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BACKGROUND: NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. METHOD: Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. RESULTS: NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. CONCLUSIONS: These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

DOI： 10.1136/jnnp-2022-330769

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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.

DOI： 10.1038/s10038-022-01019-y

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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.

DOI： 10.1002/acn3.51555.

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BACKGROUND: Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot-Marie-Tooth (CMT) disease in Japanese patients. METHODS: We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients. RESULTS: In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum. CONCLUSIONS: Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

DOI： 10.1002/acn3.51603.

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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.

DOI： 10.3390/biomedicines10071546.

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The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.

DOI： 10.3389/fneur.2022.952493.

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DOI： 10.1111/jns.12228

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DOI： 10.1111/ene.13360

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DOI： 10.1038/s41598-026-46319-x

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Purpose Despite advances in diagnostics, many inherited peripheral neuropathies remain genetically unexplained. We investigated whether biallelic variants in FAT3 ( FAT Atypical Cadherin 3 ) are implicated in inherited axonal neuropathies. Methods We identified biallelic FAT3 variants in three unrelated individuals among 3315 Japanese patients with inherited peripheral neuropathies. Variants were evaluated by segregation analysis, in silico modeling, and functional studies in Drosophila and mouse models. Results All patients exhibited progressive distal muscle weakness and cranial nerve involvement, including tongue atrophy, dysarthria, and facial weakness. Two required ventilatory support because of respiratory muscle paralysis. One patient additionally showed central hypomyelination, autonomic dysfunction, and developmental anomalies, such as congenital scoliosis and intestinal pseudo-obstruction. Identified variants were ultrarare, affected conserved residues, segregated with disease, and were predicted to impair domain stability. FAT3 knockdown in Drosophila resulted in rough eye phenotype, shortened lifespan, impaired motor function, and defective motor neuron branching. Fat3 knockout and knockin mice displayed perinatal lethality, sciatic nerve axonal degeneration, and central nervous system abnormalities despite preserved motor performance. Conclusion Our findings establish FAT3 as a novel gene for autosomal-recessive axonal neuropathies and support the concept of a FAT3 -related multisystem neurodevelopmental disorder characterized by motor neuron degeneration and systemic abnormalities.

DOI： 10.1016/j.gim.2026.102570

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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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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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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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BACKGROUND AND OBJECTIVES: Autosomal recessive spastic ataxia of Charlevoix-Saguenay, caused by biallelic SACS variants, is classically characterized by spasticity, ataxia, and peripheral neuropathy. The aim of this study was to define the clinical and genetic spectrum of SACS-related inherited peripheral neuropathies (IPNs) in Japanese patients. METHODS: Targeted gene panel sequencing was performed in 3,353 Japanese cases clinically suspected of having IPN or Charcot-Marie-Tooth (CMT) disease, with PMP22 duplication or deletions pre-excluded in demyelinating subtypes, followed by whole-exome sequencing in a subset of undiagnosed cases. Depth-based copy number variation (CNV) analysis was conducted using CovCopCan or XHMM, with validation by quantitative PCR. RESULTS: Biallelic or putative compound heterozygous SACS variants were identified in 10 index cases, with pathogenic or likely pathogenic variants confirmed in 9 cases (0.268%; 9/3,353). The variant spectrum included frameshift (n = 9), missense (n = 3), and nonsense (n = 2) variants, along with complete SACS gene deletions identified by CNV analysis in 2 cases. Disease onset occurred between 1 and 49 years. All patients exhibited motor and sensory neuropathy, with pyramidal signs observed in 6 patients. Cerebellar ataxia or atrophy was documented in 8 patients. Cognitive impairment was observed in 4 patients, and 1 patient presented with postural hypotension. Most patients showed a length-dependent, sensory-predominant polyneuropathy characterized by slowed nerve conduction velocities. DISCUSSION: This study defines the contribution of SACS variants in a large case series of Japanese patients with IPN/CMT disease and delineates the heterogeneous genotypic and phenotypic spectrum of SACS-related neuropathies. The high frequency of gene-level deletions underscores the necessity of incorporating CNV analysis into the genetic diagnostic workflow for SACS-related disorders.

DOI： 10.1212/NXG.0000000000200318

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DOI： 10.1007/s00415-025-13326-3

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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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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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Authorship：Lead author   Language：Japanese   Publisher：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)

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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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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 analyzed 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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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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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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Language：Japanese   Publisher：Japanese Peripheral Nerve Society  

<p>　Recent advances in genetic analysis technologies have led to significant progress in identifying repeat expansion abnormalities in hereditary neuromuscular diseases. These developments have also increased the importance of repeat expansion analysis in diagnosing hereditary peripheral neuropathies ( IPN ) . In a comprehensive genetic analysis of 3,180 Japanese patients suspected of having IPN, 10.9% of the genetically diagnosed cases were found to be caused by repeat expansions in the LRP12, RFC1 and NOTCH2NLC genes. Each of these repeat expansions is associated with adult-onset symptoms. LRP12-related repeat expansions primarily manifest as motor nerve dysfunction, with most patients presenting muscle weakness and atrophy, while sensory disturbances are relatively rare. In contrast, RFC1 repeat expansions predominantly cause sensory impairments, with most patients displaying sensory neuropathy and minimal muscle weakness. Furthermore, NOTCH2NLC-related expansions are associated with intermediate electrophysiological findings, and about half of the patients also exhibit autonomic nervous system involvement, such as neurogenic bladder. These repeat expansions are critical in refining the diagnosis and understanding of the clinical spectrum of hereditary peripheral neuropathies. This review provides an in-depth overview of the clinical characteristics, electrophysiological findings, and molecular mechanisms of the LRP12, RFC1 and NOTCH2NLC repeat expansions, with a particular focus on their roles in the pathogenesis of hereditary neuropathies.</p>

DOI： 10.69407/jpns.36.1_14

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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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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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Authorship：Lead author   Language：Japanese   Publisher：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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Authorship：Lead author   Language：English   Publisher：(一社)日本神経免疫学会  

症例は65歳女性で、高血圧の既往があった。めまいとふらつき歩行を初発症状として呈していた。嚥下障害や歩行障害が悪化したため、発症12ヵ月後に入院となった。各種検査の結果、小脳失調とスティッフパーソン症候群を重複するGAD抗体-スペクトル障害と診断された。外科的介入は不可能と判断され、免疫療法が開始された。メチルプレドニゾロン静注および免疫グロブリン静注を含む免疫療法が実施され、神経症状は著しく改善した。しかし、経口プレドニゾロン(PSL)漸減により構音障害および歩行失調の悪化が認められた。発症27ヵ月後に胸腔鏡下胸腺摘出術が施行された。神経学的症状はさらに改善し、PSL漸減に成功した。

Authorship：Lead author   Language：English   Publisher：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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DOI： 10.1038/s41598-023-45011-8.

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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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BACKGROUND AND OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan. METHODS: We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images. RESULTS: Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign). CONCLUSION: We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

DOI： 10.3389/fneur.2023.1241678.

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DOI： 10.1111/jns.12590

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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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DOI： 10.1111/jns.12590

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Two patients, 48- and 50-year-old sisters, presented with a characteristic facial appearance with slowly progressive deafness and cerebellar ataxia starting in their 30s. Genetic testing identified compound heterozygous pathogenic variants in the ERCC6 gene: c.1583G>A (p.G528E) and c.1873T>G (p.Y625D). A diagnosis of Cockayne syndrome (CS) B type III was made. CS is usually diagnosed in childhood with well-defined facial characteristics and photosensitivity. This case report describes rare cases of adulthood CS with a primary presentation of slowly progressing deafness and cerebellar ataxia. CS should be considered in adults with characteristic facial and skin findings, deafness, and cerebellar ataxia.

DOI： 10.2169/internalm0.2169/internalmedicineedicine

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Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>A 69-year-old man began to experience difficulty with walking at the age of 5 years and started use of a cane at around 13 years, then finally started using a wheelchair at 17 years old. A diagnosis of Charcot-Marie-Tooth disease was previously determined at another hospital, though neither peripheral nerve biopsy nor gene analysis was conducted. He visited our institution at the age of 54 years and irregular outpatient examinations were started, which indicated slowly progressive muscle weakness and sensory disturbance of the limbs, leading to a decline in activities of daily living. Gene analysis at 60 years old identified a novel homozygous missense mutation in the gigaxonin gene, c.1478A>C, p.E493A. Intellectual capacity was preserved and kinky hair was not present, though complications such as vocal cord paralysis, paralytic ileus, and dysarthria were noted starting at age 61. Based on these findings, the patient was diagnosed with a mild form of giant axonal neuropathy.</p>

DOI： 10.5692/clinicalneurol.cn-001822

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Replication factor C subunit 1 (RFC1) spectrum disorders are characterized by a variety of symptoms, including cerebellar ataxia, sensory neuropathy, and vestibular dysfunction, which may occur singularly or in various combinations. RFC1 spectrum disorders may mimic the clinical manifestations and imaging findings of multiple system atrophy. We describe the prevalence, genetic features, and imaging findings of RFC1 spectrum disorders.

DOI： 10.11477/mf.1416202227

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Authorship：Lead author   Language：Japanese   Publisher：(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。

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DOI： 10.1056/NEJMoa2204705

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Authorship：Lead author   Language：Japanese   Publisher：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

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Authorship：Lead author   Language：Japanese   Publisher：The Japanese Congress on Neurological Emergencies  

<p>Patients with splenic hypoplasia are more susceptible to infections with capsular bacteria such as <i>Streptococcus pneumoniae</i> and are more likely to develop severe infections, including bacterial meningitis. Here, we report the case of a 62-year-old male who was transferred to our hospital by emergency transport due to worsening headache and bilateral deafness. Based on the results of cerebrospinal fluid tests, the patient was diagnosed with pneumococcal meningitis and was started on antibiotic treatment. Computed tomography showed hypoplastic spleen and low levels of IgM and IgG, suggesting that hyposplenism was involved in the patient’s pneumococcal infection. Despite the administration of appropriate antibiotics, the patient developed recurrent fever and back pain; subsequent magnetic resonance imaging scans showed intervertebral discitis, spinal epidural abscess, and paravertebral abscess. After administration of intravenous immunoglobulin and subsequent vancomycin (6 weeks), and oral amoxicillin (3 weeks), symptoms and imaging findings improved and the patient was discharged on day 66. There are several reports in the literature of splenic hypoplasia associated with aggravation of pneumococcal infection and abscess formation. In cases of splenic hypoplasia, active treatment and periodic abscess search are key factors, as is a vaccination to prevent infections.</p>

DOI： 10.11170/jjsnecc.34.2_21

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Authorship：Lead author   Language：Japanese   Publisher：(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。

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

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

DOI： 10.1038/s10038-021-01005-w.

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DOI： 10.1007/s10072-021-05817-8

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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.

DOI： 10.1007/s00415-022-11026-w.

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Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999-2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70 years vs. 9.23 ± 5.21 years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.

DOI： 10.1007/s00415-022-11305-6.

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OBJECTIVE: HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP. METHODS: This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability. RESULTS: The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time -3.5%, 95% CI -10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (-9.4%, 95% CI -16.6% to -2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (-9.1%, 95% CI -15.5% to -2.7%; P < 0.01), and in neopterin concentration in CSF (-2.1 pmol/mL, 95% CI -3.8 to -0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly. INTERPRETATION: l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP. TRIAL REGISTRATION NUMBER: UMIN000023854.

DOI： 10.1002/acn3.51715.

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DOI： 10.3389/fneur.2022.986504.

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Authorship：Lead author   Language：English   Publisher：Frontiers in Neurology  

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

DOI： 10.3389/fneur.2022.986504

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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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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

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DOI： 10.5692/clinicalneurol.60.cn-001419

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DOI： 10.1136/jnnp-2018-318839

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DOI： 10.1038/s10038-017-0388-5

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DOI： 10.1186/s12883-018-1131-3

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DOI： 10.1111/ene.13750

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DOI： 10.1093/brain/awy104

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DOI： 10.1111/cge.13037

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DOI： 10.1111/cge.13002

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DOI： 10.1038/jhg.2017.15

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DOI： 10.2169/internalmedicine.53.8922

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