2013.12

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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   2013.12

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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   2013.12

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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   2013.12

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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   2013.12

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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   2013.11

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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   2013.11

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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   2013.10

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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   2013.6

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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   2013.3

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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   2013.2

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

    石浦浩之, 高橋祐二, 三井純, 市川弥生子, 伊達英俊, 後藤順, 辻省次, 小野寺理, 今野卓哉, 西澤正豊, 吉田宗平, 紀平為子, 小久保康昌, 内藤實, 葛原茂樹, 玉置知子, 富山弘幸, 大垣光太郎, 服部信孝, 和泉唯信, 梶龍兒, 熱田直樹, 祖父江元

    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   22 - 24   2013

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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

    紀平為子, 吉田宗平, 梶本賀義, 石口宏, 廣西昌也, 坂本繁, 小久保康昌, 葛原茂樹, 石浦浩之, 辻省次

    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

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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

    ISOJIMA TAKESHI, DOI KOICHIRO, MITSUI JUN, ODA YOICHIRO, TOKUHIRO ETSURO, YASODA AKIHIRO, YORIFUJI TOORU, HORIKAWA REIKO, YOSHIMURA ATSUSHI, ISHIURA HIROYUKI, MORISHITA SHIN'ICHI, TSUJI SHOJI, KITANAKA SACHIKO

    日本小児内分泌学会学術集会プログラム・抄録集   47th   90   2013

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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

    日本神経学会学術大会プログラム・抄録集   54th   430   2013

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  • 神経変性疾患に関する調査研究 近位筋優位運動感覚ニューロパチー(HMSN‐P)の原因遺伝子同定

    辻省次, 石浦浩之, 三井純, パドルルアーサン, 高橋祐二, 後藤順, 瓦井俊孝, 梶龍兒, 吉野英, 村山繁雄, 祖父江元

    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

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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

    平良 摩紀子, 石浦 浩之, 市川 弥生子, Ahsan Budrul, 福田 陽子, 三井 純, 高橋 祐二, 清水 潤, 日笠 幸一郎, 吉村 淳, 斉藤 太郎, 森下 真一, 後藤 順, 辻 省次

    臨床神経学   52 ( 12 )   1403 - 1403   2012.12

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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   2012.12

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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   2012.12

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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   2012.12

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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   2012.12

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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   2012.12

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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   2012.12

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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   2012.10

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    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   2012.7

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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   2012.4

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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   2012.1

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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

    日本神経学会学術大会プログラム・抄録集   53rd   440   2012

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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

    瀧山嘉久, 坂井千香, 畠山英之, 後藤雄一, 嶋崎晴雄, 中野今治, 石浦浩之, 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23年度 総括・分担研究報告書   152 - 156   2012

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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

    日本神経学会学術大会プログラム・抄録集   53rd   229   2012

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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

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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

    辻省次, 市川弥生子, 石浦浩之, 三井純, 高橋祐二, 後藤順, 清水潤, 小林俊輔, 金澤一郎

    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   143 - 146   2012

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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

    平良摩紀子, 石浦浩之, 市川弥生子, AHSAN Budrul, 福田陽子, 三井純, 高橋祐二, 清水潤, 日笠幸一郎, 吉村淳, 斉藤太郎, 森下真一, 後藤順, 辻省次

    日本神経学会学術大会プログラム・抄録集   53rd   231   2012

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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

    辻省次, 石浦浩之, 三井純, 福田陽子, 後藤順, 小久保康昌, 葛原茂樹, 日笠幸一郎, 吉村淳, 斉藤太郎, 森下真一, 原賢寿, 西澤正豊

    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

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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

    辻省次, 石浦浩之, 三井純

    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   53 - 54   2012

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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

    辻省次, 石浦浩之, 三井純

    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   41 - 44   2012

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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

    日本神経学会学術大会プログラム・抄録集   53rd   387   2012

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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

    日本神経学会学術大会プログラム・抄録集   53rd   387   2012

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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

    小出 百合, 宮川 統爾, 林 俊宏, 石浦 浩之, 吉田 瑞, 藤井 くるみ, 百瀬 敏光, 高橋 美和子, 岩田 淳, 辻 省次

    臨床神経学   51 ( 12 )   1341 - 1341   2011.12

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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

    平良 摩紀子, 石浦 浩之, 三井 純, 高橋 祐二, 斎藤 奈穂子, 松川 敬志, 林 俊宏, 清水 潤, 後藤 順, 辻 省次

    臨床神経学   51 ( 12 )   1456 - 1456   2011.12

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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

    石浦 浩之, 福田 陽子, 三井 純, 中原 康雄, Ahsan Budrul, 高橋 祐二, 市川 弥生子, 後藤 順, 酒井 徹雄, 辻 省次

    臨床神経学   51 ( 12 )   1394 - 1394   2011.12

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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

    嶋崎 晴雄, 石浦 浩之, 福田 陽子, 本多 純子, 太田 京子, 直井 為任, 滑川 道人, 迫江 公己, 高橋 祐二, 後藤 順, 辻 省次, 瀧山 嘉久, 中野 今治

    臨床神経学   51 ( 12 )   1394 - 1394   2011.12

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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

    三井 純, 土井 晃一郎, 石浦 浩之, 高橋 祐二, 後藤 順, 森下 真一, 辻 省次

    臨床神経学   51 ( 12 )   1428 - 1428   2011.12

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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

    赤堀 正和, 角田 和繁, 三宅 養三, 福田 陽子, 石浦 浩之, 辻 省次, 臼井 知聡, 畑瀬 哲尚, 中村 誠, 大出 尚郎, 板橋 剛, 岡本 はる, 岩田 岳

    日本眼科学会雑誌   115 ( 臨増 )   249 - 249   2011.4

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  • A Japanese Family of a Novel Autosomal Dominant Nemaline Myopathy Associated with Dilated Cardiomyopathy

    Yaeko Ichikawa, Hiroyuki Ishiura, Jun Goto, Hisatomo Kowa, Yasushi Oya, Hidetoshi Date, Shoji Tsuji

    NEUROLOGY   76 ( 9 )   A283 - A283   2011.3

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  • Clinical Characteristics of Oculopharyngeal Myopathy Linked to a Novel Locus

    Hiroyuki Ishiura, Yuji Takahashi, Yoko Fukuda, Makiko Taira, Jun Mitsui, Takashi Matsukawa, Katsuhisa Ogata, Kana Nakayama, Ichizo Nishino, Jun Goto, Shoji Tsuji

    NEUROLOGY   76 ( 9 )   A284 - A284   2011.3

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  • Clinical Features and Haplotype Analysis of Newly Identified Patients with Gelsolin-Related Familial Amyoidotic Polyneuropathy TypeIV in Japan Reviewed

    Makiko Taira, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Toshihiro Hayashi, Jun Shimizu, Takashi Matsukawa, Naoko Saito, Jun Goto, Shoji Tsuji

    NEUROLOGY   76 ( 9 )   A111 - A112   2011.3

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  • Application of a High-Throughput Linkage Analysis System, SNP HiTLink, to Autosomal Recessive Familial Myoclonus Epilepsy

    Kiyomi Morita, Yuji Takahashi, Hiroyuki Ishiura, Jun Mitsui, Jun Goto, Shoji Tsuji

    NEUROLOGY   76 ( 9 )   A377 - A378   2011.3

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  • 【遺伝性痙性対麻痺 update】 遺伝性痙性対麻痺の分子遺伝学と遺伝子診断

    石浦 浩之

    神経内科   74 ( 2 )   146 - 151   2011.2

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  • 【遺伝性痙性対麻痺 update】 遺伝性痙性対麻痺の疫学 JASPAC

    瀧山 嘉久, 石浦 浩之, 嶋崎 晴雄, 辻 省次, 西澤 正豊

    神経内科   74 ( 2 )   141 - 145   2011.2

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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 Target captureと大規模塩基配列解析によるposterior column ataxia with retinitis pigmentosaの原因遺伝子探索

    辻省次, 石浦浩之, 福田陽子, 三井純, 中原康雄, AHSAN Budrul, 高橋祐二, 市川弥生子, 伊達英俊, 後藤順, 酒井徹雄

    運動失調症の病態解明と治療法開発に関する研究班 平成22年度 総括・分担研究報告書   48 - 49   2011

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  • 家族性アミロイドポリニューロパチー・フィンランド型の本邦における臨床像と創始者ハプロタイプの検討

    平良摩紀子, 石浦浩之, 三井純, 高橋祐二, 齋藤菜穂子, 松川敬志, 林俊宏, 清水潤, 後藤順, 辻省次

    日本人類遺伝学会大会プログラム・抄録集   56th   195   2011

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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 脊髄小脳変性症の分子遺伝学的研究

    辻省次, 石浦浩之, 市川弥生子, 後藤順, 高橋祐二, 伊達英俊, 福田陽子, 中原康雄, 松川敬志, 三井純, AHSAN Budrul, 下澤伸行, 徳永勝士, 山本健, 酒井徹雄

    運動失調症の病態解明と治療法開発に関する研究班 平成20-22年度総合 総括・分担研究報告書   107 - 109   2011

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  • Massively parallel sequence analysis reveals the causative gene of an autosomal recessive neurodegenerative disorder, posterior column ataxia with retinitis pigmentosa

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

    NEUROSCIENCE RESEARCH   71   E292 - E292   2011

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    DOI: 10.1016/j.neures.2011.07.1274

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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

    三井純, 土井晃一郎, 石浦浩之, 高橋祐二, 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   52nd   500   2011

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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posierior column ataxia with retinitis pigmentosaの原因遺伝子探索

    石浦浩之, 福田陽子, 三井純, 中原康雄, BUDRUL Ahsan, 高橋祐二, 市川弥生子, 後藤順, 酒井徹雄, 辻省次

    日本神経学会学術大会プログラム・抄録集   52nd   464   2011

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  • 臨床医学の展望,神経病学:血管系を除く.

    辻 省次, 岩田 淳, 日出山 拓人, 石浦 浩之, 代田 悠一郎, 長島 優, 宮川統爾

    日本医事新報   ( 4533 )   46 - 58   2011

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  • 振戦・認知症・末梢神経障害・網膜色素変性症を認めた白質脳症家系

    大友 亮, 代田 悠一郎, 石浦 浩之, 古和 久朋, 岩田 淳, 辻 省次

    臨床神経学   50 ( 12 )   1247 - 1247   2010.12

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  • SNPアレイを用いたハイスループット連鎖解析システムの診療への応用

    石浦 浩之, 福田 陽子, 高橋 祐二, 中原 康雄, 三井 純, 松川 敬志, 市川 弥生子, 後藤 順, 辻 省次

    臨床神経学   50 ( 12 )   1075 - 1075   2010.12

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  • 常染色体優性遺伝ネマリンミオパチー家系の解析

    長島 優, 石浦 浩之, 弓削田 晃弘, 清水 潤, 福田 陽子, 高橋 祐二, 市川 弥生子, 後藤 順, 辻 省次

    臨床神経学   50 ( 12 )   1162 - 1162   2010.12

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  • 神経ゲノミクスの最先端 神経筋疾患解明のための大規模シークエンシング

    石浦 浩之, 辻 省次

    臨床神経学   50 ( 11 )   957 - 958   2010.11

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  • 神経内科診療における遺伝子解析の有用性

    市川弥生子, 石浦浩之, 三井純, 松川敬志, 成瀬紘也, 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   55th   219   2010.10

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  • Application of a Microarray-Based Whole Mitochondrial DNA Sequence Analysis for Molecular Diagnosis of Mitochondrial Diseases

    Hiroyuki Ishiura, Yuji Takahashi, Shinobu Fukumura, Yoshiko Nomura, Ritsuko Hanajima, Yasuo Terao, Akihiro Yugeta, Jun Shimizu, Jun Goto, Shoji Tsuji

    NEUROLOGY   74 ( 9 )   A265 - A265   2010.3

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  • 遺伝性痙性対麻痺の分子遺伝学

    石浦 浩之, 辻 省次

    最新医学   65 ( 1 )   113 - 120   2010.1

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    Other Link: http://search.jamas.or.jp/link/ui/2010104458

  • Japan spastic paraplegia research consortium (JASPAC)

    Yoshihisa Takiyama, Hiroyuki Ishiura, Haruo Shimazaki, Michito Namekawa, Yuji Takahashi, Jun Goto, Shoji Tsuji, Masatoyo Nishizawa

    Clinical Neurology   50 ( 11 )   931 - 934   2010

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    DOI: 10.5692/clinicalneurol.50.931

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  • A case of autosomal recessive hypomyelinating leukodystrophy without GJA12 mutation presenting a novel phenotype

    Tomoko Ishikawa, Kimiko Sato, Rie Shimazaki, Katsumasa Goto, Takao Matsuda, Hiroyuki Ishiura

    Clinical Neurology   50 ( 1 )   7 - 11   2010

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    DOI: 10.5692/clinicalneurol.50.7

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  • 遺伝性痙性対麻痺の大規模分子疫学の解明

    石浦 浩之, 高橋 祐二, 滑川 道人, 嶋崎 晴雄, 瀧山 嘉久, 後藤 順, 辻 省次

    臨床神経学   49 ( 12 )   978 - 978   2009.12

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  • SPG17の原因遺伝子seipinのナンセンス変異をヘテロ接合で認めた痙性対麻痺の1家系

    嶋崎 晴雄, 滑川 道人, 中野 今治, 石浦 浩之, 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

    臨床神経学   49 ( 12 )   1114 - 1114   2009.12

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  • 両側線条体壊死を呈しND3に新規変異を認めた複合体I単独欠損症の1例

    福村 忍, 坂井 拓朗, 池本 亘, 水江 伸夫, 足立 憲昭, 舘 延忠, 石浦 浩之, 後藤 順, 辻 省次, 村山 圭, 大竹 明

    脳と発達   41 ( 6 )   470 - 470   2009.11

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  • 神経伝導検査で脱髄性変化が疑われ、診断に苦慮したアミロイドポリニューロパチー(TTRS50R)の59歳男性例

    代田 悠一郎, 岩田 淳, 清水 潤, 石浦 浩之, 辻 省次

    臨床神経学   49 ( 9 )   607 - 607   2009.9

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  • A COMPREHENSIVE MUTATIONAL ANALYSIS SYSTEM REVEALED MUTATIONAL SPECTRUM OF HEREDITARY SPASTIC PARAPLEGIA

    H. Ishiura, Y. Takahashi, J. Goto, S. Tsuji

    JOURNAL OF NEUROCHEMISTRY   110   56 - 56   2009.9

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  • 紀伊半島のALS/パーキンソン認知症複合におけるTRPM7遺伝子変異に関する検討

    小久保 康昌, 原 賢寿, 石浦 浩之, 福田 陽子, 宮下 哲典, 桑野 良三, 佐々木 良元, 後藤 順, 西澤 正豊, 葛原 茂樹, 辻 省次

    Dementia Japan   23 ( 2 )   217 - 217   2009.8

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  • 【抗NMDA受容体脳炎】 腫瘍非合併例における抗NMDA受容体脳炎

    石浦 浩之, 山本 知孝, 辻 省次

    最新医学   64 ( 7 )   1553 - 1559   2009.7

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    Other Link: http://search.jamas.or.jp/link/ui/2009248285

  • 純粋型ミオパチーの病像を呈しミトコンドリアDNA 5591G>A(tRNAAla)変異を認めた40歳男性例

    石浦 浩之, 嶋田 勢二郎, 清水 潤, 後藤 順, 辻 省次

    臨床神経学   49 ( 6 )   390 - 390   2009.6

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  • 10歳時に視力低下で発症し、脊髄病変・中脳病変を併発したLeber"plus"病の22歳男性例

    堤 涼介, 代田 悠一郎, 石浦 浩之, 清水 潤, 野村 芳子, 辻 省次

    臨床神経学   49 ( 2-3 )   141 - 141   2009.3

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  • 【抗NMDA受容体抗体と脳炎】 抗NR1/NR2抗体陽性脳炎 腫瘍非合併例

    石浦 浩之, 辻 省次

    神経内科   70 ( 1 )   69 - 73   2009.1

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  • 臨床医学の展望 神経病学-血管系を除く-

    辻 省次, 郭 伸, 岩田 淳, 古和 久朋, 石浦 浩之, 代田 悠一郎, 長島 優

    日本医事新報   ( 4431 )   53 - 61   2009

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  • 連鎖解析および全エキソンキャプチャー法を用いたDNAリシークエンシングと,神経疾患の原因遺伝子同定への応用

    福田陽子, REGINALDO Kuroshu, 薇曲, 中原康雄, 石浦浩之, 原賢寿, 鈴木穣, 菅野純夫, 森下真一, 辻省次

    日本人類遺伝学会大会プログラム・抄録集   54th   218   2009

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  • Pooled DNAを用いたバーコードによるmultiplexed resequencingの試み

    三井純, 東きょう, 戸崎浩和, 石浦浩之, 高橋祐二, 後藤順, 辻省次

    日本人類遺伝学会大会プログラム・抄録集   54th   154   2009

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  • Anti-NMDA receptor-related Autoantibodies and therapeutic outcome in acute non-herpetic encephalitis accompanied with refractory seizures in young women

    Hiroyuki Ishiura, Mana Higashihara, Tornotaka Yamamoto, Jun Shimizu, Jun Goto, Josep Dalmau, Yukitoshi Takahashi, Shoji Tsuji

    NEUROLOGY   70 ( 11 )   A455 - A455   2008.3

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  • 【脊髄小脳変性症研究の最近の進歩】 家族性痙性対麻痺 家族性痙性対麻痺の分子遺伝学

    石浦 浩之, 高橋 祐二, 後藤 順, 辻 省次

    神経研究の進歩   50 ( 3 )   429 - 437   2006.6

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  • Molecular epidemiology of hereditary and sporadic spastic paraplegias in the Japanese population analyzed with a high-throughput DNA microarray-based resequencing system

    H Ishiura, Y Takahashi, J Goto, S Tsuji

    NEUROLOGY   66 ( 5 )   A128 - A128   2006.3

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  • 蜂窩織炎からのショックの経過中にACTH・コルチゾールの正常化を認めた周期性Cushing症候群の一例

    石浦 浩之, 姚 皇治, 清末 有宏, 岩橋 陽介, 野村 和至, 日野 治子, 吉本 智信, 宮尾 益理子, 水野 有三, 堀内 敏行

    ACTH RELATED PEPTIDES   15   251 - 258   2004.12

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Awards

  • 日本神経学会賞

    2021.5   日本神経学会   神経筋疾患における新規リピート伸長病の発見

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    2018.10   The Japan Society of Human Genetics   Genetic study on neurological diseases

    ISHIURA Hiroyuki

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  • English Presentation Award

    2018.10   The Japan Epilepsy Society   Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

    ISHIURA Hiroyuki

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  • Travel Award

    2011.10   The Japan Society of Human Genetics   Massively parallel sequence analysis reveals the causative gene of posterior column ataxia with retinitis pigmentosa

    ISHIURA Hiroyuki

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Research Projects

  • Research on neurodegenerative disorders

    Grant number:23H02823  2023.04 - 2027.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    石浦 浩之, 角元 利行

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    Grant amount:\18460000 ( Direct expense: \14200000 、 Indirect expense:\4260000 )

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  • comprehensive search for expanded repeats in neurodegenerative diseaess

    Grant number:22H02823  2022.04 - 2025.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    辻 省次, 池内 健, 田中 真生, 石浦 浩之

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    Grant amount:\17160000 ( Direct expense: \13200000 、 Indirect expense:\3960000 )

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  • comprehensive search for expanded repeats in neurodegenerative diseaess

    Grant number:23K24085  2022.04 - 2025.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    辻 省次, 池内 健, 田中 真生, 石浦 浩之, 三井 純

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    Grant amount:\17160000 ( Direct expense: \13200000 、 Indirect expense:\3960000 )

    本研究では、封入体形成が病理学的特徴である神経変性疾患に着目して、非翻訳領域の伸長リピート配列を探索し、神経変性疾患の発症機構を解明することを目的とする。この考え方は、非翻訳領域のリピート伸長配列は、Repeat Associated Non-AUG translation (RAN translation) を引き起こし、異常なアミノ酸配列を有するタンパクへの翻訳が行われ、その結果、封入体を形成するという仮説に基づいている。リピート伸長配列の検出は、short read sequencerでは困難であることから、long read sequencer による全ゲノムシーケンス解析を実施し、3-6塩基の繰り返し配列に焦点を当てて、伸長リピート配列を検出する独自に開発したプログラムを用いて、伸長リピート配列をゲノム全域から検出し、神経変性疾患の発症に関連する伸長リピート配列の発見を進めた。解析対象として、発症年齢の早いextreme phenotype を示すアルツハイマー病、家族歴を有する家族性アルツハイマー病症例を中心に7例を選択して、long read sequencer (Pacific Bioscience s 社のSequel II) を用いて、ロングリードシーケンス解析を実施した。long read sequencerは、error readを生じやすく精度が十分でないことから、circular consensus sequencing (CCS) というアルゴリズムにより、得られた全ゲノム配列データを用いた。その結果,これまでに報告のない、伸長リピート配列がさらに縦列に重複している例を見出した。本研究で開発したプログラムを用いて、伸長リピート配列の解析を進め、その疾患発症における意義の検討を進める。

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  • Revealing pathogenesis of noncoding repeat expansion diseases using long-read sequencing

    Grant number:20H03588  2020.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    石浦 浩之

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    Grant amount:\17680000 ( Direct expense: \13600000 、 Indirect expense:\4080000 )

    ミオクローヌスてんかん患者でリピート伸長変異を有さない症例については全ゲノム配列解析を行い、通常のbasecallingに加えて、ExpansionHunterDenovoも使用してリピート配列のプロファイリングも行っている。これらの解析により、全ゲノム配列解析の有用性を含め、検討中である。
    ロングリード全ゲノム配列解析データについても現在データ解析中であるが、非常に高精度に塩基配列解析が出来ていることが判明している。特に、circular consensus sequencingにより実際高い精度を出せることがわかっている。
    伸長リピートを効率良く増幅することが可能になったため、ロングリードシーケンサーによる全長解読を行うために現在検体を準備している。また、PCR以外の方法を用いたリピート配列のクローニングも可能となり、この技術を用いて、機能解析に使用出来るコンストラクト作成を進めている。

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  • Role of immune checkpoint molecules and macrophages in inflammatory myopathies

    Grant number:19K07956  2019.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    SHIMIZU Jun

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    Grant amount:\4030000 ( Direct expense: \3100000 、 Indirect expense:\930000 )

    The clinical and pathological features of myositis as a side effect of immune checkpoint inhibitors (irAE myositis) were analyzed in 12 cases to clarify the role of immune checkpoint molecules and macrophages. Similar pathology to irAE myositis was shown to be present in Graft-versus-host disease (GvHD) related myositis, revealing that immune checkpoint abnormalities are also involved in chronic GvHD myositis.In RNA-sequencing analysis of muscle samples from patients with inclusion body myositis (IBM) or polymyositis, it was revealed that, CDH1, which encodes the epidermal cell junction protein cadherin 1, was ectopically expressed in the muscles of IBM.

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  • Exploring rare variants associated with Alzheimer disease

    Grant number:19H03425  2019.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Tsuji Shoji

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    Grant amount:\17550000 ( Direct expense: \13500000 、 Indirect expense:\4050000 )

    To improve the power of association studies for relatively small sample size, we employed permutation testing to determine the p-value to be used for association studies. Employing exome sequence data obtained from 446 cases of sporadic Alzheimer disease (AD) and 446 aged controls with preserved cognitive function, we identified a candidate gene associated with AD. Since the candidate gene contains GC-rich regions, we optimized the methods for exon capture and library construction. We newly conducted exome sequence analysis of 262 cases of AD and 260 aged controls with preserved cognitive function. We confirmed that sequence data with high quality were obtained with the improved procedures. Although significant association of the candidate gene was not replicated, we found several candidate genes possibly associated with AD. The current study confirmed the utility of permutation testing for exome association studies.

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  • Toward pathogenesis of noncoding repeat expansion disease focusing on RNA toxicity

    Grant number:18K19506  2018.06 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)  Grant-in-Aid for Challenging Research (Exploratory)

    Ishiura Hiroyuki

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    Grant amount:\6370000 ( Direct expense: \4900000 、 Indirect expense:\1470000 )

    Benign adult familial myoclonic epilepsy type 1 (BAFME1) is an autosomal dominant disease which is characterized by infrequent seizures and myoclonic tremor. The cause of the disease have been identified as TTTTA and TTTCA repeat expansion mutation in intron 4 of SAMD12.
    We focused on RNA-mediated pathomechanism in BAFME1 in this study. We identified RNA foci in autopsied brain in patients with BAFME1. RNA foci were not found in lymphoblastoid cell lines from patients with BAFME1. RNA-seq using autopsied brains revealed differentially expressed genes (40 downregulated and 44 upregulated). There seems no alternatively transcribed genes. In addition we found abortive transcription around the expanded repeats in SAMD12. We also cloned TTTTA, TTTCA, and TTTTA/TTTCA repeats in vectors and successfully expressed in HEK293 cells. Collectively, RNA-mediated toxicity is considered to play an important role in pathogenesis of BAFME and more investigation focusing on RNA metabolism should be paid.

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  • Comprehensive whole genome sequence analysis using a long read sequencer for delineating molecular mechanism of neurological diseases

    Grant number:17H05085  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)  Grant-in-Aid for Young Scientists (A)

    Ishiura Hiroyuki

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    Grant amount:\25090000 ( Direct expense: \19300000 、 Indirect expense:\5790000 )

    In benign adult familial myoclonic epilepsy (BAFME), expansions of intronic TTTCA and TTTTA repeats were identified in SAMD12, TNRC6A, and RAPGEF2. A new concept of repeat motif-phenotype correlation was proposed. The finding strongly indicates the gain-of-function of the expanded repeats is pathomechanism of BAFME.
    The study also indicate the importance of genetic analysis focusing on repeat expansions. By applying this strategy to neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukoencephalopathy, and oculopharyngodistal myopathy, CGG repeat expansions were identified in NOTCH2NLC, LOC642361/NUTM2B-AS1, LRP12, respectively.

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  • Gene expression profiling of inflammatory myopathy in correlation with autoantibodies

    Grant number:15K09347  2015.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Shimizu Jun

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    Grant amount:\4810000 ( Direct expense: \3700000 、 Indirect expense:\1110000 )

    We performed mRNA microarray analysis of biopsied muscles from patients with IIMs and analyzed the relation with myositis specific antibodies (MSAs). In analysis of muscles with perifascicular atrophy, specific sets of mRNAs allow for molecular classification of patients with anti-Jo1 (n=4), -TIF1γ (n=5), and -Mi-2 (n=5) antibodies. In analysis of muscles with early pathological findings with anti-Jo1(n=4), -TIF1γ(n=4), and -MDA5 (n=4) antibodies, a total of 1705 mRNAs were significantly expressed (fold change>3, p<0.05). Pathway analysis for the 192 mRNAs commonly significantly changed in three groups were Toll-like and NOD-like receptor pathways. In analysis of mRNAs with significant changes, specific sets of mRNAs allow for molecular classification of patients with MSAs, respectively. Our findings showed that there are characteristic mRNAs expression profiles in relation with the types of MSAs even in muscles with mild pathological changes.

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  • Comprehensive whole genome sequence analysis using a long read sequencer for delineating molecular mechanism of neurological diseases

    Grant number:15K20941  2015.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    Ishiura Hiroyuki

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    Several kinds of mutations including rearrangements and repeat expansions as well as single nucleotide variants and short insertion/deletions cause neurodegenerative and neuromuscular disorders. Usual exome sequencing, however, overlook some of the mutations. To overcome this, I performed whole genome sequencing using a short read sequencer and a long read sequencer. Some of the mutations can only be delineated by the long read sequencer, indicating the importance of long read sequencing. This strategy will help us to understand the molecular mechanism of neurodegenerative disorders.

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  • Expression profiling of inclusion body myositis by massive parallel sequencing

    Grant number:26461265  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Goto Jun, ISHIURA Hiroyuki, IKENAGA Chiseko

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    Grant amount:\4940000 ( Direct expense: \3800000 、 Indirect expense:\1140000 )

    The aim of this study was to elucidate pathophysiology of inclusion body myositis by comprehensive expression profiling. Seventy-nine samples (11 controls, 11 PM, 47 IBM and 10 non-PM, non-IBM MHC-1 complex positive cases) were subjected to RNA-seq analysis. Seventy-one cases, of which RIN were more than 5, were statistically analyzed. Cluster analysis suggested that there was correlation between morphological classification and expression profile cluster. In IBM expression of cell adhesion molecules, inflammatory system, autophagy-lysosome system, and splicesome system were up-regulated. Expression of oxidative phosphorylation, citric cycle and electron transport genes was down-regilated.

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  • Identification of causative gene for autosomal recessive hereditary spastic paraplegia

    Grant number:24890044  2012.08 - 2014.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up  Grant-in-Aid for Research Activity Start-up

    ISHIURA Hiroyuki

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    Grant amount:\2990000 ( Direct expense: \2300000 、 Indirect expense:\690000 )

    Exome analysis for 16 patients with autosomal recessive hereditary spastic paraplegia was performed. Among them, I found a patient with SPG15, a rare form of autosomal recessive spastic paraplegia. Three homozygous mutations was found in a gene in 3 patients with hereditary spastic paraplegia with retinitis pigmentosa. Further studies are needed to characterize the mutations.

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  • 遺伝性痙性対麻痺と紀伊筋萎縮性側索硬化症・パーキンソン認知症複合の遺伝子解析研究

    Grant number:10J05639  2010 - 2011

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    石浦 浩之

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    Grant amount:\1400000 ( Direct expense: \1400000 )

    遺伝性痙性対麻痺:に関しては、SPG12に関する国際共同研究に参画し、遺伝子同定に寄与することができた(Montenegro G,Ishiura H,et al,J Clin Invest 2012)。また、リソース収集を進め、引き続き遺伝性痙性対麻痺の分子病態の解明を進める予定である。
    紀伊筋萎縮性側索硬化症・パーキンソン認知症複合(ALS/PDC)に関しては、紀伊半島の最南端のALS3症例においてC90RF72内の6塩基反復配列の伸長を認め、9番染色体に連鎖する筋萎縮性側索硬化症であることが判明した。本地域における9番染色体に連鎖する筋萎縮性側索硬化症の頻度は、本邦の他の地域(Majounie E,Ishiura H et al. 2012)に比較して有意に頻度が高いことを見出し、紀伊半島におけるALSの高罹病率を部分的に説明できると考えられた(Ishiura H,et al.Archives of Neurology in press)。その他、紀伊半島最南端地域においてはOPTNのヘテロ接合性新規アミノ酸置換を持つALS症例も見出したが、他のALS症例においては観察されず、病原性については検討の余地が残った(Naruse H,Ishiura H,et al.Amyotroph Lateral Scler in press)。パーキンソン認知症複合(PDC)に関しては、本研究では遺伝子同定には至らず、今後の研究が必要であると考えられた。

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