記述言語：日本語   出版者・発行元：日本神経学会  

<p>左眼瞼下垂と複視の既往がある45歳，男性．両下肢先からしびれが上行した．T8以下の感覚低下，残尿感，便秘を生じlongitudinally extensive spinal cord lesionを示す脊髄炎を認めた．右眼の求心性視野狭窄，MRIで両視神経鞘が高信号を呈し，視神経周囲炎（optic perineuritis，以下OPNと略記）を考慮した．抗myelin oligodendrocyte glycoprotein（MOG）抗体は陽性で，脊髄炎にOPNを合併した抗MOG抗体関連疾患と診断した．脊髄炎発症例では視神経炎のほかOPNの合併も考慮し，視力や眼底検査とともに視野検査を行う必要がある．</p>

DOI： 10.5692/clinicalneurol.cn-001705

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記述言語：日本語   出版者・発行元：Journal of Human Genetics  

DOI： 10.1038/s10038-022-01031-2

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担当区分：最終著者   記述言語：英語   出版者・発行元：AIDS Research and Human Retroviruses  

Japan is one of the world's highly endemic areas for human T cell leukemia virus type 1 (HTLV-1), and it is known that the infection rate of HTLV-1 increases with age. The infection rate among the elderly has been estimated based on data from blood donors under the age of 65, and the actual number and rate of infection among the elderly are unknown. Data of 26,090 preoperative HTLV-1 screening tests conducted at Kagoshima University Hospital from 2001 to 2020, including 2726 HTLV-1-positive patients, were used for calculating the decadal infection rates for the year of birth. Estimated infection rates by birth year and demographic tables were used to estimate the current number of infected people in Kagoshima. The estimated total numbers of people infected with HTLV-1 in Kagoshima prefecture were 139,436 in 2005 and 80,975 in 2019. The infection rate increased with age for both men and women, reaching 17.3% for women born before the 1920s. Next, we tried to clarify whether the increase in infection rates with age was due to post-school age infections. The age of birth with the greatest increase in infection rate after 10 years was women born in the 1970s, and the increase in infection rate was only 0.98%, which is not a statistically significant increase. The number of infected people in Kagoshima was >80,000 in 2019. No data were available in this study to point to the involvement of horizontal transmission after school age in the high infection rate among the elderly. The high infection rate among the elderly is thought to have been high even when they were infants.

DOI： 10.1089/AID.2021.0164

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

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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記述言語：英語   出版者・発行元：American Journal of Ophthalmology Case Reports  

Purpose: Wolfram syndrome is a rare genetic disorder characterized by juvenile onset of diabetes mellitus with bilateral optic atrophy. We report a case of adult onset Wolfram syndrome with diabetes mellitus at age 22 and optic atrophy after age 40. The WFS1 gene sequence was analyzed in the patient and her father. Observations: A 46-year-old woman presented with bilateral vision loss. She had developed diabetes mellitus at age 22 and underwent bilateral cataract surgery at age 37. Visual acuity was 20/50 in the right eye and 20/200 in the left eye. The pupillary light reflex was sluggish in both eyes. Fundus examination showed bilateral optic atrophy, but there was no diabetic retinopathy. Cecocentral scotoma of both eyes was observed in Goldmann perimetry. There were no intracranial lesions on magnetic resonance imaging. Audiometry demonstrated high-frequency sensorineural hearing loss. Sequence analysis of the WFS1 gene revealed compound heterozygous mutation: c.908T>C p.L303P and c.1232_1233del, p.S411Cfs*131 in the patient and heterozygous mutation c. 908 T>C, p. L303P in her father. Conclusions and importance: The patient was diagnosed with adult-onset Wolfram syndrome with compound heterozygous mutations of the WFS1 alleles. Wolfram syndrome must be ruled out even in adult-onset diabetic patients with optic atrophy.

DOI： 10.1016/j.ajoc.2022.101315

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Human Genetics  

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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記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は67歳男性．緩徐進行性の四肢筋力低下を認め，神経伝導検査で軸索性の運動神経障害，針筋電図で複数の四肢筋で神経原性変化を示した．筋萎縮性側索硬化症（amyotrophic lateral sclerosis，以下ALSと略記）の診断基準であるAwaji基準のProbable ALSに該当したが，呼吸筋麻痺・球麻痺は認めず，遺伝子解析でALS4の原因遺伝子である<i>SETX</i>に過去に報告のないバリアントを認めた．家系調査が実施できず確定診断には至らなかったが，同部位は哺乳類で高度に保存され，<i>in silico</i>の解析でsenataxin機能障害が推定されることから，病原性バリアントである可能性が示唆された．</p>

DOI： 10.5692/clinicalneurol.cn-001675

PubMed

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

<p>The PRPS1 gene encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). The phenotypes associated with <i>PRPS1</i> mutations include DFN2 (mild PRS-1 deficiency), CMTX5 (moderate PRS-1 deficiency), Arts syndrome (severe PRS-1 deficiency), and PRS-1 superactivity1. X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is a very rare hereditary neuropathy characterized by deafness, optic atrophy, and polyneuropathy. We herein report a Japanese patient with CMTX5 who had a novel hemizygous mutation c.82 G>C in <i>PRPS1</i>. Despite showing a typical clinical picture, the decrease in enzyme activity measured in the patient's erythrocytes was milder than in previously reported cases. </p>

DOI： 10.2169/internalmedicine.8029-21

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記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

<p>Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in <i>mitofusin 2</i> (<i>MFN2</i>) are the most frequent cause of its axonal type, CMT type 2A, with diverse phenotypes. We herein report a Japanese patient with a novel heterozygous <i>MFN2</i> pathogenic variant (c.740 G>C, p.R247P) and severe CMT phenotypes, including progressive muscle weakness, optic atrophy, urinary inconsistency, and restrictive pulmonary dysfunction with eventration of the diaphragm that developed over her 60-year disease course. Our case expands the clinico-genetic features of<i> MFN2</i>-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients. </p>

DOI： 10.2169/internalmedicine.6487-20

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記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例1は62歳女性で、51歳時に神経障害が疑われ、紹介受診していた。本再受診時には瞳孔の著明な縮瞳を認め、両眼の瞳孔光反射が認められなかった。四肢の遠位筋優位の筋力低下と萎縮を認め、足関節の背屈が重度に障害されて鶏歩をきたしていた。遠位下肢の感覚鈍麻、痛覚鈍麻、振動覚低下を認め、バビンスキー反射のない全身性反射消失が判明した。腰椎MRIでは、著明な馬尾肥厚が明らかとなった。遺伝子検査では、シャルコー・マリー・トゥース病4H型の原因遺伝子であるFGD4遺伝子にホモ接合ミスセンス変異(c.1730G>A[p.Arg577Gln])が認められた。症例2は68歳男性(症例1の兄)で、症例1と同様の症状を認め、腰椎MRIで馬尾肥厚が示された。FGD4遺伝子の解析では、症例1と同一のホモ接合ミスセンス変異が認められた。

担当区分：最終著者   記述言語：英語   出版者・発行元：BMC Neurology  

Background: Granulomatous amoebic encephalitis (GAE) is an infrequent and fatal infectious disease worldwide. Antemortem diagnosis in this condition is very difficult because clinical manifestations and neuroimaging are nonspecific. Case presentation: A 60-year-old Japanese woman was admitted with a chief complaint of left homonymous hemianopsia. Brain-MRI showed extensive necrotizing lesions enhanced by gadolinium, in the right frontal lobe, right occipital lobe, and left parietal lobe. Epithelioid granulomas of unknown etiology were found in the biopsied brain specimens. Shotgun metagenomic sequencing using a next-generation sequencer detected DNA fragments of Balamuthia mandrillaris in the tissue specimens. The diagnosis of granulomatous amoebic encephalitis was confirmed using an amoeba-specific polymerase chain reaction and immunostaining on the biopsied tissues. Conclusions: Shotgun metagenomics is useful for the diagnosis of central nervous system infections such as GAE wherein the pathogens are difficult to identify.

DOI： 10.1186/s12883-021-02418-y

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記述言語：英語   出版者・発行元：Cerebellum  

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

DOI： 10.1007/s12311-021-01323-x

DOI： 10.1007/s12311-021-01323-x

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記述言語：英語  

DOI： 10.1007/s00415-021-10467-z.

DOI： 10.1016/j.ensci.2021.100358

DOI： 10.2169/internalmedicine.7247-21.

担当区分：最終著者   記述言語：日本語   出版者・発行元：Clinical Neurology and Neurosurgery  

EEG findings in advanced Gerstmann-Sträussler-Scheinker syndrome (GSS) are shown. A 56-year-old woman developed GSS symptoms and was diagnosed as having GSS with the P102L mutation at age 58. During the early stage, there were no significant EEG findings. Her clinical condition worsened and she developed akinetic mutism at age 62. The patient died of pneumonia at age 65. EEGs were recorded annually from age 61 to 65. Bilateral independent periodic discharges (BIPDs) in both temporal areas appeared at age 64. No clinical seizures were noticed. MEG showed the sharp waves of BIPDs originated independently in each temporal lobe. Other causes of BIPDs were absent.

DOI： 10.1016/j.clineuro.2021.106602

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担当区分：最終著者,　責任著者  

DOI： 10.5692/clinicalneurol.cn-001558

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America  

HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genomewide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10-9) and class II (P = 1.21 × 10-8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLAC∗ 07:02 (P = 2.61 × 10-5), HLA-B∗07:02 (P = 4.97 × 10-10), HLADRB1∗ 01:01 (P = 1.15 × 10-9) and HLA-DQB1∗05:01 (P = 2.30 × 10-9) were associated with disease risk, while HLA-B∗40:06 (P = 3.03 × 10-5), HLA-DRB1∗15:01 (P = 1.06 × 10-5) and HLA-DQB1∗06:02 (P = 1.78 × 10-6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10-10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/ TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

DOI： 10.1073/pnas.2004199118

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Clinical Genetics  

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

DOI： 10.1111/cge.13881

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

Background: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. Methods: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. Results: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. Conclusions: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

DOI： 10.1007/s00415-021-10467-z

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記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は男性，60歳から物忘れ，歩行障害，動作緩慢が出現，パーキンソン病や多系統萎縮症として近医加療受けていたが，軽度の意識障害も加わり入院となった．意識障害が1年の経過で悪化し無動無反応となった．臨床症状ではミオクローヌスはみられず，四肢の粗大な振戦の不随意運動があり，脳波で周期性同期性放電（periodic synchronous discharge）及び頭部MRI拡散強調画像で大脳皮質の高信号所見を認めなかった．プリオン蛋白遺伝子検査でオクタペプチドリピート（octapeptide repeat，以下OPRと略記）領域に4回の繰り返し挿入変異が確認され遺伝性クロイツフェルト・ヤコブ病と診断された．OPR挿入変異例は報告が少なく，その臨床症状，検査所見に多様性があり，診断には遺伝子検査が重要である．</p>

DOI： 10.5692/clinicalneurol.cn-001558

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出版者・発行元：Entomological Science  

DOI： 10.1111/ens.12469

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記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.38.6_S178

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本内科学会  

<p>Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive inherited demyelinating neuropathy caused by an FYVE, RhoGEF, and a PH domain-containing protein 4 (<i>FGD4</i>) gene mutation. CMT4H is characterized by an early onset, slow progression, scoliosis, distal muscle atrophy, and foot deformities. We herein present sibling cases of CMT4H with a homozygous mutation in the <i>FGD4</i> gene. Both patients exhibited cauda equina thickening on magnetic resonance imaging, which had not been reported among the previous CMT4H cases. This is the first report of CMT4H with a homozygous <i>FGD4</i> c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening. </p>

DOI： 10.2169/internalmedicine.7247-21

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記述言語：英語   出版者・発行元：Journal of Neurology, Neurosurgery and Psychiatry  

DOI： 10.1136/jnnp-2020-323960

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担当区分：責任著者   記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は50歳男性で、他院で代謝性/呼吸性アシドーシスを伴う肝性脳症と診断され、搬送されてきた。ラクツロース、ビタミンB1、重炭酸リンゲル液による治療を行っても意識障害を認め、上肢の振戦も出現した。入院7日目、辺縁系脳炎および感染性髄膜炎と暫定診断し、アシクロビル、メロペネム、デキサメタゾンによる治療を開始した。症状は改善したが、意識障害と頸部硬直が再出現した。入院21日目、脳脊髄液(CSF)検査でクリプトコッカス莢膜多糖体抗原が検出され、治療をアムホテリシンBリポソーム製剤(L-AMB)、5-フルオロシトシンに変更した。同日、急性水頭症が出現し、脳室ドレナージを行った。意識状態が徐々に回復したが、28日目に運動性失語症と右半麻痺が出現した。脳MRIと磁気共鳴血管造影では、多発性脳梗塞、髄膜炎、水頭症が認められた。入院39日目、L-AMBによる血小板減少症が観察され、ボリコナゾールに変更した。入院76日目、リハビリテーション施設に移送した。初回のCSF標本では、抗N-メチル-D-アスパラギン酸受容体抗体と抗グルタミン酸受容体抗体が陽性であった。

DOI： 10.2169/internalmedicine.4629-20.

記述言語：英語   出版者・発行元：PLoS Neglected Tropical Diseases  

DOI： 10.1371/journal.pntd.0008361

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the Peripheral Nervous System  

DOI： 10.1111/jns.12369

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi.org/10.1016/j.jns.2019.116623

DOI： 10.1136/jnnp-2019-32

担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本内科学会  

<p>Spinocerebellar ataxia type 8 (SCA8) is a rare hereditary cerebellar ataxia showing mainly pure cerebellar ataxia. We herein report cases of SCA8 in Japanese monozygotic twins that presented with nystagmus, dysarthria, and limb and truncal ataxia. Their <i>ATXN8OS</i> CTA/CTG repeats were 25/97. They showed similar manifestations, clinical courses, and cerebellar atrophy on magnetic resonance imaging. Some of their pedigrees had nystagmus but not ataxia. These are the first monozygotic twins with SCA8 to be reported anywhere in the world. Although not all subjects with the <i>ATXN8OS</i> CTG expansion develop cerebellar ataxia, these cases suggest the pathogenesis of <i>ATXN8OS</i> repeat expansions in hereditary cerebellar ataxia. </p>

DOI： 10.2169/internalmedicine.2905-19

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PubMed

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   出版者・発行元：日本神経治療学会  

<p>Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. In clinical situations, we often recognize that patients with autoimmune encephalopathy are misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. Most patients with autoimmune encephalopathy showed motor disturbance mostly with unsustained and/or give–way weakness. About 70% of patients showed sensory abnormalities that was not explainable anatomically. One–fourth of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.</p>

DOI： 10.15082/jsnt.37.4_636

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Neurology, Neurosurgery and Psychiatry  

DOI： 10.1136/jnnp-2018-318839

Scopus

PubMed

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本神経治療学会  

<p>Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. We often recognize that patients with autoimmune encephalopathy are often misdiagnosed as functional psychogenic movement or somatoform disorders. We have reported 63 patients with autoimmune encephalopathy. Two–thirds of patients showed motor disturbance mostly with unsustained or give–way weakness. About 70% of patients showed sensory abnormalities that was not explainable anatomically. 27% of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.</p>

DOI： 10.15082/jsnt.36.4_341

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Neurology  

DOI： 10.1111/ene.13750

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PubMed

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the Neurological Sciences  

DOI： 10.1016/j.jns.2018.05.012

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PubMed

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Brain  

DOI： 10.1093/brain/awy104

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PubMed

担当区分：最終著者,　責任著者   記述言語：英語   出版者・発行元：Journal of Human Genetics  

DOI： 10.1038/s10038-017-0388-5

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PubMed

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the Peripheral Nervous System  

DOI： 10.1111/jns.12252

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PubMed

担当区分：最終著者,　責任著者   記述言語：英語   出版者・発行元：Nature Publishing Group  

2007年〜2016年9月に当院に来院したシャルコー・マリー・トゥース病(CMT)の日本人患者1483例のうち、劣性SH3TC2多様体を有する患者を後ろ向きに調査して、SH3TC2の臨床および電気生理学的特徴と変異スペクトルを評価した。その結果、9例(男性1例、女性8例、年齢11〜85歳)で10の劣性SH3TC2多様体を同定した。9例中7例は脱髄性CMTで、SH3TC2遺伝子で八つ劣性多様体を同定し、そのうち五つは新規多様体であった。2例は軸索CMTで、既報告の劣性多様体p.Arg77Trpが検出された。脱髄性CMT患者では3例が10〜20歳、4例は成人になってから発症した。脱髄性CMT患者の1.76%でSH3TC2に劣性多様体が同定された。

担当区分：最終著者   記述言語：英語   出版者・発行元：特定非営利活動法人 バイオ＆ソーシャル・サイエンス推進国際研究交流会  

<p>Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, slowly progressive course, and is associated with <i>TRK-fused gene</i> (TFG) mutation. At advanced stages, respiratory failure and dysphagia becomes life-threatoning, and patients typically die by their 70s. Although there is currently no evidence for effective treatment, a therapy may be found by elucidation of the function of TFG. Recently its pathomechanism has been proposed to be associated with abnormalities in protein transfer from the endoplasmic reticulum. Such pathomechanisms might involve a similar process in amyotrophic lateral sclerosis; thus, its pathomechanisms and treatment strategy might make it a good model for neurodegenerative disorders. It is of great value to clarify the natural history of HMSN-P, in oder to judge the treatment effect. By evaluating 97 patients (79 out of 97 were examined and all confirmed with p.Pro 285 Leu mutation) in this study, it was confirmed that this disease follows a uniform course in the earlier stages, and there are individual differences in the onset between 20 and 30 years. Such uniformity might be due to the proposed single gene abnormality. At advanced stages, there are larger individual differences in the progression, but the reasons for these are unknown. Longer survival might be achieved with a better care for respiratory failure and dysphagia if such cares were undertaken at appropriate times.</p>

DOI： 10.5582/irdr.2017.01084

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PubMed

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本神経治療学会  

<p>Many patients present with extremely serious problems such as headache, photophobia, acoustic hyperresponsiveness, severe pain, menstrual disorders, various sleep disorders, and POTS after human papillomavirus vaccination (HPV vaccine). In addition, patients exhibit various neurological symptoms such as movement disorders, walking disturbance, involuntary movement, abnormal sensation, memory disturbance, and so on. However, these symptoms are variable and have been considered to be symptoms of hysteria (somatoform disorder, somatic symptoms). Immunosuppressive treatments were not administered because many cases were considered to be of neurological origin. In such cases, the disease condition is objectively evaluated to diagnose and treat patients with neurological symptoms. In conclusion, the wide–ranging symptoms of the central nervous system include those caused by disseminated autoimmune encephalitis and also symptoms of the peripheral small fibers. Thus, according to the obtained findings, the neurological symptoms caused by HPV vaccination are related to immunological diseases, and not psychogenic diseases. In addition, the cause of misdiagnosis has also been described.</p>

DOI： 10.15082/jsnt.35.4_536

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Clinical Genetics  

DOI： 10.1111/cge.13037

Scopus

担当区分：最終著者,　責任著者   記述言語：日本語   出版者・発行元：Brain and Nerve  

Scopus

記述言語：英語  

DOI： 10.1093/jnen/nlx068

PubMed

担当区分：最終著者,　責任著者  

DOI： 10.11477/mf.1416200881

PubMed

担当区分：最終著者,　責任著者   記述言語：日本語   出版者・発行元：Brain and Nerve  

Scopus

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Neurology  

DOI： 10.1111/ene.13360

Web of Science

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PubMed

出版者・発行元：Neuromuscular Disorders  

DOI： 10.1016/j.nmd.2017.07.011

Web of Science

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PubMed

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1016/j.jns.2017.08.2017

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1016/j.jns.2017.08.2017

担当区分：最終著者,　責任著者   出版者・発行元：Journal of the Peripheral Nervous System  

DOI： 10.1111/jns.12228

Web of Science

Scopus

PubMed

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Clinical Genetics  

DOI： 10.1111/cge.13002

Web of Science

Scopus

PubMed

担当区分：最終著者,　責任著者   記述言語：英語   出版者・発行元：Journal of Human Genetics  

DOI： 10.1038/jhg.2017.15

Web of Science

Scopus

PubMed

担当区分：最終著者,　責任著者   記述言語：英語   出版者・発行元：Nature Publishing Group  

2014年6月〜2015年12月に、臨床症状と電気生理学的検査でCharcot-Marie-Tooth病(CMT)やその他の遺伝性末梢ニューロパシー(IPS)と疑われた408例を対象に、次世代配列分析システムにて変異スクリーニングを行った。72種の原因遺伝子または疑いのある遺伝子が検出された。4名の患者で免疫グロブリンヘリカーゼμ結合性蛋白質2(IGHMBP2)の新規ホモ接合性または複合ヘテロ接合性変異が見つかった。3名は幼児発症性軸索型優性感覚運動性多発性神経障害であった。他の1名は呼吸窮迫を伴う脊髄性筋萎縮症1型(SMARD1)と診断した。低出生時体重、弱い泣き声、自発運動低下と出生4ヵ月後には呼吸窮迫を起こした。日本におけるCMT2S型の報告を調べたところ、劣性IGHMBP2変異は軸索型CMTの約1.6%にすぎなかった。臨床症状が多様であり、遺伝的因子の同定が必須であると考えられた。

出版者・発行元：Neuroradiology Journal  

DOI： 10.1177/1971400916687585

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PubMed

記述言語：英語   出版者・発行元：Neurology: Genetics  

DOI： 10.1212/NXG.0000000000000171

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PubMed

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

DOI： 10.2169/naika.106.1598

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本神経治療学会  

<p>Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. In clinical situations, we often recognize that patients with autoimmune encephalopathy are often misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. We clinically analyzed 63 patients with autoimmune encephalopathy. Two–thirds of patients showed motor disturbance mostly with give–way weakness. About 70% of patients showed sensory abnormalities such as strong pain, deep muscle pain, dysesthesia, paresthesia, or fast neurologic pain. Most pain was distributed in manner that was not explainable anatomically. 27% of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. We observed memory loss, PNES (psychogenic non–epileptic seizure), dissociative amnesia, hyperventilation, opsoclonus, epilepsy, or autonomic symptoms amongst our patients. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.</p>

DOI： 10.15082/jsnt.34.3_160

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.34.6_S136

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

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

DOI： 10.1186/s40478-024-01847-3

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PubMed

記述言語：日本語   出版者・発行元：Neurology and Clinical Neuroscience  

Background: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and various motor symptoms. While MSA-C (cerebellar type) predominates in East Asia, MSA-P (parkinsonian type) predominates in Europe and North America. This nationwide patient registry aimed to (1) conduct a prospective natural history study of MSA in Japan, (2) facilitate patient recruitment for clinical trials, and (3) deposit bioresources and clinical information in a biobank. Methods: Thirteen institutions participated in this study. Clinical information was obtained by neurologists from the patients visiting the hospital every 12 months to assess the UMSARS Part 2 scores and by telephone interviews by nurses every 6 months to assess UMSARS Part 1 scores and to determine whether clinical events had occurred. Results: Demographic data from 329 MSA patients (216 MSA-C and 113 MSA-P) were analyzed. The mean age at symptom onset was 58.2 years (standard deviation, 8.9); the mean duration of symptoms at enrollment was 3.5 years (standard deviation, 2.2). The mean 12-month changes in the UMSARS Part 1 and Part 2 scores were 7.9 (standard deviation, 5.6) and 6.4 (standard deviation, 5.9), respectively. The patient registry proved useful in recruiting participants for clinical trials, including those with gene variants. Clinical information and biospecimens were deposited in a biobank. Discussion: The study highlighted the importance of telephone interviews in minimizing drop-out rates in natural history studies and demonstrated similar MSA progression rates across populations. The deposited bioresources are available to researchers upon request, aiming to contribute to future MSA researches.

DOI： 10.1111/ncn3.12809

Scopus

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

Spinocerebellar ataxia type 14 (SCA14) is a rare form of autosomal dominant cerebellar ataxia caused by mutations in PRKCG. 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 PRKCG (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.

DOI： 10.2169/internalmedicine.2943-23

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PubMed

記述言語：英語   出版者・発行元：(一社)日本内科学会  

記述言語：日本語   出版者・発行元：International Journal of Molecular Sciences  

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301–309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301–309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11–19 or Tax 301–309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1β or in the expression of CD107a—a marker for the degranulation of cytotoxic molecules. However, Tax 301–309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11–19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

DOI： 10.3390/ijms25136858

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PubMed

記述言語：日本語   出版者・発行元：Neurogenetics  

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

DOI： 10.1007/s10048-024-00746-y

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PubMed

記述言語：英語   出版者・発行元：(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。

記述言語：日本語   出版者・発行元：PLoS Neglected Tropical Diseases  

Background Although Japan is a major endemic area for human T-lymphotropic virus type 1 (HTLV-1) and the virus has been well-studied in this region, there is limited research on HTLV-1 in sur-rounding regions. In this study, we determined the complete genome sequences of HTLV-1 strains isolated from Taiwan and Japan and investigated the geographic characteristics of molecular subgroups and substitution mutations to understand the spread of HTLV-1 and its correlation with human migration. Methodology/Principal findings The complete genome sequences of 26 HTLV-1 isolates from Taiwan were determined using next-generation sequencing and were compared with those of 211 isolates from Japan in terms of subgroup and genetic mutations. In total, 15/26 (58%) isolates from Taiwan belonged to the transcontinental subgroup and 11/26 (42%) isolates belonged to the Japanese subgroup. The transcontinental subgroup was significantly more prevalent among Taiwanese isolates than Japanese isolates (58% vs 18%, P < 0.0001). The mutation rate for the complete HTLV-1 sequence was as low as 0.2%. On examining individual base substitutions, the G-to-A mutation was predominant. Bayesian phylogenetic tree analysis estimated the time to the most recent common ancestor for the transcontinental and Japanese subgroups to be 28447 years. The transcontinental subgroups from Taiwan and Japan appeared to form clusters according to their respective regions.Conclusions/Significance The transcontinental subgroup of HTLV-1 is predominant in Taiwan, while the Japanese subgroup is common in Japan. The difference in subgroup distribution may be attributed to the initial spread of the transcontinental subgroup in East Asia, followed by the influx of the Japanese subgroup.

DOI： 10.1371/journal.pntd.0011928

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PubMed

記述言語：日本語   出版者・発行元：Journal of Neurology, Neurosurgery and Psychiatry  

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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PubMed

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

Background: Endovascular therapy (EVT) for distal medium vessel occlusions requires prioritizing effectiveness and safety. We developed a technique combining the deployment of only the distal basket segment of the EMBOTRAP III and an aspiration catheter (AC) for M2 occlusions, called the “ONE-SEG technique,” and evaluated its clinical and technical impacts. Methods: This was a retrospective review of 30 consecutive patients with M2 segment middle cerebral artery occlusion treated using the ONE-SEG technique. This method involves deploying the EMBOTRAP III through a microcatheter in only one segment and guiding the AC to the M2 origin or distal M1. The rates of final-pass expanded thrombolysis in cerebral infarction (eTICI) scores of 2c/3 or 2b/2c/3, safety (symptomatic intracranial hemorrhage [sICH]), and clinical outcomes (modified Rankin Scale [mRS] score 0–2, 0–3 at 90 days, and mortality at 90 days) were evaluated. Results: Of the 30 cases, 36.7% were female, and the mean age was 75.6 ± 11.0 years. The ONE-SEG technique was used for 17 cases (56.7%, median NIHSS 10 [5–15.5]) with primary M2 occlusion and 13 cases (43.3%, median NIHSS 20 [14–22.5]) with secondary M2 occlusion after proximal thrombus removal. The successful final reperfusion rate (eTICI 2b/2c/3) was 90% overall (27/30 cases). One case (3.3%) developed sICH with secondary M2 occlusion. At 3 months, mRS scores 0–2 were seen in 64.7% of patients with primary M2 occlusion (11/17 cases) and in 23.1% (3/13 cases) with secondary M2 occlusion. Conclusion: EVT using the ONE-SEG technique appears to be safe and effective for M2 occlusion.

DOI： 10.3389/fneur.2024.1424030

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PubMed

記述言語：英語   出版者・発行元：一般社団法人 日本脳神経外科学会  

DOI： 10.2176/jns-nmc.2023-0071

PubMed

記述言語：日本語   出版者・発行元：BMC Musculoskeletal Disorders  

Background: Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date. Case presentation: A 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment. Conclusion: This is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.

DOI： 10.1186/s12891-023-06461-3

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PubMed

記述言語：英語   出版者・発行元：(一社)日本脳神経外科学会  

症例は67歳男性。頸動脈超音波検査で左内頸動脈の高度狭窄が偶然発見され、当院を受診した。高血圧、脂質異常症、腹部大動脈、慢性閉塞性肺疾患の既往があった。経上腕動脈および経橈骨動脈アプローチを用いて、左内頸動脈の高度狭窄に対する近位フローを伴う頸動脈ステント留置術を施行した。術後合併症は認められず、超音波検査でもプラークの突出はみられなかった。頸動脈ステント留置術施行5日後のCT血管造影で、上腕動脈および橈骨動脈に異常はみられなかった。最終的にmodified Rankin scale(mRS)スコア0点で退院した。退院後3ヵ月もmRSは依然として0のままであった。

記述言語：英語   出版者・発行元：Oxford University Press  

顕微鏡的多発血管炎に伴うグルココルチコイド抵抗性神経障害を有する患者に対する免疫グロブリン静注療法(IVIg)の有効性と安全性を評価する目的で、第III相多施設無作為化二重盲検プラセボ対照並行群間比較試験を実施した。37例をIVIg群(19例)またはプラセボ群(18例)に割り付け、第1週および第5週にIVIgまたはプラセボ投与を5日間行い、第9週はIVIg群にプラセボ投与、プラセボ群にIVIgを行った。有効性解析対象は36例(それぞれ19例、17例)であった。8週後(第9週の治療開始前)における徒手筋力テストの合計スコア変化量(最小二乗平均値)は、IVIg群で9.02、プラセボ群で6.71(群間差2.32、95%CI -2.60～7.23、p=0.345)、4週後(第5週の治療開始前)ではそれぞれ6.81、2.83(同3.99、-1.22～9.19、p=0.129)であり、IVIgにより合計スコアは改善したものの両群間に有意差は認めなかった。IVIg群において安全性に関する新たな懸念は認めなかった。

記述言語：英語   出版者・発行元：(一社)日本神経免疫学会  

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

記述言語：英語   出版者・発行元：Scientific Reports  

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

DOI： 10.1038/s41598-023-45011-8

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PubMed

記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は45歳男性。12歳時に両側下肢遠位筋の筋力低下を認め、18歳時に握力低下を自覚した。症例の母親も手に軽度の筋力低下と萎縮を有していたことから、臨床所見と電気生理学的検査の所見をあわせ、遺伝性運動感覚多発神経障害と診断された。その後、症状が緩徐に悪化し、38歳時に健康診断で視神経乳頭陥凹の両側対称性縦拡大および網膜神経線維束欠損と診断された。両眼の視力は正常であったが、視野検査で視神経乳頭異常に一致する部分的視野欠損が明らかとなった。43歳時、両足関節不安定のために支えなしでの立位維持が困難となった。45歳時、神経学的検査で四肢の遠位筋萎縮、腱反射消失、振動覚低下が判明した。18歳時にCharcot-Marie-Tooth(CMT)病1型と診断されていたが、原因遺伝子が特定されていなかった。45歳時、64のCMT関連原因遺伝子における病的バリアントのスクリーニングを行い、ギャップジャンクションタンパクβ1に新規バリアント(c.173C>A[p.P58H])が判明した。

記述言語：英語   出版者・発行元：獨協医学会  

症例は16歳女児。特発性側彎症であり、当院整形外科で前方腰椎固定術が施行された。経頭蓋電気刺激運動誘発電位と体性感覚誘発電位を用いて術中神経生理モニタリング(IONM)が行われたが、異常所見が認められた。また、術後神経伝導検査でも異常所見がみられ、当科紹介となった。両側上下肢で腱反射が消失していた。ビタミンB1値が低く(17ng/mL)、右正中神経の運動および感覚神経伝導速度が顕著に減少しており、遠位潜時の延長と振幅の減少を伴っていた。Charcot-Marie-Tooth病(CMT)疑いのための遺伝子検査を行ったところ、ミエリンタンパク質ゼロ(MPZ)変異が同定され、CMT 1B型と診断した。患者の両親にはMPZ遺伝子に変異がみられなかったため、de novo変異と考えられた。

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

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

DOI： 10.2169/internalmedicine.0061-22

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PubMed

記述言語：英語   出版者・発行元：(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。

記述言語：日本語   出版者・発行元：Genes  

Charcot–Marie–Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and causes lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, are appraised. Each of these gene therapies has the potential for substantial advancements in future research.

DOI： 10.3390/genes14071391

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PubMed

記述言語：日本語   出版者・発行元：Pathogens  

Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease that arises from HTLV-1 infection. Pathologically, the condition is characterized by diffuse myelitis, which is most evident in the thoracic spinal cord. Clinical manifestations of the infectious disease, HAM/TSP, are empirically known to include weakness of the proximal muscles of the lower extremities and atrophy of the paraspinal muscles, which is characteristic of the distribution of disturbed muscles usually seen in muscular diseases, except that the upper extremities are almost normal. This unique clinical presentation is useful information for physicians and physical therapists involved in diagnosing and rehabilitating patients with HAM/TSP, as well as critical information for understanding the pathogenesis of HAM/TSP. However, the precise pattern of muscle involvement in this condition has yet to be reported. The purpose of this study was to identify the muscles affected by HAM/TSP in order to understand the pathogenesis of HAM/TSP as well as to aid in the diagnosis and rehabilitation of HAM/TSP. A retrospective review of medical records was conducted on 101 consecutively admitted patients with HAM/TSP at Kagoshima University Hospital. Among 101 patients with HAM/TSP, all but three had muscle weakness in the lower extremities. Specifically, the hamstrings and iliopsoas muscle were the most frequently affected in over 90% of the patients. Manual muscle testing (MMT) revealed that the iliopsoas was the weakest of the muscles assessed, a consistent feature from the early to advanced stages of the disease. Our findings demonstrate a unique distribution of muscle weakness in HAM/TSP, with the proximal muscles of the lower extremities, particularly the iliopsoas muscle, being the most frequently and severely affected.

DOI： 10.3390/pathogens12040592

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PubMed

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

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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PubMed

記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は67歳女性。突然に左片麻痺、左同名半盲、左半側空間無視が出現した。頭部MRI検査で右頭頂葉に脳梗塞を認めた。Fluid-attenuated inversion recovery(FLAIR)画像ではクモ膜下腔にivy signを認め、それらは梗塞領域の拡大とともに増加・拡大した。脳血管造影所見からもやもや病と診断し、抗血栓療法は回避して、ドパミン点滴静注による血圧コントロールと濃グリセリン・果糖点滴静注による脳浮腫の拡大予防を継続したところ、神経症状と脳梗塞の進行は抑止され、ivy signも消失した。ivy signは脳梗塞の拡大とともに増強し、虚血の解除とともに消失したことから、血行力学的変化が起こったことが示唆された。

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

DOI： 10.2169/internalmedicine.0969-22

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PubMed

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

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

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

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

DOI： 10.3389/fneur.2023.1137958

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PubMed

記述言語：日本語   出版者・発行元：eClinicalMedicine  

Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (−1.7 [95% CI, −3.2 to −0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. Funding: Japan Agency for Medical Research and Development.

DOI： 10.1016/j.eclinm.2023.101920

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PubMed

記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.40.2_99

記述言語：日本語   出版者・発行元：JCI Insight  

Human T lymphotropic virus type 1-assoicated (HTLV-1-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the persistent proliferation of HTLV-1-infected T cells. Here, we performed a T cell receptor (TCR) repertoire analysis focused on HTLV-1-infected cells to identify and track the infected T cell clones that are preserved in patients with HAM/TSP and migrate to the CNS. TCRβ repertoire analysis revealed higher clonal expansion in HTLV-1-infected cells compared with noninfected cells from patients with HAM/TSP and asymptomatic carriers (ACs). TCR clonality in HTLV-1-infected cells was similar in patients with HAM/TSP and ACs. Longitudinal analysis showed that the TCR repertoire signature in HTLV-1-infected cells remained stable, and highly expanded infected clones were preserved within each patient with HAM/TSP over years. Expanded HTLV-1-infected clones revealed different distributions between cerebrospinal fluid (CSF) and peripheral blood and were enriched in the CSF of patients with HAM/TSP. Cluster analysis showed similarity in TCRβ sequences in HTLV-1-infected cells, suggesting that they proliferate after common antigen stimulation. Our results indicate that exploring TCR repertoires of HTLV-1-infected cells can elucidate individual clonal dynamics and identify potential pathogenic clones expanded in the CNS.

DOI： 10.1172/jci.insight.167422

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PubMed

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

Pathogenic variants in Gap Junction Protein Beta 1 (GJB1) cause X-linked Charcot-Marie-Tooth (CMT) disease type 1 (CMTX1), which is a common hereditary motor and sensory neuropathy. A 45-year-old man presented with progressive muscle weakness, atrophy, sensory disturbance of all limbs from childhood, and visual field defects in both eyes at 40 years old. A segregation analysis revealed a novel variant, c.173C>A (p.P58H), in the GJB1 gene. Patients with variants at codon 58 in GJB1 showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of GJB1 variants.

DOI： 10.2169/internalmedicine.1403-22

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記述言語：日本語   出版者・発行元：日本神経学会  

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

DOI： 10.5692/clinicalneurol.cn-001822

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記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), the most common form of CMTX, is caused by gap-junction beta 1 (GJB1) 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 GJB1 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.

DOI： 10.2169/internalmedicine.1713-23

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PubMed

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

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

記述言語：日本語   出版者・発行元：Journal of the Peripheral Nervous System  

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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PubMed

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

DOI： 10.2169/internalmedicine.2704-23

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PubMed

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

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

DOI： 10.1007/s00415-023-11998-3

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PubMed

記述言語：日本語   出版者・発行元：日本神経感染症学会  

DOI： 10.34397/jsnd.28.1_1

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

Mitochondrial trifunctional protein (MTP) deficiency is an autosomal recessive disorder caused by impaired metabolism of long-chain fatty acids (LCFAs). Childhood and late-onset MTP deficiency is characterized by myopathy/rhabdomyolysis and peripheral neuropathy; however, the features are unclear. A 44-year-old woman was clinically diagnosed with Charcot-Marie-Tooth disease at 3 years of age due to gait disturbance. Her activity and voluntary speech gradually decreased in her 40s. Cognitive function was evaluated and brain imaging tests were performed. The Mini-Mental State Examination and frontal assessment battery scores were 25/30 and 10/18, respectively, suggesting higher brain dysfunction. Peripheral nerve conduction studies revealed axonal impairments. Brain computed tomography showed significant calcification. Magnetic resonance imaging revealed an increased gadolinium contrast-enhanced signal in the white matter, suggesting demyelination of the central nervous system (CNS) due to LCFAs. The diagnosis of MTP deficiency was confirmed through genetic examination. Administration of L-carnitine and a medium-chain fatty triglyceride diet was initiated, and the progression of higher brain dysfunction was retarded within 1 year. This patient's presentation was suggestive of CNS demyelination. The presence of brain calcification, higher brain dysfunction, or gadolinium enhancement in the white matter in patients with peripheral neuropathy may be suggestive of MTP deficiency.

DOI： 10.3389/fneur.2023.1187822

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PubMed

記述言語：日本語   出版者・発行元：Clinical and Experimental Neuroimmunology  

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

DOI： 10.1111/cen3.12764

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記述言語：英語   出版者・発行元：Dokkyo Medical Society  

<p>The current case report describes the clinical and genetic characteristics of a 16-year-old female proband. She did not have any subjective neurological symptoms preoperatively and who was incidentally diagnosed due to abnormal intraoperative neurophysiological monitoring (IONM) using transcranial electrical stimulation motor evoked potentials (TES-MEP) and somatosensory evoked potentials (SEP) for idiopathic scoliosis, leading to the diagnosis of Charcot-Marie-Tooth disease (CMT) 1B. There was no similar disease in her family history. Nerve conduction velocity testing revealed decreased conduction velocity of the median nerve, and genetic testing indicated myelin protein zero (<i>MPZ</i>) mutation (c242A > G), leading to the diagnosis of demyelinating type CMT1B. The parents had no genetic mutation, and this was a case of de novo mutation. CMT1B is an important differential diagnosis because, similar to our case, there may not be any clinical symptoms. The disease was discovered during a careful evaluation of the patient's scoliosis and other complications. TES-MEP was more useful than SEP for IONM of scoliosis with CMT1B.</p>

DOI： 10.51040/dkmj.2023-005

記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は生来健康な44歳男性．両親にいとこ婚あり．42歳頃から両足指の脱力が出現し，同時期から両足部のチアノーゼを自覚．その後，症状進行し44歳時には走れなくなった．両足部に顕著なチアノーゼと下肢遠位筋脱力とアキレス腱反射の消失を認め，神経伝導検査で軸索型多発ニューロパチーを認めた．網羅的遺伝子検査により<i>membrane metalloendopeptidase</i>（<i>MME</i>）遺伝子変異を伴うautosomal-recessive Charcot–Marie–Tooth disease 2Tと診断した．本例の足部チアノーゼは高度であり背景病態に<i>MME</i>遺伝子変異との関連が推測された．</p>

DOI： 10.5692/clinicalneurol.cn-001870

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PubMed

記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.40.6_s199

記述言語：日本語   出版者・発行元：日本神経学会  

<p>末梢神経障害を合併した<i>BAG3</i>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<i>Bcl2-Associated Athanogene 3</i>（<i>BAG3</i>）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．</p>

DOI： 10.5692/clinicalneurol.cn-001915

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PubMed

記述言語：日本語   出版者・発行元：Annals of Clinical and Translational Neurology  

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

記述言語：日本語   出版者・発行元：Annals of Clinical and Translational Neurology  

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

記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.40.5_707

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

Background: Satralizumab, a monoclonal antibody that recognizes interleukin-6 receptors, is known to reduce the relapse rate in neuromyelitis optica spectrum disorder (NMOSD), but its safety during pregnancy has not been established. We present the case of an NMOSD patient who safely completed pregnancy, parturition, and breastfeeding under satralizumab treatment. Importantly, satralizumab transfer to umbilical cord blood, infant serum, or breast milk was not observed. Case presentation: A 37-year-old Japanese female developed anti-aquaporin 4 antibody-positive NMOSD with left optic neuritis. Despite responding to steroid and azathioprine therapy, she experienced moon face and weight gain and desired the prompt reduction of the steroid dosage. She also wanted to conceive a child with a safe and preferably early pregnancy and parturition. Because pregnancy and parturition after the onset of NMOSD elevate the risk of relapse and miscarriage, treatment with satralizumab was initiated with the patient's consent. She experienced normal parturition and continued with satralizumab, steroid, and azathioprine treatments while breastfeeding without experiencing any relapses. Concentrations of satralizumab in the umbilical cord blood, infant serum, and breast milk were below the detection sensitivity. Conclusion: These findings suggest that satralizumab may be safe and effective for the perinatal management of NMOSD, especially when there are concerns about continuing pregnancy and the risk of relapse after parturition.

DOI： 10.3389/fneur.2023.1322412

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本小児神経学会  

<p> 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<i>GNB4</i>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，<i>GNB4</i>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<i>PMP22</i>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<i>GNB4</i>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<i>de novo</i>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．<i>GNB4</i>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．</p>

DOI： 10.11251/ojjscn.55.448

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出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu283101038

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

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

記述言語：英語   出版者・発行元：Modern Rheumatology  

Objectives: We conducted a Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) in patients with glucocorticoid-refractory neuropathy associated with microscopic polyangiitis. Methods: Patients received immunoglobulin or placebo intravenously for 5 consecutive days at baseline and after 4 weeks. The IVIg and placebo groups received IVIg and placebo, respectively, after 8 weeks. The primary and major secondary end-points were the least squares mean of the change in the manual muscle test (MMT) sum score after 8 and 4 weeks, respectively. Results: A total of 37 patients were randomised into two groups (IVIg [19] and placebo [18]). The least squares mean for the change in the MMT sum score was 9.02 for IVIg and 6.71 for placebo (difference 2.32, 95% confidence interval −2.60 to 7.23, p = .345) after 8 weeks and 6.81 and 2.83 (difference 3.99, 95% confidence interval −1.22 to 9.19, p = .129), respectively, after 4 weeks. There were no new safety concerns for IVIg. Conclusions: MMT sum scores improved with IVIg compared with placebo after 8 weeks of dosing and two courses of treatment, but the differences were not statistically significant, and the results showed no clear efficacy of IVIg in this patient population. No new safety concerns were raised.

DOI： 10.1093/mr/roac137

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PubMed

記述言語：日本語   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1416202227

PubMed

記述言語：英語   出版者・発行元：(一社)日本神経学会  

症例は48歳男性で、網膜症を発症し、8年後に運動障害と失語症を発症した。脳MRIにより左頭頂葉に腫瘍様病変が観察され、遺伝子検査の結果、three prime repair exonuclease 1(TREX1)遺伝子にヘテロ接合性バリアントc.703dup(p.V235Gfs*6)が検出された。これらの所見から、脳白質脳症および全身症状を伴った網膜血管症(RVCL-S)と診断され、メチルプレドニゾロンパルス療法と免疫グロブリン静注療法が施行された。治療後には髄液検査結果と臨床症状が改善されたが、3年後に新たな病変が出現し、免疫療法の治療効果が無効で、再発も反復して認められた。また、初回治療から6年間に及ぶ臨床検査と脳MRI検査結果を調べたところ、改善が得られていなかったことが明らかにされた。本例から、RVCL-Sに対する免疫療法の効果は限定的と考えられた。

記述言語：日本語   出版者・発行元：Neurology and Clinical Neuroscience  

We present here the case of a 48-year-old man who first developed retinopathy, and motor deficit and aphasia occurred 8 years later. A tumor-like lesion was seen by brain MRI. He was diagnosed with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) because a three prime repair exonuclease 1 (TREX1) gene abnormality was identified. After intravenous methylprednisolone pulse (IVMP) and intravenous immunoglobulin (IVIg) therapy, cerebrospinal fluid (CSF) test results and clinical manifestations improved. However, a new lesion appeared 3 years later. Immunotherapy became ineffective, and repeated relapses occurred. We evaluated the results of laboratory tests and brain MRI for 6 years after the first treatment. Coagulation tests, including measurements of vWF activity, remained high, so immunotherapy was thought to have a limited effect.

DOI： 10.1111/ncn3.12664

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記述言語：日本語   出版者・発行元：Journal of the American Heart Association  

BACKGROUND: We elucidated the safety of treatment with alteplase at 0.6 mg/kg within 24 hours for patients on direct oral anticoagulants (DOACs) before ischemic stroke onset. METHODS AND RESULTS: Consecutive patients with acute ischemic stroke who underwent intravenous thrombolysis using alteplase at 0.6 mg/kg from 2011 to 2021 were enrolled from our single-center prospective stroke registry. We compared outcomes between patients taking DOACs and those not taking oral anticoagulants within 48 hours of stroke onset. The primary safety outcome was the rate of symptomatic intracranial hemorrhage with a ≥4-point increase on the National Institutes of Health Stroke Scale score from baseline. The efficacy outcome was defined as 3-month modified Rankin Scale score of 0 to 2 after stroke onset. Of 915 patients with acute ischemic stroke who received intravenous thrombolysis (358 women; median age, 76 years; median National Institutes of Health Stroke Scale score, 10), 40 patients took DOACs (6 took dabigatran, 8 took rivaroxaban, 16 took apixaban, and 10 took edoxaban) within 24 hours of onset and 753 patients did not take any oral anticoagulants. The rate of symptomatic intracranial hemorrhage was comparable between patients on DOACs and those not on oral anticoagulants (2.5% versus 2.4%, P=0.95). The rate of favorable outcomes was comparable between the 2 groups (59.4% versus 58.2%, P=0.46), although the admission National Institutes of Health Stroke Scale score was higher in patients on DOACs. No significant differences showed in any intracranial hemorrhage within 36 hours or mortality at 3 months. CONCLUSIONS: Intravenous thrombolysis would be safely performed for patients on DOACs following the recommendations of the Japanese guidelines. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02251665.

DOI： 10.1161/JAHA.122.025809

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PubMed

記述言語：英語   出版者・発行元：(一社)日本神経学会  

重度の網膜色素変性症を呈し、MORC2遺伝子に変異が検出されたCharcot-Marie-Tooth病2Z型(CMT2Z)の日本人症例について報告した。症例は48歳の日本人女性で、小児期から両下肢の筋力低下と歩行障害の進行が認められ、37歳時に歩行困難となった。また、42歳時には夜盲症と難聴を生じ、網膜色素変性症と診断され、視力は次第に低下し、48歳時に右目が失明したため入院となった。各種検査により、軽度の認知障害、感覚神経障害(感覚低下)、脳萎縮と脊髄萎縮が認められ、患者の21歳の長男にも患者同様に、小児期から続く両下肢の筋力低下と歩行障害の進行、感覚低下が認められていた。患者と長男から得たDNAを用いて、全エクソームシーケンシングを行ったところ、双方から、MORC2遺伝子変異c.754C>T(p.R252W)が同定された。これらの変異はSangerシーケンシングにより確認され、本例で得られた知見から、MORC2遺伝子変異が、光受容体の変性と網膜色素変性症の発症に関与していることが示唆された。

記述言語：英語   出版者・発行元：(一社)日本神経学会  

INF2遺伝子にde novo変異をもつ、巣状分節性糸球体硬化症(FSGS)を伴ったCharcot-Marie-Tooth病(CMT)症例を報告した。症例は末期腎不全の35歳男性で、13歳時に歩行障害が認められ、20歳時にCMTと診断された。15歳時にはタンパク尿が出現し、腎生検でFSGSと診断され、28歳時に末期腎不全に対する血液透析が開始された。35歳時に母親をドナーとした生体腎移植とCMTの評価のため、当院に入院し、血清分析を行ったところ、クレアチニン値の上昇が認められた。また、DNA分析の結果からは、INF2遺伝子にヘテロ接合性の点突然変異c.206T>C(p.L69P)が検出され、これらの変異が両親からは未検出であったことから、de novo変異と判断された。母親をドナーとした生体腎移植は治療成功が得られ、術後経過も良好で、血清クレアチニン値も速やかに低下し、ベースラインレベルに維持されたが、CMTの神経学的所見に明らかな改善はみられなかった。本例ではINF2遺伝子変異の同定により、免疫抑制薬を減薬することが可能となり、これらの知見から、遺伝子検査の施行が、腎移植の治療計画の策定に有用であることが示唆された。

記述言語：日本語   出版者・発行元：Neurology and Clinical Neuroscience  

Focal and segmental areas of glomerular sclerosis (FSGS) have various subcategories. Here, we report on a 35-year-old man who suffered from Charcot-Marie-Tooth disease (CMT) with FSGS carrying the INF2 mutation (c.206 T > C, p.L69P). The INF2 mutation might cause abnormal actin filaments of the podocytes and Schwann cells, leading to CMT associated with FSGS. He successfully underwent living donor kidney transplantation from a mother with a normal INF2 gene without any serious adverse events. Following genetic testing, the identification of the INF2 mutation allows a recipient to reduce the use of immunosuppressive drugs. Genetic testing may provide a treatment plan for kidney transplantation.

DOI： 10.1111/ncn3.12651

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記述言語：日本語   出版者・発行元：Neurology and Clinical Neuroscience  

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

DOI： 10.1111/ncn3.12660

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

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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PubMed

記述言語：日本語   出版者・発行元：Annals of Clinical and Translational Neurology  

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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PubMed

記述言語：英語   出版者・発行元：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。

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

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 summa-rized. 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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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本神経救急学会  

DOI： 10.11170/jjsnecc.34.2_21

記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は33歳男性で、先天性両側聴力障害を有し、3歳まで歩行の遅延が認められ、11歳時に視力低下が判明した。高校生までは短下肢装具で歩行できたが、その後は車椅子使用となった。30歳まではパソコンや携帯電話を使用できたが、視力が徐々に低下し、両側視神経萎縮が判明したため、確定診断のために入院した。神経学的検査により、両側視神経萎縮と聴力障害が明らかとなった。猿手と鷲手、凹足変形、四肢の遠位筋萎縮を認め、徒手筋力検査では遠位筋の筋力低下が示された。下肢遠位に感覚鈍麻があり、足関節の振動覚がなく、爪先の位置覚が障害されていた。四肢の腱反射は低下していた。血清クレアチンキナーゼ値が1118U/Lに上昇していた。神経伝導検査により、重度の運動感覚性ニューロパチーが判明した。Charcot-Marie-Tooth病についての遺伝子検査を行い、PRPS1遺伝子の新規半接合変異c82 G>C(p.G28R)が特定された。赤血球ホスホリボシルピロリン酸合成酵素1の酵素活性が著明に低下していた。

記述言語：英語   出版者・発行元：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。

記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は64歳女性で、緩徐進行型筋力低下、脊柱側彎症、視神経萎縮、神経因性膀胱による尿失禁、便秘、横隔膜弛緩症を伴う拘束性肺機能障害を認めた。47歳時に神経学的検査、眼科検査、聴覚検査、複合筋活動電位と知覚神経活動電位(SNAP)の評価、筋電図検査、脳MRIを行い、臨床的にCharcot-Marie-Tooth病(CMT)と診断した。62歳時に呼吸困難が出現し、CMTの横隔神経浸潤によると思われる拘束性肺機能障害と診断した。63歳時に遺伝子検査を行い、MFN2エクソン8の新規ヘテロ接合一塩基多型(c.740 G>C)が特定され、MFN2 GTPaseドメインのミスセンス変異(p.R247P)をきたしていることが判明した。64歳時の追跡検査では、徒手筋力検査に47歳時からの大きな低下は認められず、神経伝導検査では正中神経のSNAPのみが惹起された。超音波検査では、残尿量が約120mLであることが判明した。頸部・胸部・腰部MRIで、神経因性膀胱の明らかな原因となる中枢神経病変は認めなかった。肺活量は31%に低下し、無呼吸低呼吸指数は上昇していた。

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

Background: 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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PubMed

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410214347

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

We herein report a case of increased and expanded ipsilateral ivy sign paralleling the expansion of cerebral infarction in a patient with moyamoya disease. A 67-year-old woman visited our hospital with symptoms of left hemiplegia, left homonymous hemianopia, and left unilateral spatial neglect. Magnetic resonance imaging of the head showed cerebral infarction in the right parietal lobe. In addition, ivy signs were evident on fluidattenuated inversion recovery imaging. These findings were enhanced by the expansion of cerebral infarction and disappeared once the ischemia resolved, implying hemodynamic changes. As a result of continuing medical treatment without antithrombotic therapy, the patient obtained a good outcome. Treatment for moyamoya disease in the acute phase is considered to require complex knowledge of multiple factors, such as the anatomical background of the individual patient and the progression grade of ischemia.

DOI： 10.2169/internalmedicine.9326-22

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PubMed

記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.39.4_540

記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.39.5_773

記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.39.1_3

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

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

DOI： 10.3389/fneur.2022.986504

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本小児神経学会  

<p> X連鎖Charcot-Marie-Tooth病1型 (CMTX1) では, 脳梁膨大部病変を有する軽症脳症 (MERS) に該当する一過性中枢神経障害の併発例が報告されている. MERS 2型罹患を契機にCMTX1と診断した兄弟例を報告する. 12歳の弟はマイコプラズマ肺炎罹患後に意識障害, 四肢麻痺, 構音障害が出現した. 頭部MRI拡散強調画像では脳梁膨大部と大脳深部白質に対称性高信号病変が一過性に出現し, 臨床症状と併せMERS 2型と診断した. 兄もMERS 2型に罹患した既往があり, さらに兄弟と母親に下肢腱反射消失, 逆シャンパンボトル型の下腿筋萎縮, 凹足を認めることからCMTX1を疑った. その後, 弟の<i>GJB1</i>にミスセンス変異NM_000166.6 (GJB1) : c. 77C>T (p. Ser26Leu) が確認され, CMTX1と診断した. けいれんを認めず, 大脳局所症状を有するMERS 2型例は基礎疾患としてCMTX1の可能性を考慮するが, 小児期は末梢神経障害が目立たない場合が多い. そのため症状が早期に出現する下肢の神経学的診察を注意深く行う事に加え, 家族も同様に診察する事が重要である.</p>

DOI： 10.11251/ojjscn.54.56

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

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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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

記述言語：日本語   出版者・発行元：Journal of Clinical Microbiology  

The anti-human T-cell leukemia virus type 1 (HTLV-1) antibody assay in common use has changed from the particle agglutination (PA) method to chemiluminescent immunoassay (CLIA) and chemiluminescent enzyme immunoassay (CLEIA). These assays were validated in serum but not in cerebrospinal fluid (CSF). However, anti-HTLV-1 antibody positivity in CSF is a requisite for diagnosing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We qualitatively compared the assays in CSF from 47 HAM/TSP patients diagnosed using PA, 15 HTLV-1 carriers (HCs), and 18 negative controls. In determining the positivity or negativity of CSF anti-HTLV-1 antibodies, we used serum cutoff points for CLIA and CLEIA because CSF cutoff points had not been decided. Truth table analysis revealed that the performance of CLIA was closer to that of PA and that CLEIA had low sensitivity. CSF antibodies from HAM/TSP patients were all positive by PA and CLIA but 83.0% positive by CLEIA. CSF antibodies from HCs were positive in 73.3%, 80.0%, and 6.7% by PA, CLIA, and CLEIA, respectively. Receiver operator characteristic curve analysis for CSF revealed that with the default cutoff point used for serum, CLIA and PA had comparable performances and CLEIA was less sensitive. The best performances of CLIA and CLEIA with adjusted cutoff points were 94.8% sensitivity and 95.5% specificity and 89.7% sensitivity and 95.5% specificity, respectively. We conclude that low-sensitivity CLEIA can underdiagnose HAM/TSP and that CLIA is a better alternative to PA in anti-HTLV-1 antibody assay for CSF with the current cutoff points.

DOI： 10.1128/JCM.03230-20

Scopus

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

The anti-human T-cell leukemia virus type 1 (HTLV-1) antibody assay in common use has changed from the particle agglutination (PA) method to chemiluminescent immunoassay (CLIA) and chemiluminescent enzyme immunoassay (CLEIA). These assays were validated in serum but not in cerebrospinal fluid (CSF). However, anti-HTLV-1 antibody positivity in CSF is a requisite for diagnosing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We qualitatively compared the assays in CSF from 47 HAM/TSP patients diagnosed using PA, 15 HTLV-1 carriers (HCs), and 18 negative controls. In determining the positivity or negativity of CSF anti-HTLV-1 antibodies, we used serum cutoff points for CLIA and CLEIA because CSF cutoff points had not been decided. Truth table analysis revealed that the performance of CLIA was closer to that of PA and that CLEIA had low sensitivity. CSF antibodies from HAM/TSP patients were all positive by PA and CLIA but 83.0% positive by CLEIA. CSF antibodies from HCs were positive in 73.3%, 80.0%, and 6.7% by PA, CLIA, and CLEIA, respectively. Receiver operator characteristic curve analysis for CSF revealed that with the default cutoff point used for serum, CLIA and PA had comparable performances and CLEIA was less sensitive. The best performances of CLIA and CLEIA with adjusted cutoff points were 94.8% sensitivity and 95.5% specificity and 89.7% sensitivity and 95.5% specificity, respectively. We conclude that low-sensitivity CLEIA can underdiagnose HAM/TSP and that CLIA is a better alternative to PA in anti-HTLV-1 antibody assay for CSF with the current cutoff points.

DOI： 10.1128/JCM.03230-20

Web of Science

掲載種別：研究論文（学術雑誌）  

The anti-human T-cell leukemia virus type 1 (HTLV-1) antibody assay in common use has changed from the particle agglutination (PA) method to chemiluminescent immunoassay (CLIA) and chemiluminescent enzyme immunoassay (CLEIA). These assays were validated in serum but not in cerebrospinal fluid (CSF). However, anti-HTLV-1 antibody positivity in CSF is a requisite for diagnosing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We qualitatively compared the assays in CSF from 47 HAM/TSP patients diagnosed using PA, 15 HTLV-1 carriers (HCs), and 18 negative controls. In determining the positivity or negativity of CSF anti-HTLV-1 antibodies, we used serum cutoff points for CLIA and CLEIA because CSF cutoff points had not been decided. Truth table analysis revealed that the performance of CLIA was closer to that of PA and that CLEIA had low sensitivity. CSF antibodies from HAM/TSP patients were all positive by PA and CLIA but 83.0% positive by CLEIA. CSF antibodies from HCs were positive in 73.3%, 80.0%, and 6.7% by PA, CLIA, and CLEIA, respectively. Receiver operator characteristic curve analysis for CSF revealed that with the default cutoff point used for serum, CLIA and PA had comparable performances and CLEIA was less sensitive. The best performances of CLIA and CLEIA with adjusted cutoff points were 94.8% sensitivity and 95.5% specificity and 89.7% sensitivity and 95.5% specificity, respectively. We conclude that low-sensitivity CLEIA can underdiagnose HAM/TSP and that CLIA is a better alternative to PA in anti-HTLV-1 antibody assay for CSF with the current cutoff points.

DOI： 10.1128/JCM.03230-20

Scopus

PubMed

記述言語：英語  

DOI： 10.1128/JCM.03230-20

PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

<p>30歳，男性．全身の筋痛と急速に進行する近位筋優位の筋力低下と共に，上下肢の著明な浮腫を認めた．筋病理よりacute edematous dermatomyositis（急性浮腫性皮膚筋炎）と診断し，ステロイドパルス療法をしたが，効果なく，寝たきり状態となった．CK（creatine kinase）も170,000 U/<i>l</i>と異常高値を呈した．その後，血液浄化療法を含む積極的加療により，症状は速やかに改善し，浮腫主体の筋炎症例での積極的加療の有効性が示唆された．</p>

DOI： 10.2169/naika.110.598

記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.38.3_369

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.2425201205

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

DOI： 10.2169/internalmedicine.4629-20

Scopus

PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本小児神経学会  

記述言語：英語   出版者・発行元：(一社)日本救急医学会  

症例は34歳男性で、異常行動と嗜眠が突然出現し、入院となった。高アンモニア血症(108μmol/L)を認めた。臨床所見から焦点性てんかんと診断し、レベチラセタム治療を開始したところ、2日目に霧視を除いて症状は改善し、血清アンモニア濃度は正常化した。31日目に異常行動、嗜眠、高アンモニア血症(122μmol/L)が再び出現したため、再入院となった。鶏肉に対する不耐症と早世の家族歴から尿素サイクル異常症を疑い、33日目よりタンパク質制限食およびアルギニン治療を開始した。その結果、翌日に霧視を含めて症状は消失し、血清アンモニア濃度は正常化した。34日目よりフェニル酪酸ナトリウム治療を追加した。血清アミノ酸プロファイルから遅発型のオルニチントランスカルバミラーゼ(OTC)欠損症が示唆された。44日目に退院に至り、その後は再発を認めていない。OTC遺伝子にR40H(c.119G>A)変異が同定された。

掲載種別：研究論文（学術雑誌）  

Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T-and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhib-iting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.

DOI： 10.1371/journal.pntd.0008361

Scopus

PubMed

掲載種別：研究論文（学術雑誌）  

Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T-and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhib-iting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.

DOI： 10.1371/journal.pntd.0008361

Scopus

PubMed

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

Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that theABL1is an important gene in HAM/TSP.ABL1is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whetherABL1is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore,ABL1siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting thatABL1is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.Author summary Human T-cell leukemia virus type 1 (HTLV-1) is integrated as a provirus in the genomic DNA mainly of CD4+ T cell population in the infected people. HTLV-1-infected CD4+ T cells are transmitted via breast milk, semen, and blood transfusions. HTLV-1 is endemic in Japan, the Middle East, Africa, Caribbean islands, and Central and South America. A small proportion of infected people develop adult T-cell leukemia, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other diseases. HAM/TSP, a chronic neuroinflammatory disorder, is characterized by spastic paraparesis and urinary disturbance. HTLV-1-infected CD4+ T cells infiltrate the spinal cord and cause inflammation, which results in such neurological symptoms. We have identified the tyrosine kinase geneABL1as a gene frequently found in the signal transduction pathways in HTLV-1-infected CD4+ T cells. Therefore,ABL1appears to be important in the pathogenesis of HAM/TSP. Inhibiting ABL1 with tyrosine kinase inhibitors (TKIs), which is used for chronic myelogenous leukemia (CML), reduced the proviral load (PVL)in vitro. We found a rare case of a patient with HAM/TSP and CML by our clinical records, who showed a decrease in PVL after TKI treatment for CML. Hence, TKIs are potential therapeutic agents for HAM/TSP.

DOI： 10.1371/journal.pntd.0008361

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.

DOI： 10.1371/journal.pntd.0008361

PubMed

記述言語：英語  

DOI： 10.1371/journal.pntd.0008361

PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本末梢神経学会  

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本糖尿病学会  

DOI： https://doi.org/10.11213/tonyobyo.63.344

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi.org/10.1111/jns.12369

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi.org/10.1016/j.braindev.2019.10.008

出版者・発行元：エルゼビア・ジャパン(株)  

下位運動ニューロン症状がみられ、当初は脊髄性筋萎縮症が疑われたが診断がつかなかった患者を分子診断するため、次世代シーケンス解析(NGS)と従来式のシーケンス解析を適用した。2005〜2016年に当施設を受診した上記患者のうち、最終的に8家系に属する12名を対象に、NGSを利用したターゲットリシケーンシング解析を施行した。検出された遺伝子変異体を文献検索とデータベースに基づいて選別し、病原性変異体の候補となったものについてはSanger法によるシーケンス解析にて検証した。その結果、2家系に属する患者3名から新規変異体を発見した。患者1と2は共に6歳の男児で双生児であり、TTN遺伝子の2種の変異体を有する複合ヘテロ接合体(c.6621delG, p.W2207Cfs*28およびc.23718T>A, p.F7906L)であった。患者3はKIF1A遺伝子変異体の複合ヘテロ接合体(c.3871C>T, p.R1291Cおよびc.3898G>A,p.V1300M)であった。このように未診断患者3名において新規原因遺伝子の発見に成功したことから、本アプローチは有効であることが示された。

出版者・発行元：Brain and Development  

DOI： 10.1016/j.braindev.2019.10.008

Scopus

PubMed

DOI： 10.1002/ams2.565

PubMed

出版者・発行元：(一社)日本内科学会  

症例1は女性で、26歳時によろめき歩行、発話および嚥下障害が出現して徐々に悪化し、32歳時に来院した。症例2は症例1の一卵性双生児の姉。25歳時によろめき歩行が出現し、31歳時に来院した。両症例ともに眼振、構語障害、四肢および体幹の運動失調を認め、脳MRIで小脳萎縮が判明した。母方の祖父と叔父、症例2の次男でも眼振が認められた。遺伝子検査では、両症例ともにアタキシン8逆鎖(ATXN8OS)CTA/CTG反復が25/97であり、脊髄小脳失調症8型と診断した。タルチレリン水和物による治療を行ったが、失調症は徐々に悪化した。本症例は、ATXN8OS遺伝子反復伸長を認めた一卵性双生児についての初の報告であった。

記述言語：日本語   出版者・発行元：一般社団法人 日本臨床神経生理学会  

<p>X-linked Charcot–Marie–Tooth disease type 1 (CMTX1) には亜急性増悪を示し免疫グロブリン大量静注療法 (intravenous immunoglobulin therapy; IVIg) が奏功する例の報告があり, 少なくとも一部において末梢神経の免疫学的脆弱性の存在が考えられている。症例は51歳男性, 46歳頃より躓きやすさが出現, 51歳時より約3か月の経過で右手の巧緻運動障害や歩行障害が進行した。槌趾のほか, 右母指球筋萎縮, 四肢筋の脱力と腱反射消失, 感覚失調を認め, 神経伝導検査では複合筋活動電位の時間的分散を含む脱髄所見を認めた。IVIgを行い症状は一旦改善したが, 徐々に増悪し53歳時に再度受診した。母親にも下肢優位の末梢神経障害を認めた。本人・母親に<i>GJB1</i> P70S変異が確認されCMTX1の診断に至ったが, 初回IVIgへの反応性から再度IVIgを行うと明らかな改善が得られ, 亜急性増悪に免疫学的機序が関与すると考えられた。</p>

DOI： 10.11422/jscn.48.8

記述言語：日本語   出版者・発行元：日本神経感染症学会  

<p>【要旨】HAM 患者データベース『HAM ねっと』に登録されている 527 例において、疾患進行速度の予測因子としての初発症状の意義を検討した。初発症状は歩行障害、下肢感覚障害、排尿障害の三分類とした。初発症状の出現から車椅子使用レベルである納の運動障害重症度分類（OMDS）で Grade 6 にいたるまでの期間を疾患進行速度の指標とした。検討の結果、初発症状が下肢感覚障害であれば有意に急速で、排尿障害であれば有意に緩徐であった。初発症状は疾患進行の予測因子であることを確認した。また、初発症状が排尿障害である例は男女ともに若年発症の傾向があった。若年で排尿障害を呈する患者には HTLV-1（Human T-lymphotropic virus type 1）感染を積極的に疑い、抗炎症治療の対象となるか検討することが求められる。</p>

DOI： 10.34397/jsnd.25.1_146

記述言語：日本語   出版者・発行元：一般社団法人 日本小児神経学会  

<p> <i>SUCLA2</i>関連ミトコンドリアDNA枯渇症候群は, メチルマロン酸尿症を伴うLeigh症候群と知られる. 症例は12歳女児で血族婚なし. 臨床所見は精神運動発達遅滞, 低緊張, 感音性難聴, 摂食困難, 成長障害, 筋萎縮, 外眼筋麻痺, 眼瞼下垂, 胃食道逆流, 反復嘔吐, 矢状縫合早期癒合, 軸索型末梢神経障害, 拘束性呼吸障害, 脊柱後側彎症を認めた. 8か月での血液・髄液検査で乳酸高値を認め, 頭部MRIで大脳萎縮を認めた. 2歳時の頭部MRI (T2強調画像) で両側基底核に高信号を認めた. 以上からLeigh症候群と診断した. 血清アシルカルニチン分析でプロピオニルカルニチンの軽度増加を認めるも, 尿中有機酸分析で異常なしとの判断であった. 9歳時に末梢神経障害の研究のためエクソーム解析を行い, NM_003850.2 (SUCLA2) : c.1300del (p.Asp434Metfs^＊8) ＋c.664-1G＞Aと新規複合ヘテロ変異を認めた. 両親は各々保因者であった. 再度の尿中有機酸分析で, メチルマロン酸の軽度排泄増加を認めた. 筋組織の呼吸鎖複合体ⅠおよびⅣの活性が正常下限であった. 以上から<i>SUCLA2</i>関連ミトコンドリアDNA枯渇症候群と診断した. ミトコンドリア病患者の血清プロピオニルカルニチンおよび尿中メチルマロン酸の軽度増加を見逃さないことが重要である.</p>

DOI： 10.11251/ojjscn.52.318

Scopus

記述言語：日本語   出版者・発行元：日本神経学会  

<p>59歳，女性．兄に類似の歩行障害がみられた．47歳時に左下肢をひきずると指摘され，48歳から歩行障害を自覚，50歳時にすり足歩行になった．52歳から両下肢や手指の有痛性れん縮を生じた．神経学的に知能は正常で，両下肢の筋力は中等度低下し著明な痙性を認めた．頭部MRIでは脳梁菲薄化と，FLAIRで側脳室周囲白質に高信号がみられた．以上から遺伝性痙性対麻痺と診断した．adaptor-related protein complex 5 subunit zeta 1（<i>AP5Z1</i>）遺伝子に新規変異（c.1662_1672del;p.Q554Hfs*15）をホモ接合性に，家族はヘテロ接合性に認めた．Spastic paraplegia 48は稀で報告例が少なく臨床像と病態について検討した．</p>

DOI： 10.5692/clinicalneurol.60.cn-001419

Scopus

PubMed

記述言語：日本語   出版者・発行元：日本神経学会  

<p>東日本大震災の甚大な被害を踏まえて日本神経学会の災害対策活動はスタートした．2014年，正式に日本神経学会災害対策委員会が発足し，災害支援ネットワーク構築と指揮発動要件設定を行い，模擬訓練を実施した．2016年の熊本地震で我々は平常時の難病患者リスト作成，個別支援計画策定の重要性を認識し，避難所等における難病患者のサポートのあり方を検討した．2017年，我々は災害対策マニュアルを刊行し，難病患者の災害時調整役として各都道府県に神経難病リエゾンを配置することを定めた．神経難病リエゾンの役割は「被災地の情報収集・発信」，「医療支援調整」，「保健活動」であり，平常時と災害時の活動が期待される．</p>

DOI： 10.5692/clinicalneurol.cn-001493

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PubMed

記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は29歳男性である．2歳半で独歩を獲得したが，筋力低下が進行し12歳時に歩行不能となった．20歳時に呼吸不全を合併した．診察では，顔面を含めた遠位筋優位の筋力低下と筋萎縮，脊椎側弯，四肢末梢優位の感覚障害を認めた．神経伝導検査では，複合筋活動電位の低下と運動神経伝導速度低下を認め，感覚神経電位は誘発不能であった．遺伝子解析でセナタキシン遺伝子（<i>SETX</i>）にc.23C>T (p.T8M)ヘテロ接合性の新規変異を認めた．<i>SETX</i>変異はヘテロ接合体では家族性筋萎縮性側索硬化症4型（familial amyotrophic lateral sclerosis type 4; ALS4）の原因遺伝子であるが，運動感覚性末梢神経障害の原因ともなる可能性が示唆された．</p>

DOI： 10.5692/clinicalneurol.60.cn-001415

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本糖尿病学会  

<p>64歳女性．X－24年巣状糸球体硬化症，X－11年糖尿病の診断と加療を受け，X－4年にはインスリン治療が開始された．X－2年10月頃からは物忘れが激しくなり，血糖コントロール悪化の原因と考えられ，神経内科を受診した．上肢巧緻運動障害と高次脳機能障害の存在を指摘され，X年8月に精査入院した．頭部MRIでは両側大脳皮質病変，大脳・脳幹・小脳の萎縮を，左上腕二頭筋の筋生検でragged red fiberを伴うmyopathyを認め，ミトコンドリア糖尿病と診断された．腎組織を再検討したところ，ミトコンドリア病による腎病変に合致する所見を認めた．姉も同疾患と診断されたが，本症例と同様にミトコンドリアDNAに多重欠損を認めるのみで，既報の遺伝子変異は同定されなかった．認知機能低下が原因と考えられる血糖コントロール悪化を契機に診断されたミトコンドリア糖尿病の症例報告は既報にはなく，文献的考察を加えて報告する．</p>

DOI： 10.11213/tonyobyo.63.344

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記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.37.4_634

記述言語：日本語   出版者・発行元：日本神経治療学会  

<p>We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2019. Ion channel modulation may contribute to recover for Purkinje neuron dysfunction and motor impairment in a variety of cerebellar ataxias. The role of RNA–binding proteins as RNA chaperones may lead to the development of new treatments for SCA31. Aminopyridines and acetyl–DL–leucine will provide new therapeutic strategies of cerebellar disorders. We expect that these treatments will contribute to patients with cerebellar motor dysfunction and ataxia.</p>

DOI： 10.15082/jsnt.37.5_732

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

DOI： 10.1002/mus.26683

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi.org/10.2169/internalmedicine.3029-19

出版者・発行元：(一社)日本内科学会  

確定した自己免疫性辺縁系脳炎(LE)患者の臨床特性を後向きに評価した。日本3施設でLEと診断された患者16759例の医療記録を評価し、臨床的に確定した自己免疫性LE患者30例を特定した(有病率0.2%)。8例が抗N-メチル-D-アスパラギン酸受容体(NMDAR)抗体陽性、2例が抗電位依存性カリウムチャネル(VGKC)複合抗体陽性、2例が腫瘍随伴症候群関連抗体陽性で、18例は抗体陰性であった。NMDAR陽性群では典型的症状が認められた。脳MRI所見では、退院後1年間の追跡時に有意な内側側頭葉の萎縮が認められた。合併症としての認知機能障害の有病率は64%(9/14例)であった。一次免疫療法の成績は良好で、修正Rankin尺度スコアは4.0±1.1から1.1±1.1に著明に改善した。NMDAR陽性群、VGKC陽性群、抗体陰性群のいずれにおいても治療成績は良好であったことから、早期臨床診断と早期治療開始の重要性が示唆された。

DOI： 10.1016/j.jstrokecerebrovasdis.2019.07.017

PubMed

出版者・発行元：兵庫医科大学医学会  

異常な視覚誘発性電位を呈したCharcort-Marie-Tooth病2A型(CMT2A)の日本人家系にヘテロ接合MFN2遺伝子変異(c.733A>C: p.Ser245Arg)を検出した。そこで、ニューロンにmitofusin 2(MFN2) S245Rを特異的に発現するトランスジェニック(TG)マウスを作成し、その生態病理について検討した。その結果、このTGマウスは対照マウスに比べて坐骨神経内のg-ratioが有意に大きかった。次にTGマウスの視神経を検討すると、横断面と縦断面のいずれでもミトコンドリアのサイズが対照マウスに比べて有意に小さく、これはミトコンドリアの融合障害に起因すると推測された。以上より、変異MFN2はミトコンドリア融合に影響を及ぼし、視神経症を引き起こすと考えられた。

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

DOI： 10.2169/naika.108.1515

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

DOI： 10.1038/s41588-019-0459-y

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

DOI： 10.1016/j.jns.2019.05.023

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PubMed

出版者・発行元：(一社)日本内科学会  

家族性筋萎縮性側索硬化症(fALS)の同胞6例を対象に、臨床的インタビューと臨床検査を行ってfALSの非定型表現型について報告し、末梢血標本の遺伝子解析を行った。罹患同胞は5例(男性3例、女性2例)、健康同胞は1例(女性)であった。fALSの臨床特性は、緩徐進行性(平均罹病期間19.6±3.9年)、下肢優勢晩期発症筋力低下(筋力低下の平均発症時年齢52.8±2.6歳)であった。遺伝子解析により、すべての罹患同胞においてPLEC遺伝子のヘテロ接合型ミスセンス変異(OMIM 601282,c.2668C>T,p.R890C)、ST3GAL6遺伝子のヘテロ接合型ミスセンス変異(OMIM 607156,c.421G>C,p.V141L)が検出された。臨床経過が比較的良好な新規の非定型fALS家族について報告し、この表現型に関連する二つの候補遺伝子変異を特定した。

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuromuscular Disorders  

PMP22 is the most frequent mutated gene in Charcot-Marie-Tooth disease (CMT) type 1A. Another phenotype, hereditary neuropathy with pressure palsies (HNPP), could be caused by PMP22 mutations. PMP22 encodes a peripheral myelin protein with molecular weight 22-kDa. Various pathomechanisms have been postulated in PMP22-related disease, including dysfunction due to missense mutations, and alteration of a gene dose due to duplication/deletion mutations. We identified a novel PMP22 splice site acceptor variant, c.179-1G&gt;A, in a patient with adult-onset chronic generalized polyneuropathy and two asymptomatic family members. Pathophysiological features of the members mainly overlapped with those reported in HNPP, but broad intrafamilial clinical variations were observed. PMP22 transcripts lacking of exon 4 were produced by the variant, presumably leading to in-frame deletion of 47 amino acids. The variant was also shown to exert effect on dosage of PMP22 mRNA. The complex molecular pathology would lead to the unique clinical and pathophysiological conditions.

DOI： 10.1016/j.nmd.2019.03.010

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

DOI： 10.1016/j.yexcr.2019.03.040

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記述言語：英語   出版者・発行元：Neurology Asia  

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

DOI： 10.1038/s10038-018-0538-4

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PubMed

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

DOI： 10.1016/j.braindev.2018.08.006

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PubMed

出版者・発行元：エルゼビア・ジャパン(株)  

症例1は13歳男児で、出生時から言語習得前難聴が認められた。8歳から11歳にかけて、呼吸器感染症に罹患した後に突然発症の筋力低下を計3回にわたり繰り返していた。12歳時に行った神経伝導検査では、遠位下肢における複合筋活動電位(CMAP)の低下がみられ、13歳時、歩行障害、反射低下および難聴を認めた。症例2は症例1の弟。生後1年目に言語習得前難聴がみられ、2歳ごろから発熱後の歩行困難を呈していた。8歳時に受診となり、神経学的検査で膝関節と足関節の反射低下、重度の近位筋力低下を認めた。頭部・脊椎・筋MRIでは異常所見なく、髄液検査でも異常はなかった。神経伝導検査でCMAPの低下、脛骨神経と総合腓骨神経の一時的分散がみられた。ニューロパシー関連遺伝子72個のSangerシークエンス解析を行ったところ、PRSP1遺伝子内に新規c.319A>C半接合ミスセンス変異が検出された。発端者は半接合変異、母親はヘテロ接合変異を有することが判明し、5型X連鎖Charcot-Marie-Tooth病との確定診断を得た。

出版者・発行元：Nature Publishing Group  

本報では日本人初の常染色体劣性遺伝性痙性対麻痺(SPG57)患者を報告し、4番目のSPG57遺伝子型の新規変異体について報告した。症例は43歳女性で、いとこ婚による健常両親の第3子として出生し、長兄も同様の病歴を有し、次兄は原因不明の軽度知覚障害を伴っていた。本例は3〜4歳で自立歩行となり、三輪車にも乗れたが、5歳で歩行困難を来し、脳性麻痺と診断された。10歳時には自立歩行困難になったが、知能は正常で、専門学校を卒業後は事務員として勤務していた。30歳で緑内障を発症し、39歳で腰痛のため来院した際に、痙性両麻痺および遠位優性末梢性感覚運動障害を指摘された。全エクソーム解析等の遺伝学的解析により、病原性変異として、tropomyosin-receptor kinase fused gene(TFG)のエクソン3にホモ接合性ミスセンス変異体c.197T>C:p.Ile66Thrが同定され、SPG57と確定診断された。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本内科学会  

<p><b>Objective </b>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the progressive loss of the upper and lower motor neurons that progresses to paralysis of almost all skeletal muscles of the extremities, bulbar, and respiratory system. Although most ALS cases are sporadic, about 10% are dominantly inherited. We herein report an atypical phenotype of familial ALS (fALS). To elucidate the phenotype-genotype correlation of this atypical phenotype of fALS, clinical and genetic investigations were performed. </p><p><b>Methods and Patients </b>Five sibling patients (three men, two women) from a Japanese family and one healthy sibling (a woman) were clinically interviewed and examined. Genetic analyses, including genome-wide linkage analyses and whole-exome sequencing, were performed using genomic DNA extracted from the peripheral blood samples of these siblings. </p><p><b>Results </b>The clinical features of fALS are characterized by slow progression (mean duration of the disease±standard deviation [SD]: 19.6±3.9 years) and lower extremities-predominant late-onset muscular weakness (mean onset of muscular weakness±SD: 52.8±2.6 years). Genetic analyses revealed novel heterozygous missense mutations of c.2668C>T, p.R890C in the <i>PLEC</i> gene and c.421G>C, p.V141L in the <i>ST3GAL6</i> gene in all affected siblings. </p><p><b>Conclusion </b>A new atypical fALS family with a benign clinical course is herein reported. We identified two candidate gene mutations of <i>PLEC</i> and <i>ST3GAL6</i> linked to this phenotype. </p>

DOI： 10.2169/internalmedicine.2222-18

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記述言語：日本語   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.36.6_S154

出版者・発行元：Journal of NeuroVirology  

DOI： 10.1007/s13365-018-0704-7

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記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

<p><b>Objective </b>Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. </p><p><b>Materials and Methods </b>Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). </p><p><b>Results </b>LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. </p><p><b>Conclusion </b>Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy. </p>

DOI： 10.2169/internalmedicine.3029-19

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PubMed

担当区分：最終著者   記述言語：日本語   出版者・発行元：日本神経治療学会  

<p>We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2018. This article introduces the outline of therapies with mesenchymal stem cells, cerebello–spinal tDCS, betamethasone, and cyclodextrin. We expect that these treatments will contribute to patients with cerebellar motor dysfunction and ataxia.</p>

DOI： 10.15082/jsnt.36.5_580

掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.cn-001221

PubMed

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

DOI： 10.1111/1346-8138.14336

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PubMed

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

DOI： 10.1186/s40478-018-0617-y

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DOI： 10.1038/s41598-018-33442-7

PubMed

担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC Neurology  

DOI： 10.1186/s12883-018-1131-3

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PubMed

出版者・発行元：(NPO)日本脳神経血管内治療学会  

目的)治療時間短縮のために、初回のアプローチルートとして橈骨動脈アプローチ(Transradial Approach:TRA)を選択した後方循環の急性期再開通療法について報告する。症例)2015年11月から2017年3月の期間に、4例の後方循環主幹動脈閉塞症に対してTRAを用いて急性期再開通療法をおこなった。TRAは術前のMRIで右側の椎骨動脈(Vertebral Artery:VA)が優位である症例において初回のアプローチルートとして用いた。全例でアプローチルートの変更なく手技を完遂でき、TICI2b以上の再開通を全例の100%に、TICI3の再開通を3例の75.0%で得られた。橈骨動脈穿刺から初回の頭蓋内造影までの時間は7.3±1.5分で、有効再開通までの治療時間は28.8±6.2分であった。穿刺部合併症は認めなかった。結論)橈骨動脈アプローチを初回から行った後方循環の急性期再開通療法では、迅速で確実な再開通が得られた。右VAにアプローチ可能な症例では第一選択として利用できる可能性が示唆された。(著者抄録)

記述言語：英語   出版者・発行元：Experimental Cell Research  

DOI： 10.1016/j.yexcr.2018.02.035

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： javascript:selectMenu('ENTKKB0190','%E7%A7%91%E7%A0%94%E8%B2%BB%EF%BC%88%E6%96%87%E7%A7%91%E7%9C%81%

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.braindev.2017.08.004

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出版者・発行元：IACMHR.Co.,Ltd.  

1980年以降の30年間に当院で検査を受けた近位筋優位遺伝性運動感覚ニューロパチー(HMSN-P)患者130例のうち、詳細な診療録を確認できた97例(男性55例、女性42例、初診時年齢中央値48.5歳)の臨床経過を評価した。評価項目として、初診時の年齢、疼痛性筋痙攣の発症年齢、上/下肢筋力、知覚、起立、歩行、嚥下、呼吸、死亡年齢、初診時のCK値、TRK-fused gene(TFG)の変異型などを調べた。さらに疾患進行期の嚥下障害、呼吸不全、気管切開術、死亡年齢、死亡時の状況などを確認した。97例中79例でTFG変異を検査し、その全例でp.Pro285 Leu変異であることが確認された。発症には20〜30年の個人差があり、進行にも大きな個人差があった。

記述言語：英語   出版者・発行元：(一社)日本内科学会  

症例は63歳女性で、小学生の頃はランニングなどの運動が得意ではなく、30歳時に次第に歩行が困難になった。60歳時に両手、63歳時に両足の脱力と筋萎縮を自覚した。身体検査で二頭筋、三頭筋、腕橈骨筋、膝の両側反射亢進、凹足、両手・両足の遠位優位の筋萎縮・脱力が明らかになった。バビンスキー反射およびチャドック反射は陰性であったが、左トレムナー反射は陽性であった。針筋電図で両側第一背側骨間筋および前脛骨筋に慢性神経因性変化が認められ、遺伝子解析ではBSCL2遺伝子のp.N88Sにヘテロ変異が明らかになった。BSCL2遺伝子変異は小胞体ストレスを介して運動ニューロン変性を引き起こすことが知られている。筋萎縮性側索硬化症に類似した症状を呈する患者では、Seipinopathyを考慮すべきであることが示唆された。

記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

症例は男児で、妊娠36週で子宮内胎児発育遅延が明らかになり、妊娠39週で出生した。出生時より筋緊張低下、弱い泣き声、内反尖足が認められた。生後4ヵ月でも頭部を持ち上げることができず、その後、呼吸器感染症による急性呼吸不全のため入院となった。呼吸窮迫がみられ、身体検査では下肢の反射消失、軽度凹足があり、上肢の深部腱反射が弱かった。脳MRIでは白質量の減少が認められ、生後5ヵ月時の神経伝導検査では上肢の複合筋活動電位と運動伝道速度の減少が示された。筋電図検査では下肢に神経原性パターンが明らかになった。生後8ヵ月で気管開口術を施行し、在宅人工呼吸療法を継続したところ、呼吸状態と筋力が安定した。1歳1ヵ月時に腓腹神経生検を施行し、神経原性筋萎縮症が認められた。患児と両親の遺伝性末梢神経障害に対する遺伝子検査を実施した。IGHMBP2遺伝子の複合ヘテロ接合性変異(c826C>T、p.Gln276*とc.1702C>T、p.Gln568*)が検出された。1歳4ヵ月時には様々な顔面表情がみられ、名前の呼びかけに反応した。

出版者・発行元：Journal of Human Genetics  

DOI： 10.1038/s10038-017-0353-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Nature Publishing Group  

中年期になってCharcot-Marie-Tooth病2A型(CMT2A)を発症した、日本人姉妹2例を報告した。症例1は3人姉妹の三女で、41歳時に両足裏に感覚麻痺を呈し、つま先歩きが困難になった。症状は徐々に悪化し、5年以内に杖歩行となり、52歳時の神経学的検査により、遠位下肢筋力低下と萎縮および反射消失が認められた。症例2は姉妹の長女で、42歳時に緩徐進行性の歩行困難を来たし、その後、両足裏の感覚麻痺が認められた。65歳時に車椅子生活となり、神経学的検査により、遠位下肢筋力低下、反射消失および感覚消失が認められた。なお、姉妹の次女に関しては、62歳時の神経学的検査では異常はみられなかったが、症例1および2では、MFN2遺伝子の膜貫通ドメインに対応するホモ接合性ミスセンス変異c.1894C>T、p.T632Wが同定された。一方、神経学的検査で正常であった次女では、これら変異はヘテロ接合性であったことから、遺伝子型と表現型の共分離が示唆された。MRIにより、症例1と2には脊髄、特に胸髄おける萎縮と、頭頂葉および小脳の軽度な萎縮が認められ、腓腹神経の電子顕微鏡観察により、円形および膨潤したミトコンドリアのクラスターの存在が明らかにされた。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本内科学会  

<p>Seipinopathy is an autosomal dominant neurodegenerative disease caused by mutations of the <i>Berardinelli-Seip Congenital Lipodystrophy 2</i> (<i>BSCL2</i>) gene. We report the first Japanese case of seipinopathy with a heterozygous mutation of p.N88S in the <i>BSCL2</i> gene. The patient showed bilateral hyperreflexia of the biceps, triceps, brachioradialis, and knee, as well as the pes cavus and distal dominant weakness and atrophy of both arms and legs, suggesting the involvement of both upper and lower motor neurons. Mutations of the <i>BSCL2</i> gene have been known to cause motor neuron degeneration through endoplasmic reticulum stress. Seipinopathy should be considered in patients with symptoms mimicking amyotrophic lateral sclerosis. </p>

DOI： 10.2169/internalmedicine.8765-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Advances in Experimental Medicine and Biology  

DOI： 10.1007/978-981-13-0529-0_7

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本神経学会  

<p>症例は23歳男性．海外旅行中に多量飲酒を行った2日後に，口周囲，右上肢しびれ感と右下肢脱力が出現．同症状は一時消失後，再発した．発症3日後の頭部MRIで異常信号を認めたが，26日後にほぼ消失した．一過性の中枢神経病変に加え，本人及び母の多発ニューロパチーが確認されたことから，GJB1遺伝子変異によるCharcot-Marie-Tooth disease, X-linked dominant 1（CMTX1）を疑った．遺伝子検査によりc.530T>C (p.V177A)変異を確認し，診断が確定した．多量飲酒はCMTX1の中枢神経病変の誘因となり得るため，CMTX1では多量飲酒を避ける指導が重要である．</p>

DOI： 10.5692/clinicalneurol.cn-001130

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本神経学会  

<p>症例は32歳の女性．一過性の中枢性顔面神経麻痺，球症状が出現し，脳画像で大脳白質，脳梁膨大部，内包後脚に拡散強調像で高信号を認めた．兄2人が四肢遠位優位の末梢神経障害を示し，コネキシン32をコードする<i>GJB1</i>遺伝子点変異のX染色体連鎖シャルコー・マリー・トウース病（X-linked Charcot-Marie-Tooth disease; CMTX1）であり，本症例はヘテロ接合体である．神経伝導検査で脱髄型の軽度障害を示した．中枢神経（central nervous system; CNS）症状と画像変化は3症例とも極めて類似していた．CNS症状を示すCMTX1症例は数多く報告されているが，女性例は非常に少なく，本症例類似の女性例の報告例はない．一過性のCNS症状を示す例は，誘発因子が認められており，予防が重要である．</p>

DOI： 10.5692/clinicalneurol.cn-001138

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出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.35.6_S105

記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は43歳男性である．緩徐に進行する構音障害と歩行失調，幼児退行などの精神症状，脳幹・小脳の萎縮性所見より脊髄小脳変性症が疑われ入院した．口内炎，陰部潰瘍，毛囊炎様皮疹，HLA-B51をみとめ，髄液IL-6高値より慢性進行型神経ベーチェット病と診断した．ステロイド，メトトレキサートの治療効果に乏しく，インフリキシマブで髄液IL-6の減少が得られたが症状は改善しなかった．本症例は広範に不可逆性の脳組織障害が生じた難治例と考えられた．脳幹の萎縮が進行する前に免疫治療を介入すべき疾患であり，精神症状と運動失調症がみられる症例では診断に有用である髄液IL-6を測定することが望ましい．</p>

DOI： 10.5692/clinicalneurol.cn-001086

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記述言語：日本語   出版者・発行元：日本神経治療学会  

<p>We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2017. This article introduces the outline of therapies with antisense oligonucleotide, docosahexaenoic acid, mesenchymal stem cells, acetyl–DL–leucine, and rehabilitation using wearable devices and virtual reality. We expect that these treatments will contribute to patients with SCD.</p>

DOI： 10.15082/jsnt.35.5_605

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

<p>42歳，男性．全身の発汗低下を主訴に受診した．起立性低血圧や頻尿を伴い，広汎な自律神経障害が示唆された．皮膚生検で汗腺及び血管周囲にリンパ球浸潤を認め，抗ganglionicアセチルコリン受容体抗体陽性が判明した．通常，同抗体は自己免疫性自律神経節障害（autoimmune autonomic ganglionopathy：AAG）の原因となるが，汗腺への直接作用は明らかでない．本症例には汗腺と自律神経節障害の両者の特徴が混在し，ステロイド治療が有効であった．</p>

DOI： 10.2169/naika.107.95

記述言語：英語   出版者・発行元：Virology Journal  

DOI： 10.1186/s12985-017-0902-6

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

DOI： 10.1111/jns.12234

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DOI： 10.11477/mf.1416200923

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出版者・発行元：Parkinsonism and Related Disorders  

DOI： 10.1016/j.parkreldis.2017.08.012

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

DOI： 10.1186/s12985-017-0802-9

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出版者・発行元：Journal of the Neurological Sciences  

DOI： 10.1016/j.jns.2017.05.015

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記述言語：英語   出版者・発行元：Genes to Cells  

DOI： 10.1111/gtc.12500

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

記述言語：英語   出版者・発行元：Retrovirology  

DOI： 10.1186/s12977-017-0350-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jneuroim

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

DOI： 10.1016/j.jneuroim.2016.09.014

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Spinal Cord Medicine  

DOI： 10.1080/10790268.2015.1114230

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cge.13002.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： Clinical diversity caused by novel IGHMBP2 variants.

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

DOI： 10.1016/j.jns.2016.11.074

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担当区分：最終著者,　責任著者   記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

<p>一部の自己免疫性脳症と精神疾患は臨床徴候が類似することが多く，しばしば誤って診断されている．従来の神経診察法のみで正確に診断することは難しく，脳がびまん性に障害された場合の神経徴候を理解するという視点が必要である．見極めるためには詳細な問診と神経診察が重要であり，SPECT（single photon emission computed tomography），甲状腺自己抗体ならびに抗GluR抗体測定が診断に有用である．</p>

DOI： 10.2169/naika.106.1542

記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は60歳男性．小児期より運動後の筋疲労感や褐色尿を自覚したが症状は軽微であった．45歳頃より両下肢遠位部優位の筋萎縮，感覚障害が進行した．神経伝導検査で軸索型末梢神経障害を呈し，シャルコー・マリー・トゥース病（Charcot-Marie-Tooth disease; CMT）が疑われた．55歳より横紋筋融解症を繰り返すようになり，血清アシルカルニチン分析と遺伝子検査から三頭酵素欠損症と診断した．三頭酵素欠損症は先天性脂質代謝異常症の稀な一型であるが，末梢神経障害を合併してCMTに類似した臨床所見を呈しうる．筋症状を伴う進行性の末梢神経障害をみた場合，積極的に本疾患を疑って精査すべきである．</p>

DOI： 10.5692/clinicalneurol.cn-000976

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記述言語：日本語   出版者・発行元：日本神経学会  

<p>症例は59歳男性．両親がいとこ婚であり，50歳より下肢筋力低下・下肢遠位のじんじん感が出現し，緩徐に進行した．<i>MME</i>遺伝子変異をもつことが判明しautosomal-recessive Charcot-Marie-Tooth disease 2T（AR-CMT2T）と診断した．四肢筋力に左右差があり，後天性脱髄性変化を示す末梢神経伝導検査所見と神経生検結果から慢性炎症性脱髄性多発根ニューロパチー（chronic inflammatory demyelinating polyneuropathy; CIDP）の合併と考え，免疫グロブリン大量静注療法（intravenous immunoglobulin; IVIg）を行うことで症状の改善がみられた．本例は軸索型CMTにCIDPが合併した初の症例報告である．</p>

DOI： 10.5692/clinicalneurol.cn-001036

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担当区分：最終著者   出版者・発行元：日本神経学会  

<p>30年以上にわたり四肢の筋萎縮を呈した44歳男性の筋萎縮性側索硬化症（amyotrophic lateral sclerosis; ALS）4を報告する．患者は10歳代に発症し20歳代に遺伝性痙性対麻痺（hereditary spastic paraplegia; HSP）と診断された．自覚症状はないものの腓腹神経の軸索障害を認めた．父・叔父もHSPと診断されていた．父は73歳．20歳代に歩行障害を呈し60歳代で下肢の運動機能がほぼ消失し，今回の診察で四肢筋萎縮，温度覚・振動覚・関節位置覚の障害を認めた．遺伝子検査で共にsenataxin（<i>SETX</i>）遺伝子変異（c.8C>T,p.T3I）を認め，ALS4の1家系と判明した．ALS4はHSPと臨床所見が類似している点もあり，遺伝子検査なしにHSPと診断された家系にALS4家系が潜んでいる可能性が考えられた．</p>

DOI： 10.5692/clinicalneurol.cn-000996

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jns.2016.10.030.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jns.12193

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/jnnp-2015-312646

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ped.13152

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S1474-4422(16)30157-0.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.braindev.2016.05.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：医学書院  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12977-016-0263-z.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12974-016-0533-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/mus.25067

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：学位論文（博士）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

PubMed

担当ページ：237-239   記述言語：日本語 著書種別：学術書

記述言語：日本語 著書種別：学術書

CiNii Books

CiNii Books

総ページ数：3000   担当ページ：428-433   記述言語：日本語 著書種別：教科書・概説・概論

総ページ数：278   担当ページ：230-237   記述言語：日本語 著書種別：学術書

総ページ数：328   担当ページ：267-273   記述言語：日本語 著書種別：学術書

総ページ数：155   担当ページ：29-36   記述言語：日本語 著書種別：学術書

総ページ数：155   担当ページ：37-40   記述言語：日本語 著書種別：学術書

記述言語：英語 著書種別：学術書

J-GLOBAL

記述言語：英語   出版者・発行元：eNeurologicalSci  

We present pathology of the peripheral nerves of a patient with Adult-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation p.D651N. The patient was a 72-year-old woman. She had hoarseness and underwent continuous positive airway pressure therapy at night due to sleep apnea. The patient died abruptly. Remarkable demyelination with tomacula formation was found in the phrenic nerve, vagal nerve, recurrent laryngeal nerve, and oculomotor nerves. The cause of death could have been insufficient reactivity to the aspiration or sudden onset of bilateral vocal cord palsy. We must pay attention to respiratory function and cranial nerve palsies in hereditary demyelinating neuropathies.

DOI： 10.1016/j.ensci.2021.100358

Scopus

PubMed

DOI： 10.5692/clinicalneurol.cn-001558

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

担当区分：責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

担当区分：責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

担当区分：最終著者   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

J-GLOBAL

担当区分：最終著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）   出版者・発行元：医学書院  

担当区分：責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

担当区分：責任著者   記述言語：日本語  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

担当区分：責任著者   記述言語：日本語  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

担当区分：責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

DOI： 10.1016/j.jns.2019.116623

Scopus

PubMed

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

DOI： 10.2169/naika.108.1515

記述言語：日本語   出版者・発行元：日本末梢神経学会  

J-GLOBAL

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

DOI： 10.1111/1346-8138.14336

Scopus

PubMed

出版者・発行元：John Wiley & Sons Australia, Ltd  

記述言語：日本語   出版者・発行元：(一社)日本臨床神経生理学会  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.35.5_605

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：中外医学社  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：科学評論社  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：日本神経治療学会  

DOI： doi.org/10.15082/jsnt.35.4_536

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：中外医学社  

出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.34.4_472

担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：日本神経治療学会  

DOI： 10.15082/jsnt.35.4_528

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

DOI： https://doi.org/10.11477/mf.1416200923

記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

DOI： https://doi.org/10.11477/mf.1416200881

記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   出版者・発行元：(一社)日本内科学会  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

DOI： https://doi.org/10.5692/clinicalneurol.cn-000976

出版者・発行元：Journal of the Neurological Sciences  

DOI： 10.1016/j.jns.2016.11.074

Scopus

PubMed

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語  

J-GLOBAL

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

開催年月日： 2021年9月

開催地：WEB開催  

開催年月日： 2021年8月

開催年月日： 2021年6月

開催地：WEB開催  

開催年月日： 2021年6月

記述言語：日本語  

開催地：WEB開催