担当区分：筆頭著者   記述言語：英語   出版者・発行元：Journal of Human Genetics  

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

DOI： 10.1038/s10038-022-01019-y

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.1002/acn3.51555.

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.1002/acn3.51603.

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.3390/biomedicines10071546.

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.3389/fneur.2022.952493.

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.1111/jns.12228

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.1111/ene.13360

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：International Journal of Molecular Sciences  

DNMT1 variants are linked to complex neurodegenerative syndromes, yet their variant-specific functional and epigenomic consequences remain poorly defined. DNMT1 variants were identified in eight patients using gene-panel or whole-exome sequencing. Functional effects were assessed by site-directed mutagenesis and transient expression in HEK293T cells. Genome-wide methylation profiling of peripheral blood leukocyte DNA was performed using Nanopore sequencing, enabling direct quantification of 5-methylcytosine (5mC). CpG island-level differential methylation and gene set enrichment analysis (GSEA) were conducted. Variants in the replication foci targeting sequence (RFTS) domain (p.Y511H, p.Y540C, p.H569R) exhibited reduced DNMT1 protein expression, decreased enzymatic activity, and cytosolic aggregation. Variants in the C-terminal catalytic domain (p.A1334V and p.P1546S) showed reduced protein expression with relatively mild enzymatic impairment. Patients carrying the p.Y511H variant demonstrated a significant reduction in global 5mC levels compared with controls. Principal component analysis revealed distinct methylomic profiles separating most patients from controls, with marked intra- and inter-familial heterogeneity. CpG island-level analysis identified a single significantly hypomethylated region in p.Y511H carriers, and GSEA revealed differential enrichment of multiple Gene Ontology biological pathways. This study defines domain-dependent functional effects of DNMT1 variants and provides the first nanopore-based methylome analysis, revealing variant-specific and heterogeneous epigenomic alterations.

DOI： 10.3390/ijms27031232

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of Clinical and Translational Neurology  

Background: INF2 mutations cause focal segmental glomerulosclerosis (FSGS) and Charcot–Marie–Tooth disease (CMT). Accurate genetic diagnosis is critical, as INF2-related FSGS is typically resistant to immunotherapy yet rarely recurs after transplantation, and its associated neuropathy can mimic treatable immune-mediated disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: We performed a multicenter study investigating 3329 Japanese patients with inherited peripheral neuropathies/CMT who underwent gene panel sequencing or whole-exome analysis between 2007 and 2024. Clinical data, including electrophysiological assessments, were obtained from the patients' medical records. Results: We identified six pathogenic INF2 variants in eight patients, all of which were located within the diaphanous inhibitory domain. Structural modeling revealed clustering of variants near the diaphanous autoregulatory domain-binding pocket, which is critical for INF2 autoinhibition. Clinically, all cases were sporadic, with a median age at neurological onset of 9 years. All patients exhibited lower limb weakness, and 6/8 (75%) had sensory disturbances. All patients also developed kidney dysfunction, with 7/8 (88%) progressing to end-stage renal disease at a median age of 15 years. Furthermore, all patients showed demyelinating neuropathy, and 2/8 (25%) received immunotherapy due to suspected immune-mediated neuropathy. Conclusion: Although INF2 variants are a rare cause of CMT in Japan, they should be considered in pediatric patients with demyelinating neuropathy and early-onset proteinuria, even in the absence of a family history. Blood and urine tests assessing renal dysfunction can provide guidance for appropriate genetic testing.

DOI： 10.1002/acn3.70205

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

Myopathy, lactic acidosis, and sideroblastic anemia type 1 (MLASA1) is an extremely rare mitochondrial disorder caused by biallelic pathogenic variants in PUS1, which encodes a mitochondrial tRNA pseudouridine synthase essential for mitochondrial protein synthesis. We describe two affected siblings presenting with progressive myopathy, lactic acidosis, sideroblastic anemia, short stature, developmental delay, and mild cognitive impairment. Depth-based copy number variation analysis of whole-exome sequencing data revealed a novel homozygous multi-exonic deletion in PUS1. The deletion breakpoints were defined by Sanger sequencing as a 9964 bp deletion spanning part of intron 3 through exons 4–6 and extending into the 3′ untranslated region, resulting in complete loss of the C-terminal coding region. Skeletal muscle histology demonstrated ragged red fibers, whereas immunohistochemistry showed a selective and near-complete loss of NDUFB8, indicating impaired assembly of respiratory chain complex I. A systematic review of previously reported MLASA1 cases revealed marked clinical heterogeneity, including frequent developmental delay, dysmorphic features, and multi-organ involvement. These findings expand the genotypic and phenotypic landscape of MLASA1 and highlight the diagnostic value of copy number variation analysis in unresolved mitochondrial disorders. The impairment of complex I underscores the particular vulnerability of translation-dependent respiratory chain components in PUS1-related diseases.

DOI： 10.1038/s10038-025-01437-8

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担当区分：筆頭著者   記述言語：英語  

DOI： 10.1212/NXG.0000000000200318

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：Journal of Neurology  

DOI： 10.1007/s00415-025-13326-3

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

Background: Giant axonal neuropathy 1 (GAN) is a rare neurodegenerative disorder with autosomal recessive inheritance and significant phenotypic heterogeneity, ranging from milder presentations resembling Charcot–Marie–Tooth disease (CMT) to classical presentations involving central and peripheral nervous systems. We investigated the genetic and clinical spectrum of GAN in Japanese patients with inherited peripheral neuropathies (IPNs). Methods: We conducted genetic screening of 3315 Japanese patients diagnosed with IPNs between 2007 and 2023 using targeted next-generation or whole-exome sequencing. Variant pathogenicity, clinical features, and neurophysiological and neuroimaging findings were reviewed. Results: We identified seven biallelic GAN variants in five patients from four unrelated families, including one homozygous and three compound heterozygous genotypes. Two novel pathogenic variants were identified: c.922G > T (p.Glu308*) and c.456dup (p.Ala153Cysfs*27). Two families exhibited the classical phenotype, whereas the other two exhibited a CMT-like phenotype. Mean onset age was 4.4 years (range 1.5–8), and gait disturbance was the initial symptom. The most common findings included distal weakness (n = 5), sensory impairment (n = 4), scoliosis (n = 3), autonomic dysfunction (n = 2). Neurophysiologically, all patients had sensorimotor axonal polyneuropathy. One patient with mild phenotype maintained a CMT-like state without systemic involvement until the age of 43 years and was still alive at 72, representing the longest documented survival in GAN. Conclusion: This study expands the genetic and phenotypic spectrum of GAN by identifying novel variants and a long-term survivor. These findings underscore the importance of systematic genetic screening for GAN in pediatric-onset CMT, even in the absence of classical features.

DOI： 10.1007/s00415-025-13243-5

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

INTRODUCTION: The clinical, radiological, and pathological features have not been well documented for the recently discovered autosomal-dominant vacuolar tauopathy (VT) harboring the Valosin-containing protein (VCP) p.Asp395Gly variant. METHODS: We investigated the clinical, neuropsychological, physiological, laboratory, and radiological data and neuropathological findings in five symptomatic VT cases who met the diagnostic criteria for frontotemporal dementia (FTD). Radiological data were also collected from two pre-symptomatic carriers. RESULTS: All participants had heterozygous c.1184A > G, p.Asp395Gly in VCP. All symptomatic cases exhibited cognitive, behavioral, and/or language dysfunction indicative of FTD in their 30s to 50s. Neuroimaging studies revealed marked bilateral frontal neurodegeneration and occipital lobar diffusion abnormalities. Post mortem examination of three cases and brain biopsy of one case revealed abundant three- and four-repeat tau deposition and neocortical microvacuolization. Radiological changes were not evident in two pre-symptomatic carriers in their 20s. DISCUSSION: This study reveals distinct clinical-radiological-pathological correlations in VT, expanding the spectrum of early-onset frontotemporal lobar degeneration (FTLD). Highlights: We characterized the clinical, radiological, and pathological features of vacuolar tauopathy (VT). Five VT cases exhibited a behavioral syndrome, often with aphasic features, with marked frontal lobar atrophy and hypometabolism. Magnetic resonance imaging (MRI) of VT cases revealed occipital lobar diffusion abnormalities. Diffuse neurofibrillary tangles (NFTs) and microvacuolization were observed in the neocortex, with an inverse distribution.

DOI： 10.1002/alz.70427

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本末梢神経学会  

近年の遺伝子解析技術の進展に伴い,遺伝性神経筋疾患におけるリピート伸長異常の同定が進んでおり,遺伝性ニューロパチーの診断においてもその重要性が高まっている。わが国の遺伝性ニューロパチー3,180症例に対する遺伝子解析では遺伝子診断例の10.9%がLRP12,RFC1,NOTCH2NLCのリピート伸長異常に起因していた。これらのリピート伸長異常はいずれも成人発症で,LRP12では運動神経障害が優位,RFC1では感覚障害が優位,NOTCH2NLCでは中間型の電気生理所見が特徴的である。本稿では,遺伝性ニューロパチーにおけるこれら3遺伝子のリピート伸長異常について概説する。(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Multiple Sclerosis and Related Disorders  

The visual evoked potential (VEP) patterns of optic neuritis are known to often differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) but have been less reported in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). This study aimed to characterize the VEP pattern in MOGAD and evaluate its utility in distinguishing MOGAD from MS and NMOSD. We retrospectively reviewed the clinical manifestations and VEP findings in patients with MS (n = 29), NMOSD (n = 14), and MOGAD (n = 10). In eyes with acute visual impairment, VEP responses were detectable in 100 % of eyes with MOGAD, a striking difference from MS (72.7 %) and NMOSD (57.1 %). In addition, VEP abnormalities in eyes without acute visual impairment were rare in MOGAD (23.1 %) compared to MS (55.3 %) and NMOSD (42.9 %). Our results indicated that subclinical VEP abnormalities or undetectable VEP responses were less common in patients with MOGAD compared to patients with MS and NMOSD. VEP testing demonstrates potential diagnostic utility in distinguishing among these conditions.

DOI： 10.1016/j.msard.2025.106408

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

Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analysed blood and fibroblast DNA methylation, transcriptomes, proteomes and phenotypes of 53 MORC2 patients. We identified a MORC2-specific DNA methylation episignature that is universal across all MORC2-associated phenotypes and conserved across different tissues. The MORC2 episignature consists mainly of DNA hypermethylation in promoter regions, leading to transcriptional repression of target genes resulting in a MORC2-specific RNA signature. Concomitant downregulation of three disease-associated genes—ERCC8, NDUFAF2 and FKTN—at different levels mirrors the variable biochemical defects and clinical manifestations observed in MORC2 patients. Silencing of NDUFAF2 accounts for the Leigh syndrome manifestation, whereas dysmorphic features are due to the repression of ERCC8. Overall, we showed that pathogenic MORC2 variants cause specific episignature, whereby methylation level variability and its repression impact on target genes explains the pleiotropy and predicts phenotypic heterogeneity in MORC2-related disorders. We predict that epigenetic variation may underlie pleiotropy in other Mendelian disorders.

DOI： 10.1093/brain/awaf159

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

Identifying the aetiology of CNS diseases, regardless of their infectious or non-infectious nature, is often intricate. Next-generation sequencing (NGS) has emerged as a powerful tool for sensitive and unbiased screening of tissue or body fluid specimens. This study aimed to investigate the underlying aetiology of patients with suspected infectious CNS diseases. Between April 2013 and October 2021, we collected brain tissue samples from 33 patients diagnosed with encephalitis or encephalitis-like CNS diseases, obtained via biopsy or autopsy, and underwent metagenomic NGS (mNGS) in conjunction with pathological evaluations. Moreover, we employed PCR-based assays and pathogen-specific immunostaining to corroborate the presence of pathogens within the tissue samples. Among the 33 patients, mNGS elucidated pathogen-specific genomic sequences in 7 cases (21.2%), including halobacteria (archaea), Balamuthia mandrillaris, Epstein-Barr virus, Toxoplasma gondii and herpes simplex virus. Additionally, brain tissue mNGS ruled out known pathogens, identifying 14 cases (42.4%) of non-infectious CNS diseases, which included neoplastic, autoimmune/inflammatory and amyloid angiopathy conditions. The adjustment of therapeutic strategies based on these findings led to improvements in clinical symptoms, imaging outcomes and patient prognosis. Brain biopsy serves as both a direct pathological research target and a valuable source of samples for unbiased high-throughput sequencing. Our study illustrates the reliability of mNGS on brain tissue, which significantly improves the diagnostic rate for suspected encephalitis or encephalitis-like diseases of unknown aetiology. These findings underscore the importance of mNGS in guiding more precise and effective therapeutic interventions for patients in clinical practice.

DOI： 10.1093/braincomms/fcaf165

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：Clinical Neurophysiology Practice  

Objective: To evaluate the utility of nerve conduction studies as a marker of length-dependent neuropathy. Methods: We conducted a retrospective study of 44 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients and 365 genetically confirmed Charcot-Marie-Tooth disease (CMT) patients, including those with PMP22 duplications or mutations in GJB1, MFN2, MPZ, and MME. Nerve conduction study parameters were compared, with subgroup analyses of CIDP-mimicking CMT (genetically confirmed CMT with a prior clinical diagnosis of CIDP) and gene-based classifications. Receiver operating characteristic (ROC) analysis assessed the sensitivity and specificity of these parameters. Results: The tibial to ulnar nerve distal compound muscle action potential (T/U CMAP) amplitude ratio was significantly higher in CIDP patients compared to those with genetically confirmed CMT, CIDP-mimicking CMT, and gene-based subgroups. This ratio yielded the highest area under the curve (AUC: 0.95) among all evaluated parameters, with a cutoff value of 0.385 demonstrating high diagnostic sensitivity (95.5%) and specificity (85.5%). In CIDP-mimicking CMT group, a similar sensitivity and specificity were observed. Conclusions: The T/U CMAP amplitude ratio is a simple, robust electrophysiological index of length-dependent neuropathy. Significance: This marker offers a reliable and accessible way to distinguish between acquired and inherited neuropathies, improving diagnostic accuracy and helping prioritize genetic testing.

DOI： 10.1016/j.cnp.2025.10.006

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記述言語：日本語   出版者・発行元：日本末梢神経学会  

<p>近年の遺伝子解析技術の進展に伴い，遺伝性神経筋疾患におけるリピート伸長異常の同定が進んでおり，遺伝性ニューロパチーの診断においてもその重要性が高まっている。わが国の遺伝性ニューロパチー3,180症例に対する遺伝子解析では遺伝子診断例の10.9％がLRP12，RFC1，NOTCH2NLCのリピート伸長異常に起因していた。これらのリピート伸長異常はいずれも成人発症で，LRP12では運動神経障害が優位，RFC1では感覚障害が優位，NOTCH2NLCでは中間型の電気生理所見が特徴的である。本稿では，遺伝性ニューロパチーにおけるこれら3遺伝子のリピート伸長異常について概説する。</p>

DOI： 10.69407/jpns.36.1_14

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記述言語：英語   出版者・発行元：Acta Neuropathologica Communications  

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants.

DOI： 10.1186/s40478-024-01847-3

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記述言語：英語   出版者・発行元：Neurogenetics  

Biallelic variants of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene have been linked to neurodegenerative disorders ranging from severe neonatal encephalopathy to early-onset spastic paraplegia. We identified a novel homozygous variant, c.340G > T (p.Gly114Cys), in the HPDL gene in two siblings with autosomal recessive hereditary spastic paraplegia (HSP). Despite sharing the same likely pathogenic variant, the older sister had pure HSP, whereas her brother had severe and complicated HSP, accompanied by early-onset mental retardation and abnormalities in magnetic resonance imaging. Given the clinical heterogeneity and potential for treatable conditions in HPDL-related diseases, we emphasize the importance of genetic testing for the HPDL gene.

DOI： 10.1007/s10048-024-00746-y

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：Clinical and Experimental Neuroimmunology  

Background: Initially associated with stiff-person syndrome, antibodies to glutamic acid decarboxylase (GAD) antibodies are now recognized as indicators of GAD antibody-spectrum disorders (GAD-SD), which encompass cerebellar ataxia, autoimmune epilepsy and limbic encephalitis. Paraneoplastic neurological syndromes associated with GAD-SD are rare, and optimal timing of surgical intervention and impact on neurological symptoms remain poorly understood. Case Presentation: We present the case of a 65-year-old woman who developed overlapping symptoms of cerebellar ataxia and stiff-person syndrome detected through high-titer GAD antibodies in both serum and cerebrospinal fluid, alongside the presence of a thymoma. Due to severe dysphagia and gait ataxia that rendered her bedridden on admission, surgical intervention was initially deferred. Instead, she received immunotherapies including intravenous methylprednisolone and intravenous immunoglobulin, which remarkably improved neurological symptoms. However, a decline in symptoms occurred on tapering oral prednisolone. Subsequently, a thoracoscopic thymectomy was carried out 27 months after symptom onset, leading to further neurological improvement and successful reduction of prednisolone. Conclusion: In paraneoplastic GAD-SD cases with severe symptoms at presentation, prioritizing immunotherapy and considering surgical intervention once the symptoms have stabilized might be advantageous.

DOI： 10.1111/cen3.12764

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：Scientific Reports  

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

DOI： 10.1038/s41598-023-45011-8

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記述言語：英語  

DOI： 10.1038/s41598-023-45011-8.

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記述言語：英語   出版者・発行元：Journal of Neurology  

Background and objective: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. Methods: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. Results: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. Conclusion: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.

DOI： 10.1007/s00415-023-11998-3

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記述言語：英語  

DOI： 10.3389/fneur.2023.1241678.

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DOI： 10.1111/jns.12590

記述言語：英語   出版者・発行元：Frontiers in Neurology  

Objective: Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD). Methods: Clinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021. Results: Of the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed. Conclusions: An autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

DOI： 10.3389/fneur.2023.1137958

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記述言語：英語  

DOI： 10.1111/jns.12590

記述言語：英語  

DOI： 10.2169/internalm0.2169/internalmedicineedicine

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記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は69歳男性．5歳時より歩行困難を認め，13歳頃より杖歩行，17歳頃より車椅子生活となった．他院でシャルコー・マリー・トゥース病と診断されたが，遺伝子検査や神経生検は施行されなかった．54歳時当科初診．以降も四肢遠位筋の筋力低下や感覚障害が緩徐に進行し，60歳時の遺伝子検査で<i>GAN</i>新規変異（c.1478A>C, p.E493A）を認めた．臨床的には巨大軸索ニューロパチー（giant axonal neuropathy，以下GANと略記）の典型例とは異なり，知的能力は保たれ，縮れ毛はなく，61歳以降は声帯麻痺や自律神経障害を併発し，過去の報告よりGANの軽症例と診断した．</p>

DOI： 10.5692/clinicalneurol.cn-001822

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1416202227

PubMed

CiNii Research

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞RFC1遺伝子関連スペクトラム障害は小脳性運動失調や感覚ニューロパチー,前庭神経障害を含めた多彩な障害が単独ないし多様な組合せをもって出現し得る疾患である。臨床症状や画像所見から多系統萎縮症との鑑別にも重要な疾患となる。本論では小脳性運動失調症におけるRFC1遺伝子関連スペクトラム障害の頻度や遺伝学的特徴,画像所見について詳述する。

記述言語：英語  

DOI： 10.1056/NEJMoa2204705

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：Neurology and Clinical Neuroscience  

Charcot–Marie–Tooth disease type 2Z (CMT2Z) shows highly variable clinical features. We report the first Japanese CMT2Z patient with a c.754C>T (p.R252W) substitution of the MORC2 gene, complicating severe retinitis pigmentosa. The MORC2 mutants were involved in a decrease in cell survival through induction of apoptosis. Thus, the MORC2 mutation might be involved in the degeneration of photoreceptors and the development of retinitis pigmentosa.

DOI： 10.1111/ncn3.12660

Scopus

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)へるす出版  

症例は62歳男性で、入院前日より頭痛が再燃し、両耳の難聴も出現したため当院に救急搬送された。症状および検査所見から細菌性髄膜炎と診断し、急性腎不全を考盧してセフトリアキソン、リネゾリドの点滴静注および4日間のデキサメタゾンの静注を開始した。入院12日目の髄液検査でいったん改善していた細胞数、蛋白が再上昇し、背部痛も悪化、CT画像で脾臓低形成がみられ、腎機能も改善したことから、抗菌薬をメロペネム、バンコマイシンへ変更した。入院16日目の画像では腰椎3/4間に椎間板炎の所見、28日目の画像では腰椎4/5間の椎間関節付近に脊髄硬膜外膿瘍と傍椎体膿瘍がみられた。バンコマイシンの投与が6週間となった入院54日目のところでアモキシシリンの内服に切り替え、変更後も症状の再燃はなく、髄液所見の悪化やMRI画像で膿瘍像の変化がないことを確認し、入院66日目に自宅退院となった。

記述言語：英語  

DOI： 10.1038/s10038-021-01005-w.

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：Neurological Sciences  

DOI： 10.1007/s10072-021-05817-8

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PubMed

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記述言語：英語  

DOI： 10.1007/s00415-022-11026-w.

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記述言語：英語  

DOI： 10.1002/acn3.51715.

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記述言語：英語  

DOI： 10.3389/fneur.2022.986504.

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記述言語：英語  

DOI： 10.1007/s00415-022-11305-6.

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記述言語：英語   出版者・発行元：Clinical Genetics  

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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PubMed

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記述言語：英語   出版者・発行元：Cerebellum  

The presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

DOI： 10.1007/s12311-021-01323-x

Scopus

PubMed

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記述言語：日本語  

DOI： 10.5692/clinicalneurol.60.cn-001419

PubMed

記述言語：英語  

DOI： 10.1136/jnnp-2018-318839

PubMed

記述言語：英語  

DOI： 10.1038/s10038-017-0388-5

PubMed

記述言語：英語  

DOI： 10.1186/s12883-018-1131-3

PubMed

記述言語：英語  

DOI： 10.1111/ene.13750

PubMed

記述言語：英語  

DOI： 10.1093/brain/awy104

PubMed

記述言語：英語  

DOI： 10.1111/cge.13037

PubMed

記述言語：英語  

DOI： 10.1111/cge.13002

PubMed

記述言語：英語  

DOI： 10.1038/jhg.2017.15

PubMed

記述言語：英語  

DOI： 10.2169/internalmedicine.53.8922

PubMed