Authorship：Lead author  

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

Other Link： https://link.springer.com/content/pdf/10.1007/s12311-021-01323-x.pdf

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

Authorship：Lead author   Language：English   Publishing type：Doctoral thesis  

Language：Japanese   Publisher：Orphanet Journal of Rare Diseases  

Background: The clinical spectrum of autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) in Asian populations remains incompletely defined. We aimed to characterize the clinical, radiological, and genetic features of Japanese patients with ARSACS and to expand the mutational and phenotypic spectrum of this disorder. Methods: We conducted a retrospective case series of patients diagnosed with ARSACS in our department between January 2016 and December 2023. Five patients from four families with biallelic SACS variants were identified. Results: Genetic analysis revealed seven pathogenic SACS variants, of which six were novel. Clinical heterogeneity was notable, with age at onset ranging from 1 to 27 years. Four patients showed classical ARSACS-related neuroimaging findings, whereas one patient presented with a Charcot–Marie–Tooth disease (CMT)-mimicking phenotype characterized by predominant peripheral neuropathy, mild cerebellar involvement, and absence of the classical pontocerebellar magnetic resonance imaging features. Conclusions: The recognition of CMT-mimicking presentations supports considering ARSACS in the differential diagnosis of hereditary peripheral neuropathies, particularly in patients with additional cerebellar, pyramidal, or supportive neuroimaging features.

DOI： 10.1186/s13023-026-04337-y

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PubMed

Language：Japanese   Publisher：BMC Neurology  

Background: Paramedian pontine reticular formation (PPRF) syndrome is characterized by horizontal gaze palsy due to lesions in the PPRF or the abducens nucleus. It is relatively rare and is typically associated with medial longitudinal fasciculus (MLF) syndrome. Case presentation: A 53-year-old Japanese woman presented with right lateral gaze palsy and facial nerve palsy, with preserved convergence and left lateral gaze. Neurological evaluation confirmed PPRF syndrome and facial nerve palsy, with no involvement of the MLF. Brain MRI showed a lesion in the right dorsal pons, affecting the PPRF, abducens nucleus, and facial nerve. Serum testing revealed positive antinuclear and anti-AQP4 antibodies. The patient responded well to immunotherapy, with substantial clinical and radiological improvements. She was ultimately diagnosed with AQP4 antibody-positive NMOSD. Conclusion: This is the first documented case of isolated PPRF syndrome in AQP4 antibody–positive NMOSD. The findings expand the known phenotypic spectrum of NMOSD and highlight the importance of considering NMOSD, with targeted AQP4 antibody testing, in patients presenting with isolated PPRF syndrome.

DOI： 10.1186/s12883-026-04670-6

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Language：Japanese   Publisher：Hypertension Research  

Although intensive blood pressure (BP) lowering after mechanical thrombectomy (MT) may adversely affect outcomes, the prognostic significance of post-recanalization BP variability remains unclear. This study aimed to evaluate the association between systolic blood pressure (SBP) variability after successful recanalization and 90-day functional outcomes following MT. Among 342 consecutive patients who underwent MT between May 2014 and June 2025, 280 patients who achieved successful recanalization were included in this retrospective analysis. SBP was recorded from immediately after recanalization up to 72 h thereafter. BP variability indices, including variability independent of the mean (VIM), time rate, and coefficient of variation, were calculated. The primary outcome was defined as a modified Rankin Scale (mRS) score of 4–6 at 90 days. Associations between SBP variability and outcomes were assessed using multivariable logistic regression models. Of the 280 patients, 104 (37.1%) experienced poor functional outcomes. Higher SBP variability was significantly associated with unfavorable outcomes. In time-segmented analyses, only SBP variability during the 24–72-h period remained significantly associated with poor outcomes (aOR per 10-unit increase in VIM [VIM/10], 1.89; 95% CI, 1.20–3.06, p = 0.005). Sensitivity analyses excluding patients who received antihypertensive therapy during 24–72 h and those with symptomatic intracranial hemorrhage confirmed the robustness of the association between 24–72 h VIM and poor outcomes (aOR VIM/10, 1.94; 95% CI, 1.26–3.11, p = 0.003). In conclusion, these findings highlight the clinical importance of stabilizing BP beyond the first 24 h after recanalization.

DOI： 10.1038/s41440-026-02608-6

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PubMed

Language：English  

DOI： 10.1038/s41598-026-46319-x

PubMed

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.gim.2026.102570

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PubMed

Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neurot.2026.e00900

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PubMed

Language：English   Publisher：Nature Publishing Group  

Language：English  

DOI： 10.1038/s41440-026-02599-4

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PubMed

Language：Japanese   Publisher：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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Language：Japanese   Publisher：(一社)日本神経学会  

75歳女性.幼少期より体育が苦手で,54歳で両下肢筋力低下が出現し,64歳でSH3TC2遺伝子p.Arg77Trpホモ接合体変異を認め,Charcot-Marie-Tooth病(CMT)4Cと診断された.74歳で健忘を認め,頭部MRIで大脳白質のT2延長域,拡散強調像で皮髄境界の高信号を呈した.神経核内封入体病(neuronal intranuclear inclusion disease,以下NIIDと略記)を疑い,皮膚生検でp62抗体陽性核内封入体を認め,NOTCH2NLC遺伝子GGCリピート延長を認めた.本例のSH3TC2変異は病原性の根拠に欠け,症状と併せて病態の主体はNIIDと考えた.遺伝学的検査で疾患関連変異を認めた際も,病的意義不明の場合は長期の観察と追加の病態評価を考慮する必要がある.(著者抄録)

Language：Japanese   Publisher：The Japan Stroke Society  

<p><b>Background and Purpose:</b> Fostering young physicians who are interested in stroke care is an important challenge. This study aimed to identify factors that influence interest in stroke care among physicians who underwent initial clinical training at our institution. <b>Methods:</b> We conducted a questionnaire-based survey targeting physicians in their 1st to 7th postgraduate years who had trained at our hospital. The primary outcome was the change in interest in stroke care before and after the training in our department. We performed exploratory factor analysis (EFA) and conducted multivariate analysis based on the identified factors. <b>Results:</b> Responses were obtained from 58 out of 85 physicians (68.2%). In the multivariate analysis, only a specific factor—comprising participation in emergency department care, one-on-one lectures by individual physicians, scrub-in experiences, and hands-on procedures such as arterial puncture during cerebral angiography—was independently associated with an increased interest in stroke care (adjusted odds ratio: 7.6, 95% CI: 1.39–57.1, <i>p</i>=0.018). <b>Conclusion:</b> These findings suggest that providing hands-on practical experiences alongside building strong interpersonal relationships may be key to enhancing interest and aspiration toward stroke care among young physicians.</p>

DOI： 10.3995/jstroke.11362

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

<p>We report a case of a 75-year-old woman who has had poor physical performance since childhood and developed bilateral lower limb muscle weakness at age 54. At 64, she was diagnosed with Charcot–Marie–Tooth disease type 4C (CMT4C) due to a homozygous p.Arg77Trp variant in the <i>SH3TC2</i> gene. At 74, she developed memory impairment. At 75, brain MRI revealed extensive cerebral white matter lesions with T₂-weighted hyperintensity and linear high intensity signal along the corticomedullary junction on diffusion-weighted imaging. Suspecting neuronal intranuclear inclusion disease (NIID), we performed a skin biopsy which demonstrated p62-positive intranuclear inclusions, and genetic testing identified the GGC repeat expansion in the <i>NOTCH2NLC</i> gene. The pathogenicity of the <i>SH3TC2</i> variant identified in this patient remains uncertain, and her peripheral neuropathy was consistent with mild demyelination attributable to NIID. Therefore, we interpret the patient’s symptoms as primarily driven by NIID. This case highlights the importance of long-term follow-up and additional assessment when variants of uncertain significance are identified in genetic testing.</p>

DOI： 10.5692/clinicalneurol.cn-002150

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CiNii Research

Language：English  

DOI： 10.1016/j.jns.2025.125713

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PubMed

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

Liver fibrosis is a proposed risk factor for intracerebral hemorrhage (ICH) and a predictor of ICH-related mortality. However, its impact on functional outcomes and hemorrhage location remains unclear. We aimed to investigate whether liver fibrosis is associated with clinical outcomes and hematoma characteristics according to ICH location. Consecutive patients with ICH between July 2012 and November 2023 were retrospectively included. Favorable outcomes were defined as a modified Rankin Scale score of 0 to 1 at 3 months following stroke onset. We elucidated whether liver fibrosis, assessed by the Fibrosis-4 index (FIB-4 index), was associated with prognosis and hematoma volume in the entire ICH cohort, and separately in lobar and non-lobar ICH cohorts. Following screening of 608 consecutive ICH patients, 356 patients with ICH (entire cohort) who met the inclusion criteria (198 [56%] males, median age 73 years), including 69 with lobar ICH and 287 patients with non-lobar ICH, were identified. Similar to the entire ICH cohort, especially in the lobar ICH cohort, the FIB-4 index correlated negatively with favorable outcomes (prevalence ratio (PR) 0.823, 95% confidence interval (CI) 0.692-0.979, p = 0.027) and positively with hematoma volume (unstandardized coefficient 3.914, 95% CI 1.914-5.915, p < 0.001). Conversely, the FIB-4 index was associated with neither prognosis nor hematoma volume in the non-lobar ICH cohort. Liver fibrosis, as assessed by the FIB-4 index, is associated with unfavorable outcomes and hematoma volume in ICH, particularly in lobar ICH.

DOI： 10.1038/s41440-025-02487-3

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

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

OBJECTIVES: Factors associated with intraventricular extension (IE) following intracerebral hemorrhage (ICH) are not fully clarified. We aimed to elucidate the correlation between IE and cerebral small vessel disease (SVD) in ICH. MATERIALS & METHODS: Consecutive patients with acute ICH between July 2012 and November 2023 were screened. The inclusion criteria: 1) onset to door time within 7 days; 2) availability of SVD evaluation using total SVD score; and 3) availability of IE evaluation on admission and/or more than 24 h after admission. Total SVD score was calculated as the sum of the points for the following observations: old lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMBs), and enlarged perivascular spaces. RESULTS: Of 608 ICH screened, 449 (234 [52 %] males, median age 75 years) were included. IE was observed in 151 (34 %). Total SVD score was independently associated with IE (prevalence ratio (PR) 1.188, 95 % confidence interval (CI) 1.063-1.329, p = 0.002). Further, a positive linear trend was observed between total SVD score and IE relative to a total SVD score of 0 (total SVD score 0: PR 1.000, total SVD score 1-2: PR 3.769, total SVD score 3-4: PR 4.109, p = 0.011 for trend). Among the items comprising the total SVD score, WMH (PR 1.406 95 % CI 1.041-1.899, p = 0.026) and CMBs (PR 1.800, 95 % CI 1.068-3.036, p = 0.027) were associated with IE. CONCLUSION: In acute ICH, higher total SVD score is associated with IE. In particular, WMH and CMBs might correlate with the occurrence of IE.

DOI： 10.1016/j.jns.2025.125680

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

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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Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>Adult-onset Krabbe disease is a rare neurodegenerative disorder caused by mutations in the <i>galactocerebrosidase</i> (<i>GALC</i>) gene. It typically presents with slowly progressive central nervous system involvement, primarily characterized by pyramidal tract signs. We report the case of a 74-year-old man who presented with slowly progressive, asymmetric muscle atrophy associated with peripheral neuropathy, but without any clinical evidence of pyramidal tract involvement. Neurological examination revealed muscle wasting and weakness without spasticity or pathological reflexes. Based on the clinical presentation, differential diagnoses included motor neuron disease, Charcot–Marie–Tooth disease, and chronic inflammatory demyelinating polyneuropathy. Genetic analysis revealed a known pathogenic missense variant in the <i>GALC</i> gene: c.246A>G (p.I82M), confirming the diagnosis of Krabbe disease. These mutations have been previously reported in adult-onset Krabbe disease. This case lacked typical central nervous system signs and represents an atypical phenotype that may lead to delayed diagnosis. Our findings suggest that Krabbe disease should be considered in the differential diagnosis of adult patients presenting with unexplained neuropathy and marked muscle atrophy. Genetic testing plays a critical role in identifying such atypical cases, particularly when conventional diagnostic approaches fail to provide a definitive diagnosis.</p>

DOI： 10.5692/clinicalneurol.cn-002148

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CiNii Research

Language：Japanese   Publisher：(一社)日本神経学会  

成人型Krabbe病は,ガラクトセレブロシダーゼ(galactocerebrosidase,以下GALCと略記)遺伝子変異により発症し,通常は錐体路障害を伴う.今回,著明な筋萎縮を伴う末梢神経障害を呈し,錐体路障害に乏しい74歳男性例を経験した.運動ニューロン疾患やCharcot-Marie-Tooth病,慢性炎症性脱髄性多発神経炎が鑑別に挙がったが,遺伝子解析でGALC遺伝子に既知のミスセンス変異c.246A>G(p.I82M)を認め,Krabbe病と診断した.非典型例では診断が遅れる可能性があり,本疾患を念頭に置いた検査の実施が診断に有用と考えられた.(著者抄録)

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Background

This study aimed to examine whether the presence of atrial fibrillation (AF), severity as judged by total small vessel disease (SVD) score, or a combination of these is associated with prognosis and hematoma volume of spontaneous intracerebral hemorrhage (sICH).

Methods

This retrospective analysis investigated 608 patients who were admitted within 7 days of ICH onset between July 2012 and November 2023. The primary outcome was prognosis at 3 months after onset according to the modified Rankin Scale (mRS) score. Associations of AF, SVD and a combination of these with outcomes and hematoma volume were examined using univariate analyses, logistic regression analysis, and multiple regression analysis.

Results

A total of 608 consecutive patients with sICH were screened, and 330 patients were finally included in the analysis after applying the inclusion and exclusion criteria. Among the 330 patients analyzed, 145 (43.9%) experienced poor outcomes (mRS score 4–6). The presence of AF was independently associated with poor outcome (adjusted OR 4.93, 95% CI 1.72–16.1; p  = 0.002), whereas total SVD score alone was not. Multiple regression analysis with estimated hematoma volume also showed a significant association with AF (standard partial regression coefficient 0.16; p  = 0.033), but not with total SVD score. However, a linear trend was observed between the combination of AF and total SVD score severity and poor outcome (total SVD score 0–1 without AF: aOR 1.00, total SVD score 2–4 without AF: 1.44, total SVD score 0–1 with AF: 4.26, total SVD score 2–4 with AF: 7.57; p for trend = 0.002). Multiple regression analysis using estimated hematoma volume also showed a synergistic effect of AF and total SVD score severity (standardized regression coefficient 0.14; p  = 0.032).

Conclusion

The presence of AF was associated with poor 3-month outcomes and increased estimated hematoma volume in sICH patients, whereas total SVD score alone was not. The effects of AF and SVD together appear to contribute synergistically to worsened prognosis and increased hematoma volume in sICH patients.

DOI： 10.3389/fneur.2025.1682520

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Language：Japanese   Publisher：JAMA Cardiology  

Importance: Antithrombotic therapy is crucial for older patients with coronary artery disease (CAD) and atrial fibrillation (AF) who are at a high risk of bleeding and thrombotic events. Objective: To examine the age-stratified effects of rivaroxaban monotherapy compared with those of rivaroxaban plus antiplatelet agent combination therapy. Design, Setting, and Participants: This was a post hoc secondary analysis of the Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease (AFIRE) open-label randomized clinical trial. This was a multicenter study conducted in Japan from February 23, 2015, to July 31, 2018. Patients with AF and stable CAD who had undergone percutaneous coronary intervention or coronary artery bypass grafting 1 or more years earlier or who had angiographically confirmed CAD that did not require revascularization were enrolled. Participants were stratified into 4 groups by age (<70 years, 70-74 years, 75-79 years, and ≥80 years). Study data were analyzed from August 2024 to July 2025. Interventions: Rivaroxaban monotherapy or rivaroxaban plus antiplatelet agent therapy. Main Outcomes and Measures: The primary efficacy end point was a major adverse cardiovascular event, defined as a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding. Results: This study included a total of 2215 participants (mean [SD] age, 74.3 [8.2] years; 1751 male [79.1%]). The incidence of primary efficacy end points per patient-year for rivaroxaban monotherapy vs rivaroxaban plus antiplatelet agent therapy was 3.2% vs 4.3% (<70 years), 3.2% vs 2.8% (70-74 years), 3.8% vs 5.3% (75-79 years), and 6.2% vs 10.3% (≥80 years). The hazard ratios were 0.74 (95% CI, 0.40-1.37) for those younger than 70 years, 1.16 (95% CI, 0.55-2.45) for those aged 70 to 74 years, 0.72 (95% CI, 0.41-1.26) for those aged 75 to 79 years, and 0.61 (95% CI, 0.40-0.93) for those 80 years and older (P for interaction =.51). For the primary safety end points, the incidence was 0.5% vs 2.3% (<70 years), 2.2% vs 2.4% (70-74 years), 1.1% vs 2.1% (75-79 years), and 2.9% vs 4.3% (≥80 years). The hazard ratios were 0.23 (95% CI, 0.06-0.79) for those younger than 70 years, 0.91 (95% CI, 0.39-2.15) for those aged 70 to 74 years, 0.52 (95% CI, 0.19-1.42) for those aged 75 to 79 years, and 0.67 (95% CI, 0.35-1.27) for those 80 years and older (P for interaction =.33). Conclusions and Relevance: Results of this post hoc analysis of the AFIRE randomized clinical trial reveal that rivaroxaban monotherapy reduced the risk of major cardiovascular events and major bleeding across the broad range of age in patients with AF and stable CAD. Possible age-related differences in trends, with more pronounced efficacy in older patients and more pronounced safety in younger patients, should be considered as hypothesis generating and require further research.

DOI： 10.1001/jamacardio.2025.2611

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Language：Japanese   Publisher：(一社)日本神経学会  

症例は17歳男性.11歳時にインフルエンザに罹患した際の頭部MRIで,脳梁膨大部および大脳白質に可逆性の脳病変を認めた.15ヵ月前に嚥下障害,構音障害,顔面麻痺,筋力低下のため小児科を受診した際も頭部MRIで同様の病変を認め,神経伝導検査で脱髄性ニューロパチーが示唆された.免疫グロブリン大量静注療法(intravenous immunoglobulin,以下IVIgと略記)およびステロイドパルス療法を施行し症状は改善,MRIの病変は消失した.3ヵ月前に歩行時に膝折れが出現しIVIg後に症状は改善した.遺伝子検査でGJB1(Gap Junction Protein Beta 1)遺伝子にc.124A>T(p.Ser42Cys)の病的バリアントを認めX連鎖性Charcot-Marie-Tooth病1型(CMTX1)と診断した.CMTX1の末梢神経障害は症状に変動を認め,IVIgによる治療反応性を認めることがある.またCMTX1の診断においては繰り返す脳病変にも留意する.(著者抄録)

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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

ABSTRACT

Background

Mitofusin 2 (MFN2) is a major causative gene for axonal Charcot – Marie – Tooth disease type 2A (CMT2A), with a wide phenotypic spectrum. Comprehensive large ‐ scale genotype – phenotype association studies are essential for understanding disease pathogenesis and improved clinical management.

Methods

We conducted a nationwide retrospective study of 176 Japanese patients with genetically confirmed pathogenic or likely pathogenic MFN2 variants encompassing clinical, electrophysiological, and genetic characterization.

Results

MFN2 was the second most frequent causative gene among 1211 genetically diagnosed inherited peripheral neuropathy cases in Japan. A total of 76 MFN2 variants were identified, including nine novel likely pathogenic variants. Disease onset occurred at a mean age of 11.1 years, with distal motor weakness and tibialis anterior involvement as prominent features. Sensory symptoms were present in ~60% of patients and were more common in cases with longer disease duration. Central and systemic features, including pyramidal signs, optic atrophy, and vocal cord paralysis, were also observed. Electrophysiological studies revealed a predominantly axonal sensorimotor pattern, with relatively preserved upper limb conduction and marked lower limb abnormalities. Importantly, 24 patients (16%) were non‐ambulatory, with earlier onset and greater weakness. Domain‐based analysis further revealed that variant location may influence age at onset.

Conclusion

This large‐scale study highlights the genetic and clinical diversity of MFN2‐related CMT in Japan. Our findings confirm a motor‐dominant, length‐dependent axonal neuropathy with additional sensory and systemic features in some cases. These results emphasize the importance of early diagnosis, genotype‐informed care, and long‐term follow‐up in managing MFN2‐related CMT.

DOI： 10.1002/acn3.70218

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

ABSTRACT

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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Language：English   Publisher：Nature Publishing Group  

Language：English   Publisher：Elsevier B.V.  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00415-025-13326-3

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Other Link： https://link.springer.com/article/10.1007/s00415-025-13326-3/fulltext.html

Language：Japanese   Publisher：(有)科学評論社  

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

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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PubMed

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

The correlation between lipoprotein cholesterol levels and hematoma expansion (HE) following intracerebral hemorrhage (ICH) remains unknown. We aimed to elucidate the correlation between high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and HE following acute ICH in entire ICH, non-lobar ICH, and lobar ICH cohorts. Consecutive patients with ICH between July 2012 and November 2023 were screened. The inclusion criteria were: (1) onset to door time within 24 h; (2) availability of serum HDL-C and LDL-C level evaluations on admission; and (3) availability of HE evaluation. We investigated the association between HDL-C and LDL-C levels and HE using Poisson regression analyses with a robust variance estimator in three models with adjustment for various factors. Screening of 608 consecutive ICH patients revealed 409 with acute ICH (204 [50%] males, median age 75 years). HE was observed in 43 patients (11%). In the entire ICH cohort, lower HDL-C was independently associated with HE in all the study models (p < 0.05). Further, a negative linear association was observed between HDL-C quartiles and HE in reference to HDL-C Quartile 4 in all the models (p < 0.05 for trend). These significant associations were also observed in the non-lobar ICH cohort, but not in the lobar ICH cohort. LDL-C was not associated with HE in any of the cohorts. In acute ICH patients, lower HDL-C was associated with HE, especially in the non-lobar ICH cohort generally caused by hypertensive microangiopathy. HDL-C might have protective potential against HE following ICH. We aimed to elucidate the correlation between high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and hematoma expansion (HE) following acute intracerebral hemorrhage (ICH). Lower HDL-C was associated with HE, especially in the non-lobar ICH caused by hypertensive microangiopathy. HDL-C might have protective potential against HE following ICH.

DOI： 10.1038/s41440-025-02268-y

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Language：Japanese   Publisher：日本末梢神経学会  

Charcot-Marie-Tooth(CMT)病は,末梢神経の異常に起因しておもに運動神経および感覚神経が障害される疾患である。遺伝的にも臨床的にも多様な疾患であり,臨床症状から診断するのは容易ではない。遺伝子解析は技術の進歩に併せて進化し,包括的な遺伝子解析が可能となっており,診断率も上がってきている。CMTの遺伝学的特徴を明らかにし,新たな遺伝学的知見の蓄積が進むことで,CMTの病態解明がさらに深まり,疾患特異的な治療法の開発が加速することが期待される。(著者抄録)

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)

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

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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Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

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

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. CONCLUSION: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

DOI： 10.1136/jnnp-2024-333403

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Language：English   Publisher：(公社)日本生物工学会  

腸内での細菌生存について、Barnesiella intestinihominisが複合型N-グリカンを栄養素として利用しうるか検討し、その機序を調べた。B.intestinihominisは炭素源として複合型N-グリカンを利用できた。RNA-seq解析で複合型N-グリカンの分解に関与する酵素とトランスポーターを認めた。B.intestinihominisを複合型N-糖蛋白質培地で培養すると、細胞内でグリコシドヒドロラーゼ85エンド-β-N-アセチルグルコサミニダーゼをコードする遺伝子(endo-BIN1、endo-BIN2、endo-BIN3)発現が上昇した。SusC/SusD膜複合体をコードするSusCとSusD遺伝子はendo-BIN遺伝子とクラスターを形成するので、SusC/SusDが細胞内へのグリカン輸送に関与することが示唆された。exo型グリコシドヒドロラーゼ酵素をコードする他の遺伝子発現が、N-糖蛋白質培地で増殖した細菌でみられたことから、これらの酵素が細菌によるグリカンのさらなる分解に関与することが示唆された。

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>The patient is a 17-year-old male. He had a history of hospitalization for influenza at the age of 11, and Brain MRI at that time showed reversible brain lesions in the splenium of the corpus callosum and cerebral white matter. Fifteen months ago, he visited the pediatrics department due to dysphagia, dysarthria, facial paralysis, and muscle weakness. Brain MRI revealed lesions similar to those observed here, and nerve conduction study revealed demyelinating neuropathy. He was treated with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone, and his symptoms disappeared within a few days and Brain MRI 5 weeks after treatment revealed that the lesions had disappeared. Three months ago, while walking, the patient developed a knee strain, which was thought to be a recurrence of the immune-mediated neuropathy. His subjective symptom disappeared after administration of IVIg. The patient was diagnosed with X-linked Charcot–Marie–Tooth disease (CMTX1) based on genetic testing, which revealed a pathological variant of <i>GJB1</i>, c.124A>T (p.Ser42Cys). Peripheral neuropathy in CMTX1 may present with fluctuating symptoms and can be responsive to IVIg treatment. Recurrent brain lesions should also be considered in the diagnosis of CMTX1.</p>

DOI： 10.5692/clinicalneurol.cn-002127

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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

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.cnp.2025.10.006

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Language：Japanese   Publisher：Neurocase  

A 63-year-old woman presented with gait disturbance, progressive hearing loss, and sensory dominant polyneuropathy. Brain MRI mainly revealed midbrain tegmental atrophy (hummingbird sign). Genetic testing identified a heterozygous DNMT1 exon 21 mutation, previously linked to autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN), although her clinical presentation resembled hereditary sensory and autonomic neuropathy type 1E (HSAN1E). A review of previously published cases with the same mutation revealed variability in sensory involvement, cerebellar signs, and sleep disorders, supporting the existence of a wide disease spectrum of DNMT1-related disorders. This case illustrates the phenotypic and radiological overlap within DNMT1-related disorders and supports the concept of a disease spectrum, rather than discrete syndromes, highlighting the diagnostic value of combining neuroimaging with genetic analysis.

DOI： 10.1080/13554794.2025.2560858

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Language：Japanese   Publisher：Neurology Neuroimmunology and Neuroinflammation  

Background and Objectives – Human T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurologic disorder characterized by chronic inflammation in the CNS. HTLV-1–specific cytotoxic CD8+ T lymphocytes (CTLs) play a crucial role in the pathogenesis of HAM/TSP; however, the dynamics of CTLs in the CSF remain poorly understood. The aim of this study was to investigate the accumulation of HTLV-1–specific CTLs in the CSF of patients with HAM/TSP and to evaluate their association with neuroinflammation and neural damage. Methods – The frequency of HTLV-1–specific CTLs was compared between paired peripheral blood (PB) and CSF from patients with HAM/TSP and asymptomatic HTLV-1 carriers (ACs) using MHC/antigen tetramers. In addition, cytokine levels and neurofilament light chain (NfL) concentration were analyzed in the CSF of patients with HAM/TSP and ACs. Results – The frequency of HTLV-1–specific CTLs in PB was significantly higher in patients with HAM/TSP compared with ACs (median [interquartile range (IQR)] = 3.0 [0.9–8.3] % vs 0.3 [0.2–3.1] %, p < 0.01). Notably, this difference was even more pronounced in CSF, where patients with HAM/TSP exhibited a significantly elevated frequency compared with ACs (19.1 [7.9–33.4] % vs 6.1 [0.9–15.7] %, p < 0.01). Furthermore, the frequency of HTLV-1–specific CTLs in the CSF was considerably higher than in the PB of patients with HAM/TSP (p < 0.0001). The lack of accumulation of cytomegalovirus-specific CTLs indicates that HTLV-1–specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. These accumulated HTLV-1–specific CTLs in the CSF significantly correlated with increased levels of cytokines in patients with HAM/TSP. In addition, CSF NfL levels were significantly higher in patients with HAM/TSP than in ACs (696 [534–1, 407] vs 429 [373–717] pg/mL, p < 0.05) and showed a positive correlation with HTLV-1 proviral load. Discussion – HTLV-1–specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. Chronic inflammation, primarily driven by the interaction between proliferating HTLV-1–infected cells and accumulated HTLV-1–specific CTLs, may contribute to neural damage in patients with HAM/TSP.

DOI： 10.1212/NXI.0000000000200508

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Language：Japanese   Publisher：Japanese Peripheral Nerve Society  

<p>　Charcot-Marie-Tooth disease ( CMT ) is a type of inherited peripheral neuropathy ( IPN ) that primarily affects motor and sensory nerves due to abnormalities in the peripheral nervous system. CMT exhibit significant genetic and clinical heterogeneity, with over 140 causative genes identified, encompassing diverse cellular localizations and functional roles. This review discusses advancements in genetic analysis techniques, including gene panel sequencing, whole-exome sequencing ( WES ) , whole-genome sequencing ( WGS ) , and long-read sequencing, which have significantly improved the diagnostic accuracy and yield. Furthermore, we also present the genetic landscape of 3,315 CMT/IPN patients in Japan ( excluding PMP22 duplication/deletion cases ) . Comprehensive analyses are essential to deepen our understanding of CMT/IPN and facilitate the development of targeted therapies and improved patient care. The discovery of repeat expansion mutations emphasizes the necessity for continuous refinements in diagnostic strategies to address novel and emerging genetic mechanisms underlying CMT/IPN.</p>

DOI： 10.69407/jpns.36.1_7

CiNii Research

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

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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Language：Japanese   Publisher：European Journal of Vascular and Endovascular Surgery  

Objective: This study aimed to determine the impact of infrapopliteal (IP) revascularisation establishing in line flow to the wound (IFW) on wound healing in chronic limb threatening ischaemia (CLTI), using a core laboratory assessment for wounds and in line flow. Methods: The Wound directed Angiosome RevasculaRIsation apprOach to patients with cRitical limb iSchaemia (WARRIORS) multicentre observational study enrolled patients with CLTI with tissue loss undergoing IP revascularisation in Japan, with scheduled two year follow up. The primary outcome measure was complete wound healing, defined as achievement of complete epithelialisation of all wounds without major amputation. IP revascularisation establishing IFW was defined as revascularisation after which a tibiopedal artery that actually fed an injured pedal unit was patent. The incidence of wound healing was compared between the IFW and non-IFW groups using inverse probability of treatment weighting based on the propensity score. Results: A total of 440 patients with CLTI (median age, 75 years; male, 64.1%; diabetes mellitus, 72.0%; dialysis, 57.7%) with tissue loss (Wound, Ischaemia, and foot Infection stage 4, 66.4%) who underwent IP revascularisation (endovascular procedure, n = 304; bypass grafting, n = 136) between October 2017 and June 2020 were registered. During a median follow up of 23.6 months, 51.1% achieved wound healing. Successful IP revascularisation with IFW was achieved in 68.2%. After analysis, the IFW group had a higher rate of wound healing than the non-IFW group (34.5 vs. 16.1 per 100 person years; p =.030). The association between IFW and wound healing was not statistically different between patients undergoing bypass grafting and those undergoing an endovascular procedure (p for interaction =.38). There was no statistically significant interaction effect between IFW and direct revascularisation for wound healing (p for interaction =.51). Conclusion: IP revascularisation establishing IFW was statistically significantly associated with a higher wound healing rate in patients with CLTI.

DOI： 10.1016/j.ejvs.2024.07.024

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Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経免疫学会  

Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：THE JAPAN DIABETES SOCIETY  

<p>A 47-year-old man with type 2 diabetes mellitus, which was untreated for 10 years, was admitted to our hospital with diabetic ketoacidosis (HbA1c 16.5 %), which improved to HbA1c 7.1 % within 2 months after acute treatment and intensive insulin therapy. At the same time, he became aware of numbness in his upper and lower limbs and lightheadedness, which gradually worsened, and orthostatic hypotension also appeared. Nerve conduction studies revealed polyneuropathy with a sensory nerve predominance. Although the symptoms were not typical, we clinically diagnosed the patient with treatment-induced neuropathy of diabetes (TIND). A sural nerve biopsy revealed a decreased density of large and small myelinated fibers, macrophage infiltration, and elevated CSF protein, which suggested an immune-mediated and inflammatory mechanism. Therefore, we administered intravenous immunoglobulin (IVIg) therapy. As a result, the superficial sensory disturbance of the upper extremities and orthostatic hypotension improved. We report an interesting case in which neurological symptoms in a patient with TIND improved after IVIg treatment.</p>

DOI： 10.11213/tonyobyo.67.333

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CiNii Research

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

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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Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>Spinocerebellar ataxia type 14 (SCA14) is a rare form of autosomal dominant cerebellar ataxia caused by mutations in <i>PRKCG</i>. We herein report a case of SCA14 presenting with writer's cramp that predated the onset of progressive ataxia by four years. A 47-year-old Japanese woman had an 11-year history of writer's cramps, followed by unsteadiness. Whole-exome sequencing revealed a heterozygous mutation in <i>PRKCG</i> (p.C142S), leading to an SCA14 diagnosis. Therefore, writer's cramp might be a characteristic extracerebellar sign of SCA14 and can precede the onset of cerebellar ataxia. </p>

DOI： 10.2169/internalmedicine.2943-23

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CiNii Research

Language：Japanese   Publisher：(一社)日本糖尿病学会  

47歳男性.10年間未治療の2型糖尿病を有し,糖尿病性ケトアシドーシス(HbA1c 16.5%)にて入院し,急性期治療,強化インスリン療法後2ヵ月でHbA1c 7.1%まで改善した.同時期より上下肢のしびれやふらつきを自覚し,次第に悪化し起立性低血圧も出現した.神経伝導検査で感覚神経優位の多発神経障害を認めた.症状は非典型的であったが,臨床的に糖尿病治療誘発性神経障害(TIND)と診断した.一方,腓腹神経生検では大径・小径有髄線維密度の減少とマクロファージの浸潤,髄液蛋白の上昇を認め,免疫介在性・炎症性の機序も考えられたため,免疫グロブリン大量静注療法(IVIg)を行ったところ,上肢の表在感覚障害と起立性低血圧が改善した.TINDにIVIgを行い,神経症状の改善を認めた興味深い症例を報告する.(著者抄録)

Language：English   Publisher：(一社)日本内科学会  

症例は47歳女性で、36歳時に緩徐進行性の筆記困難と不安定歩行を認めた。患者の母親は47歳時に脊髄小脳変性症と診断されていた。脳神経検査は正常であったが、円滑性追跡眼球運動は衝動性眼球運動により中断され、軽度の小脳性構音障害を認めた。運動検査では、筆記中の右手姿位が正常でなく、右親指手関節の過屈曲が認められた。深部腱反射および感覚系は正常であった。指追跡試験における右手のジストニア姿勢を伴う軽度ジスメトリア、踵脛試験における下肢協調不全も認められた。歩行は不安定で、タンデム歩行障害を認めた。表面筋電図検査では、筆記中に右長母指屈筋が長母指伸筋と共収縮することが明らかとなった。脳MRIで小脳萎縮が認められた。全エクソームシーケンシングで、PRKCG遺伝子のヘテロ接合体変異(p.C142S)が判明し、脊髄小脳失調症14型と診断した。同変異は患者の母親にも認められた。トリヘキシフェニジルとクロナゼパムによる治療を行った。その結果、軽度の改善が認められた。

Language：Japanese   Publisher：(公社)日本精神神経学会  

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

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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Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p>X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), the most common form of CMTX, is caused by gap-junction beta 1 (<i>GJB1</i>) mutations. We herein report a 25-year-old Japanese man with disorientation, right hemiparesis, and dysarthria. Brain magnetic resonance imaging (MRI) showed high signal intensities in the bilateral cerebral white matter on diffusion-weighted imaging. He had experienced 2 episodes of transient central nervous system symptoms (at 7 and 13 years old). A genetic analysis identified a novel <i>GJB1</i> mutation, c.169C>T, p.Gln57*. MRI abnormalities shifted from the cerebral white matter to the corpus callosum and had disappeared at the five-month follow-up. Transient changes between these lesions may indicate CMTX1. </p>

DOI： 10.2169/internalmedicine.1713-23

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CiNii Research

Language：English   Publisher：(一社)日本内科学会  

症例は25歳男性で、7歳時に初回発作が出現し、頭部MRIのT2強調画像で頭頂葉と後頭葉の両側脳白質および脳梁膨大部に高信号域を認めた。13歳時に2回目の発作が出現し、MRIの拡散強調画像とT2強調画像で脳梁と頭頂葉の白質に高信号域を認めた。現症の発作では、歩行中に感覚障害と構音障害が出現し、地域病院に入院した。翌日に症状が悪化し、右上下肢の軽度筋力低下も認めたため、搬送されてきた。神経学的検査で見当識障害と右片麻痺が判明し、腱反射が完全に消失し、下肢の振動覚が低下していた。凹足も認めた。家族歴の聴取から、症例の弟がシャルコー・マリー・トゥース病(CMT)と診断されており、症例の母親が下垂足を有していることが判明した。DNA解析を行い、新規のギャップ結合β1(GJB1)変異(c.169C>T、p.Gln57*)が特定された。症例の母親と弟も同様の変異を有していたことから、新規GJB1変異を伴うX連鎖性CMT 1型と診断した。2週後の追跡MRIでは、拡散強調画像における白質の高信号域が消失し、脳梁膨大部に高信号域が出現していた。5ヵ月後、膨大部病変は完全に消失した。

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

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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PubMed

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

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

BACKGROUND AND OBJECTIVES: The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. METHODS: We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. RESULTS: Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270-316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. DISCUSSION: This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

DOI： 10.1002/acn3.51936

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PubMed

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

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.

DOI： 10.1111/jns.12590

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Language：Japanese   Publisher：(一社)日本神経学会  

末梢神経障害を合併したBAG3変異による筋原線維性ミオパチー(myofibrillar myopathy,以下MFMと略記)の1例を経験したので報告する.症例は19歳の女性で,階段昇降や歩行障害が進行した.神経学的に体幹筋と両下肢遠位筋優位の筋力低下を認め,筋生検で縁取り空胞や不整な筋線維配列を確認した.遺伝子解析でBcl2-Associated Athanogene3(BAG3)の病的ヘテロ接合性変異(p.P209L)が判明し,MFM6と診断した.本症は小児期に発症し心筋症を合併する予後不良の稀なミオパチーであるが,軸索型ニューロパチーを合併し,尖足拘縮,体幹屈筋が弱い特徴がある.若年発症のニューロミオパチーでは本疾患を疑い,遺伝子検査を検討すべきである.(著者抄録)

Language：Japanese   Publisher：(一社)日本小児神経学会  

遺伝性運動感覚性ニューロパチーの病因遺伝子は多数報告されているがその中でもGNB4バリアントの報告例は少なく,日本人での報告例は1家系のみである.我々は転びやすさと学習困難を主訴に精査され,GNB4バリアントを認めた遺伝性運動感覚性ニューロパチーの14歳女子を経験した.8歳時に終糸脂肪腫による脊髄係留症候群の診断で係留解除術が施行されたあとも転びやすさが改善せず,成績不振も認めていたため精査した.脳神経所見に特記事項はなかったが,前脛骨筋の筋力低下とS1領域の感覚低下を認めた.血液検査,頭部・脊髄MRI検査では異常はなかった.神経伝導検査では下肢優位の伝導速度低下を認めた.遺伝子検査でPMP22の重複・欠失は認めなかったが,Charcot-Marie-Tooth病病因遺伝子解析でGNB4バリアント(NM_021629.4:c.229G>A,p.Gly77Arg)をヘテロ接合性に認めた.データベースにも登録されていないde novoバリアントであり,両親に同バリアントは認めなかった.WISC-IVを行い,IQは知的境界域で指標間でばらつきがあり,特に知覚推理の値が低かった。GNB4バリアントの報告例は少なく神経発達症との関連の報告はないが,中枢神経症状にも関与している可能性もあり,更なる症例の蓄積が必要と考えられた.(著者抄録)

Language：Japanese   Publisher：(一社)日本神経学会  

症例1は68歳女性で,約1ヵ月の経過で悪化した筋力低下,皮下浮腫,嚥下障害と高CK血症で当科入院となった.症例2は78歳女性で,約5ヵ月間で悪化した筋力低下,両肩痛,皮下浮腫,嚥下障害で当科入院となった.2例とも著明なびまん性皮下浮腫と嚥下障害を認め,経腸栄養が必要であった.皮膚所見がなかったが,筋生検でのMxA発現と抗nuclear matrix protein 2(以下NXP-2と略記)抗体陽性の結果から皮膚炎欠如型皮膚筋炎(dermatomyositis sine dermatitis,以下DMSDと略記)と診断した.抗NXP-2抗体は,DMSDとの関連が示されており,浮腫および嚥下障害例が多いと報告されている.皮疹がなくとも,筋炎を疑う症例で皮下浮腫や嚥下障害がめだつ場合は,抗NXP-2抗体を測定すべきである.(著者抄録)

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本認知症学会  

Language：Japanese   Publisher：(一社)日本認知症学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：日本神経感染症学会  

Language：Japanese   Publisher：日本神経感染症学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

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GAN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.(著者抄録)

Language：Japanese   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p>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 <i>ERCC6</i> 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. </p>

DOI： 10.2169/internalmedicine.0061-22

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Language：Japanese   Publisher：(一社)日本神経学会  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ncn3.12770

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

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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Language：English   Publisher：(一社)日本内科学会  

症例1は50歳女性。30歳時から難聴と歩行不安定が出現し、緩徐に進行していた。症例の妹(症例2)も同様の症状を有していた。特徴的顔貌と小脳性運動失調を認め、ミニメンタルステート検査(MMSE)スコアは20/30、改訂長谷川式簡易知能評価スケール(HDS-R)スコアは20/30、運動失調評価スケール(SARA)スコアは9/40であった。遺伝子検査でERCC6遺伝子の複合ヘテロ接合体病的バリアント(c.1583G>A[p.G528E]、c.1873T>G[p.Y625D])が特定されたことから、Cockayne症候群BタイプIIIと診断した。症例2は48歳女性(症例1の妹)。30歳時から難聴と歩行不安定が出現していた。身体的所見、神経学的所見、生化学的所見、画像所見は症例1とほぼ同様で、SARAスコアは9/40、MMSEスコアは21/30、HDS-Rスコアは21/30であった。遺伝子検査でERCC6遺伝子の複合ヘテロ接合体病的バリアント(c.1583G>A[p.G528E]、c.1873T>G[p.Y625D])が特定されたことから、Cockayne症候群BタイプIIIと診断した。

Language：Japanese   Publisher：(一社)日本糖尿病学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本糖尿病学会  

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

Recent research in the field of inherited peripheral neuropathies (IPNs) such as Charcot-Marie-Tooth (CMT) disease has helped identify the causative genes provided better understanding of the pathogenesis, and unraveled potential novel therapeutic targets. Several reports have described the epidemiology, clinical characteristics, molecular pathogenesis, and novel causative genes for CMT/IPNs in Japan. Based on the functions of the causative genes identified so far, the following molecular and cellular mechanisms are believed to be involved in the causation of CMTs/IPNs: myelin assembly, cytoskeletal structure, myelin-specific transcription factor, nuclear related, endosomal sorting and cell signaling, proteasome and protein aggregation, mitochondria-related, motor proteins and axonal transport, tRNA synthetases and RNA metabolism, and ion channel-related mechanisms. In this article, we review the epidemiology, genetic diagnosis, and clinicogenetic characteristics of CMT in Japan. In addition, we discuss the newly identified novel causative genes for CMT/IPNs in Japan, namely MME and COA7. Identification of the new causes of CMT will facilitate in-depth characterization of the underlying molecular mechanisms of CMT, leading to the establishment of therapeutic approaches such as drug development and gene therapy.

DOI： 10.1038/s10038-022-01031-2

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Language：English   Publisher：Nature Publishing Group  

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

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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Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本糖尿病学会  

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

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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Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

<p>A 19-year-old female, normal at birth, grew up without neck movement when getting up. She needed a handrail to climb stairs since the age of 10 years old, and walked slowly since the age of 16 years old. Neurological examination revealed loss of deep tendon reflexes, decreased vibratory sensation, weakness of distal muscles of the lower extremities, and weakness of mainly cervical trunk muscles suspected to be due to myopathy. Nerve conduction studies suggested axonal polyneuropathy, and needle EMG showed short duration MUP, myotonic discharge, and rimmed vacuoles on muscle biopsy. Genetic analysis revealed a previously reported pathological mutation (p.P209L, heterozygous) in <i>Bcl2-Associated Athanogene 3</i> (<i>BAG3</i>), and a diagnosis of MFM6 was made. P209L is a poor prognosis myopathy that develops in childhood and is associated with cardiomyopathy. P209L is a solitary myopathy associated with axonal neuropathy and characterized by apex foot contracture and weak neck to trunk flexion. This disease is suspected in young-onset neuromyopathy.</p>

DOI： 10.5692/clinicalneurol.cn-001915

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CiNii Research

Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21H02842/

Language：Japanese   Publishing type：Research paper (scientific journal)   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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CiNii Research

Other Link： https://search.jamas.or.jp/link/ui/2024004707

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

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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PubMed

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

INTRODUCTION: Genetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan. METHODS: We obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted. RESULTS: From 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25). DISCUSSION: The low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.

DOI： 10.3389/fneur.2023.1078195

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PubMed

Language：Japanese   Publisher：The Japanese Society of Child Neurology  

<p>  Among the many reported etiologic genes for hereditary motor-sensory neuropathy, the <i>GNB4</i> variant has been rarely reported, with only one case reported in a Japanese family. We present the case of a 14-year-old girl with hereditary motor-sensory neuropathy who was diagnosed as having a <i>GNB4</i> variant after proper examination. Her chief complaints were repeated falls and learning difficulties. She had been diagnosed with tethered spinal cord syndrome due to a terminal filum lipoma at the age of 8 years and had undergone untethering surgery, but her tendency to fall and poor academic performance had not improved. No notable findings were observed in the cerebral neurological examination, but the patient had weakness of the anterior cervical muscles and decreased sensation in the S1 area. Blood tests and MRI of the head and spinal cord showed no abnormalities. Nerve conduction studies revealed decreased nerve conduction velocity with lower extremity predominance. Genetic analysis showed no duplication or deletion of <i>PMP22</i>, but a heterozygous variant was found in <i>GNB4</i> gene (NM_021629.4 : c.229G＞A, p.Gly77Arg) by the etiological gene analysis for Charcot-Marie-Tooth disease. This is a <i>de novo</i> variant that has not been included in any database ; the same variant was not found in the parents. Her intelligence quotient scores by the WISC-IV were in the borderline range. There was variability in each item, with especially low scores in perceptual reasoning. Although few studies have reported on <i>GNB4</i> variants and no association with neurodevelopmental disorders, it is necessary to compile more cases because <i>GNB4</i> variants may be related to the symptoms of the central nervous system.</p>

DOI： 10.11251/ojjscn.55.448

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CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

<p>The patient is a 44-year-old man. His parents are consanguineous. He experienced muscle weakness in his toe and distal tingling sensation in his feet at 42 years of age, which gradually progressed. Additionally, a marked cyanotic discoloration of the feet appeared and worsened progressively. Neurological examination revealed loss of tendon reflexes and distal muscle weakness in the lower extremities. Findings from nerve conduction studies indicated axonal polyneuropathy. Upon detection of the <i>MME</i> gene mutation, the patient was diagnosed with autosomal-recessive Charcot–Marie–Tooth disease 2T (ARCMT2T). In this case, cyanosis of the lower extremities possibly was associated with ARCMT2T, and it was suggested to be due to neprilysin deletion linked with the <i>MME</i> mutation. This represents the first documented occurrence of cyanosis as a distinctive feature of CMT with <i>MME</i> mutation.</p>

DOI： 10.5692/clinicalneurol.cn-001870

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CiNii Research

Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21H02842/

Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<p>We will review the recent therapeutic advances in spinocerebellar degeneration (SCD) that were published in 2022. This article provides an overview of therapies including riluzole/troriluzole, omaveloxolone, mesenchymal stem cells, Coenzyme Q10, erythropoietin, cinpanemab, prasinezumab, cerebello–spinal transcranial direct current stimulation (tDCS), and rehabilitation. We anticipate that these treatments will contribute to improving motor dysfunction and ataxia in patients with cerebellar disorders.</p>

DOI： 10.15082/jsnt.40.5_707

CiNii Research

Publisher：医歯薬出版  

DOI： 10.32118/ayu283101038

CiNii Research

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

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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PubMed

Language：Japanese   Publisher：医歯薬出版(株)  

シャルコー・マリー・トゥース病(CMT)は遺伝性ニューロパチー(IPN)のひとつであり,末梢神経の異常に起因して主に運動神経および感覚神経が障害される疾患である.IPNは,CMT以外に遺伝性運動性ニューロパチー(HMN),遺伝性感覚性ニューロパチー(HSN),遺伝性圧脆弱性ニューロパチーなどが含まれ,現在までにCMT/IPNの原因遺伝子は140以上同定されており,遺伝的にも臨床的にも多様な疾患である.IPNの診断は次世代シークエンサー(NGS)が開発されて以降,研究室レベルでは網羅的遺伝子解析が可能となっている.本稿では,筆者らの研究室で実施しているCMT/IPN2,695例およびHSN79例の包括的遺伝子解析,およびその結果について概説する.ターゲットパネル解析やエクソーム解析に加え,近年注目されているRFC1リピート伸張異常によるIPNについても紹介する.(著者抄録)

Language：Japanese   Publisher：日本神経感染症学会  

Language：Japanese   Publisher：日本神経眼科学会  

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

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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PubMed

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(株)中外医学社  

Language：Japanese   Publisher：(一社)日本神経治療学会  

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

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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PubMed

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

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

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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Language：English   Publisher：Nature Publishing Group  

複数の日本人家系から、NEFH遺伝子に関連した臨床/遺伝学的スペクトラムが認められたため報告した。Charcot-Marie-Tooth(CMT)病および脊髄性筋萎縮症(SMA)を含む、日本全国の神経筋疾患患者から得た全エクソームシークエンシングデータを用いて、NEFH遺伝子の全てのバリアントを解析した。その結果、臨床的にCMTと診断された3家系(男性6例、女性1例、検査時年齢55歳～81歳)と、SMAと診断された1家系(男性1例、検査時年齢38歳)から、NEFH遺伝子にバリアントc.3017dup (p.Pro1007Alafs*56)が同定された。また、典型的な末梢神経障害を呈した患者に加え、CMT患者1例には錐体路兆候が、SMA患者には上腕三頭筋と大腿四頭筋に特徴的な、重度の筋力低下も認められた。さらに、これら4家系が全て鹿児島県在住の家系で、その後のハプロタイプ解析では、創始者効果が強く示唆された。本報はNEFH遺伝子の創始者変異に関する初報告例となり、得られた知見により、NEFH遺伝子関連疾患の表現型スペクトラムが拡大された。

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

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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Language：English   Publisher：Nature Publishing Group  

遺伝性トランスサイレチン(ATTRv)アミロイドーシス患者では、発症時にCharcot-Marie-Tooth病(CMT)と誤診される症例が一定数存在することから、CMT疑い患者に対し効率的な治療を行うには、トランスサイレチン(TTR)遺伝子検査が不可欠か検討した。2007年4月～2019年6月までの期間内に、CMT疑診例2133例を対象とした横断研究を行い、遺伝子検査でATTRvアミロイドーシスが確認された患者10例と、CMT患者489例の臨床所見、髄液所見ならびに電気生理学所見を比較した。その結果、神経症状の発症年齢中央値はATTRvアミロイドーシ患者が69歳、CMT患者が12歳で、初期症状として感覚障害を呈した患者の割合は、ATTRvアミロイドーシス患者では70%、CMT患者では7.1%であった。また、慢性炎症性脱髄性多発根神経炎(CIDP)疑いの既往歴を有する患者の割合はATTRvアミロイドーシス患者では50%、CMT患者では8.7%で、遺伝子検査後に進行が認められたATTRvアミロイドーシス患者6例のうち、薬物治療や遺伝子治療を受けた5例は、いずれも生存例であることも確認された。以上より、発症時の神経症状や初期の感覚障害、CIDP疑い既往歴を有するCMT疑診例の高齢患者に効果的な治療を行うには、TTR遺伝子検査が不可欠と結論付けられた。

Language：Japanese   Publisher：(有)科学評論社  

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

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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Language：English  

DOI： 10.1007/s10072-021-05817-8

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PubMed

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

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

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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Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<p>We would like to review the recent therapeutic advances of spinocerebellar degeneration (SCD) that were published in 2021. Currently, SCD treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression. Various pre–clinical and clinical trials were carried out in 2021. Some interesting trials have been reported, and further developments are expected. This article introduces the outline of therapies with rovatirelin, riluzole/troriluzole, leriglitazone, sodium valproate, CRISPR/Cas9 gene editing, antisense oligonucleotides (ASOs), mesenchymal stem cells (MSCs), and cerebello–spinal transcranial direct current stimulation (tDCS). We expect that these treatments will benefit the patients with SCD.</p>

DOI： 10.15082/jsnt.39.5_773

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CiNii Research

Language：Japanese   Publisher：日本末梢神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

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

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

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

DOI： 10.1016/j.neurobiolaging.2020.07.004

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DOI： 10.1111/jns.12369

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DOI： 10.1016/j.nmd.2019.03.010

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DOI： 10.1136/jnnp-2018-318839

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DOI： 10.1016/j.braindev.2018.08.006

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DOI： 10.1111/ene.13750

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DOI： 10.1038/s41598-018-27860-w

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DOI： 10.1093/brain/awy104

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DOI： 10.1111/jns.12252

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DOI： 10.1111/ene.13360

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DOI： 10.1111/jns.12228

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DOI： 10.1111/cge.13002

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DOI： 10.1212/NXG.0000000000000171

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DOI： 10.1111/gtc.12500

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DOI： 10.1038/jhg.2017.15

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DOI： 10.1111/jns.12193

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DOI： 10.1136/jnnp-2015-312646

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DOI： 10.1002/ana.24742

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DOI： 10.1002/mus.25067

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DOI： 10.1002/ana.24612

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DOI： 10.1016/j.braindev.2015.09.001

PubMed

Language：Japanese  

DOI： 10.11477/mf.1416200341

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DOI： 10.1212/NXI.0000000000000143

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DOI： 10.1136/jnnp-2014-308211

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DOI： 10.1136/jclinpath-2012-201431

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PubMed

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：東京 : 医歯薬出版  

Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032523996

Language：Japanese   Publisher：東京 : 科学評論社  

Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032220885

J-GLOBAL

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Language：English   Publisher：(公社)日本農芸化学会  

Language：Japanese   Publisher：東京 : 日本プランニングセンター  

CiNii Research

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