Faculty Profiles - Ishiura Hiroyuki

Papers - Ishiura Hiroyuki

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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

Language：English Publishing type：Research paper (scientific journal)

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

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

Hiroyuki Ishiura

Journal of neuromuscular diseases 22143602251319164 - 22143602251319164 2025.3

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English

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

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

Language：English

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

DOI： 10.1111/neup.12651

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.2169/internalmedicine.3661-19

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1038/s41588-019-0458-z

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1136/jnnp-2018-318568

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