研究者詳細 - 石浦　浩之

論文 - 石浦　浩之

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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年4月

Clinical, neuroimaging and genetic findings in the Japanese case series of CLCN2-related leukoencephalopathy. 国際誌

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年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

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. 国際誌

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年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1038/s41439-025-00309-z

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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年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.2169/internalmedicine.4767-24

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The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model. 国際誌

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年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1016/j.neures.2025.01.006

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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年

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

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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1007/s12311-024-01782-y

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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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.2169/internalmedicine.4353-24

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Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis. 国際誌

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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1007/s00415-024-12776-5

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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年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.2169/internalmedicine.4667-24

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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年10月

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年10月

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年10月

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年10月

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年10月

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年10月

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.2169/internalmedicine.4350-24

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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- 査読国際誌

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年7月

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

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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その他リンク： https://www.nature.com/articles/s10038-024-01266-1

A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes. 査読国際誌

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年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1080/21678421.2024.2374374

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

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

Internal medicine (Tokyo, Japan) 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.2169/internalmedicine.3392-23

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