Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>We report a patient with myelin oligodendrocyte glycoprotein (MOG) antibody positivity who manifested myelitis with right optic perineuritis (OPN) 6 years following left OPN. A 45-year-old man treated 6 years previously for left OPN developed ascending numbness in both legs, urinary dysfunctions, and constipation. Neurologic examination disclosed bilateral hypesthesia extending downward over the chest from the T8 level. No motor weakness was evident. Visual field testing showed dense peripheral constriction with intact central vision on the right and a smaller superior scotoma on the left. Visual acuity and funduscopic findings were normal. Results of routine serologic investigations and autoimmune antibody titers, including those of anti-aquaporin 4 antibody, were within normal limits, except that both serum and cerebrospinal fluid were positive for anti-MOG antibody. MRI displayed a longitudinal cord lesion extending from T2 to T9, as well as optic nerve sheath enhancement characteristic of OPN. The patient was diagnosed with myelitis in addition to OPN, both resulting from MOG antibody-associated demyelination. Patients with myelitis, require careful assessment of visual acuity and visual fields to detect possible accompanying OPN and ON. We suspect that OPN in some other patients may likewise be caused by anti-MOG antibody.</p>

DOI： 10.5692/clinicalneurol.cn-001705

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Language：Japanese  

DOI： 10.1038/s10038-022-01031-2

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

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

DOI： 10.1038/s10038-022-01019-y

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

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

DOI： 10.1038/s10038-021-01005-w

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Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>A 67-year-old man presented slowly progressive weakness of the extremities visited our hospital. Nerve conduction study showed axonal neuropathy and needle electromyography showed neurogenic changes with denervation findings in multiple limb muscles. While he was diagnosed as Probable amyotrophic lateral sclerosis (ALS), which is defined by the Awaji criteria for diagnosis of ALS, he did not develop either respiratory muscle paralysis or bulbar palsy, which are characteristic symptoms of sporadic ALS. Genetic testing revealed a novel gene variant in senataxin (<i>SETX</i>), the causative gene of ALS4. We could not make a definite diagnosis of ALS4 because he had no relatives who could perform genetic testing (segregation study). However, we considered the variant can be pathogenic because it was not previously reported and absent in at least 1,000 healthy control individuals, the variant site was highly conserved in mammals, and it may impair the function of senataxin protein (<i>in silico</i> analysis).</p>

DOI： 10.5692/clinicalneurol.cn-001675

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<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), X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) (moderate PRS-1 deficiency), Arts syndrome (severe PRS-1 deficiency), and PRS-1 superactivity1. 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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Language：English   Publisher：The Japanese Society of Internal Medicine  

<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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Language：English   Publisher：(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。

Authorship：Last author   Language：English  

DOI： 10.1186/s12883-021-02418-y

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Language：English  

DOI： 10.1007/s12311-021-01323-x

DOI： 10.1007/s12311-021-01323-x

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Language：English  

DOI： 10.1007/s00415-021-10467-z.

DOI： 10.1016/j.ensci.2021.100358

DOI： 10.2169/internalmedicine.7247-21.

Authorship：Last author   Language：Japanese  

DOI： 10.1016/j.clineuro.2021.106602

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Authorship：Last author,　Corresponding author  

DOI： 10.5692/clinicalneurol.cn-001558

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

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

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

DOI： 10.1111/cge.13881

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Language：English  

DOI： 10.1007/s00415-021-10467-z

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Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>We report a case of a 60-year-old man who presented with symptoms of memory loss, gait disorder, and sluggish movement. We considered both Parkinson's disease and multiple system atrophy as possible diagnoses and consequently hospitalized the patient owing to the worsening symptoms and the development of consciousness disorder. During the course of the disease, dementia, loss of consciousness, and movement disorders worsened rapidly within one year after admission, and the patient eventually developed mutism. The significant clinical characteristics of our case included no myoclonus and involuntary tremors in the extremities. There was no periodic synchronous discharge on electro­encephalography and cranial MRI with diffusion-weighted images showed no high-intensity findings in cortex. Prion protein genetic analysis identified four repeated insertional mutations in the octapeptide repeat (OPR) region, and the patient was diagnosed with inherited Creutzfeldt–Jakob disease. Cases of OPR insertional mutations are a few in Japan and occur in about 10% of population in Europe. Creutzfeldt–Jakob disease with OPR insertional mutation shows various clinical manifestations and atypical findings on electroencephalography and cranial MRI. Diagnosing for Creutzfeldt–Jakob disease with OPR insertional mutation is important in Prion protein<i> </i>genetic analysis.</p>

DOI： 10.5692/clinicalneurol.cn-001558

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Publisher：Entomological Science  

DOI： 10.1111/ens.12469

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Language：Japanese   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.38.6_S178

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

<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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Language：English   Publisher：Journal of Neurology, Neurosurgery and Psychiatry  

DOI： 10.1136/jnnp-2020-323960

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Authorship：Corresponding author   Language：English  

DOI： 10.2169/internalmedicine.4629-20.

Language：English   Publisher：PLoS Neglected Tropical Diseases  

DOI： 10.1371/journal.pntd.0008361

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

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.

DOI： 10.1111/jns.12369

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

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

DOI： 10.1136/jnnp-2019-32

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

<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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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<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

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

DOI： 10.1136/jnnp-2018-318839

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Authorship：Lead author   Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<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

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Neurology  

DOI： 10.1111/ene.13750

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background and purpose: Gerstmann-Sträussler-Scheinker syndrome is a rare hereditary neurodegenerative disorder with clinical heterogeneity. This study is aim to demonstrate the clinical spectrum and radiologic characteristics of patients caused by Pro102Leu mutation in PRNP. Materials and methods: We retrospect clinical manifestations of five patients from four Japanese families, and comprehensively analyzed their brain MRI, SPECT (N-isopropyl-p-[123I] iodoamphetamine), and PET (18F-2-fluoro-2-deoxy-D-glucose) images. Results: All patients developed ataxia of lower limbs and trunk, gait disturbance, dysesthesia in legs, and lower limb hyporeflexia. In the early clinical stage before dementia began, no noticeable abnormalities could be observed from brain MRI, but SPECT and PET revealed mosaic-like pattern of blood flow and glucose metabolism of the brain. Predominant abnormalities were found in the occipital and frontal lobes on SPECT and PET analysis, respectively. In SPECT analysis, blood flow of the anterior cerebellar lobes was lower than that of the posterior cerebellar lobes. Conclusions: Clinical symptoms resulting from failure of dorsal horn of spinal cord and spinocerebellar tracts were observed in all cases. Radiologic findings revealed individual differences of involved region in their brain, which could produce clinical diversity. We identified a downtrend of blood flow in the anterior cerebellar lobes, a projection field of the spinocerebellar tracts, which is an important feature of Gerstmann-Sträussler-Scheinker syndrome.

DOI： 10.1016/j.jns.2018.05.012

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

Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

DOI： 10.1093/brain/awy104

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Authorship：Last author,　Corresponding author   Language：English  

SH3TC2, known as the causative gene of autosomal recessive demyelinating Charcot-Marie-Tooth type 4C (CMT4C), was also found linked to a mild mononeuropathy of the median nerve with an autosomal dominant inheritance pattern. Using DNA microarray, Illumina MiSeq, and Ion proton, we carried out gene panel sequencing among 1483 Japanese CMT patients, containing 397 patients with demyelinating CMT. From seven patients with demyelinating CMT, we identified eight recessive variants in the SH3TC2 gene, consisting of five novel (pathogenic/likely pathogenic) and three reported variants. Additionally, from two patients with axonal CMT, we detected a reported recessive variant, p.Arg77Trp, which was herein reclassified as variant with unknown significance. Of the seven CMT4C patients (six females and one male), 2/7 patients developed symptoms at their first decade, and 5/7 patients lost their ambulation around age 50. Scoliosis was observed from more than half (4/7) of these patients, whereas hearing loss is the most common symptom of central nervous system (6/7). No median nerve mononeuropathy was recorded from their family members. We identified recessive variants in SH3TC2 from 1.76% of demyelinating CMT patients. An uncommon gender difference was recognized and the wild spectrum of these variants suggests mutational diversity of SH3TC2 in Japan.

DOI： 10.1038/s10038-017-0388-5

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Inc.  

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

DOI： 10.1111/jns.12252

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Authorship：Last author,　Corresponding author   Language：English   Publisher：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。

Authorship：Last author   Language：English  

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 TRK-fused gene (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.

DOI： 10.5582/irdr.2017.01084

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Authorship：Lead author   Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<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

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

DOI： 10.1111/cge.13037

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：Brain and Nerve  

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Language：English  

DOI： 10.1093/jnen/nlx068

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Authorship：Last author,　Corresponding author  

DOI： 10.11477/mf.1416200881

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：Brain and Nerve  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background and purpose: The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of Charcot-Marie-Tooth disease (CMT) type 2Z in 2016. We aimed to describe the clinical and mutational spectrum of patients with CMT harboring MORC2 mutations in Japan.
Methods: We analyzed samples from 781 unrelated patients clinically diagnosed with CMT using deoxyribonucleic acid microarray or targeted resequencing by next-generation sequencing, and samples from 434 mutation-negative patients were subjected to whole-exome sequencing. We extracted MORC2 variants from these whole-exome sequencing data and classified them according to American College of Medical Genetics standards and guidelines.
Results: We identified MORC2 variants in 13 patients. As the second most common causative gene of CMT type 2 after MFN2, MORC2 variants were detected in 2.7% of patients with CMT type 2. The mean age of onset was 10.3 +/- 8.7 years, and the inheritance pattern was mostly sporadic (11/13 patients, 84.6%). The clinical phenotype was typically length-dependent polyneuropathy, and electrophysiological studies revealed sensory-dominant axonal neuropathy. Mental retardation was identified in 4/13 patients (30.8%). p.Arg190Trp, as a mutational hotspot, was observed in eight unrelated families. We also identified two novel probably pathogenic variants, p.Cys345Tyr and p.Ala369Val, and one novel uncertain significance variant, p.Tyr332Cys.
Conclusions: Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.

DOI： 10.1111/ene.13360

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Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Charcot Marie Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C&gt;T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby. further expanding the clinical spectrum of CMT4H. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.nmd.2017.07.011

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Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1016/j.jns.2017.08.2017

Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1016/j.jns.2017.08.2017

Authorship：Last author,　Corresponding author   Publisher：WILEY  

Charcot-Marie-Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1,334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole-exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 +/- 14 (range 0-59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co-occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is themost frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2-related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity.

DOI： 10.1111/jns.12228

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

BackgroundMutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.
Materials and MethodsFrom April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing.
ResultsWe identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C&gt;T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C&gt;T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G&gt;A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy.
ConclusionWe identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.

DOI： 10.1111/cge.13002

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Authorship：Last author,　Corresponding author   Language：English   Publisher：NATURE PUBLISHING GROUP  

Immunoglobulin helicase mu-binding protein 2 (IGHMBP2) gene is responsible for Charcot-Marie-Tooth disease (CMT) type 2S and spinal muscular atrophy with respiratory distress type 1 (SMARD1). From June 2014 to December 2015, we collected 408 cases, who referred to our genetic laboratory for genetic analysis, suspected with CMT disease or other inherited peripheral neuropathies (IPNs) on the basis of clinical manifestations and electrophysiological studies. Mutation screening was performed using Ion AmpliSeq Custom Panels, which comprise 72 disease-causing or candidate genes of IPNs. We identified novel homozygous or compound heterozygous variants of IGHMBP2 in four patients. Three patients presented with childhood-onset axonal predominant sensorimotor polyneuropathies, whereas the other case was diagnosed with SMARD1, manifesting as low birth weight, weak cry, reduced spontaneous movement and developed respiratory distress 4 months after birth. We present the original report of CMT type 2S in Japan, and illustrate that recessive IGHMBP2 variants account for similar to 1.6% of axonal CMT in our cohort.

DOI： 10.1038/jhg.2017.15

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Authorship：Last author,　Corresponding author   Language：English   Publisher：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。

Publisher：SAGE Publications Inc.  

We present three cases of anomalous origin of the left vertebral artery (LVA) detected during the evaluation of stroke. The VA usually enters the transverse foramen of the sixth cervical vertebra (C6), but an anomalous LVA originating from the aorta frequently enters at a higher level. In our series, ultrasound of the LVA showed entry at C4 in two patients and at C5 in one patient. These findings suggested anomalous LVA origin, and three-dimensional computed tomography demonstrated the LVA arising from the aorta proximal to the left subclavian arteries. Carotid duplex ultrasound is useful for the diagnosis of this anomaly.

DOI： 10.1177/1971400916687585

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Language：English  

OBJECTIVE: To describe the autopsy case of a patient with a homozygous 2-base deletion, c171_172delGA (p.N58fs), in the C12orf65 gene. METHODS: We described the clinical history, neuroimaging data, neuropathology, and genetic analysis of the patients with C12orf65 mutations. RESULTS: The patient was a Japanese woman with a history of delayed psychomotor development, primary amenorrhea, and gait disturbance in her 20s. She was hospitalized because of respiratory failure at the age of 60. Pectus excavatum, long fingers and toes, and pes cavus were revealed by physical examination. Her IQ score was 44. Neurologic examination revealed ophthalmoplegia, optic atrophy, dysphagia, distal dominant muscle weakness and atrophy, hyperreflexia at patellar tendon reflex, hyporeflexia at Achilles tendon reflex, and extensor plantar reflexes. At age 60, she died of pneumonia. Lactate levels were elevated in the patient's serum and CSF. T2-weighted brain MRI showed symmetrical hyperintense brainstem lesions. At autopsy, axial sections exposed symmetrical cyst formation with brownish lesions in the upper spinal cord, ventral medulla, pons, dorsal midbrain, and medial hypothalamus. Microscopic analysis of these areas demonstrated mild gliosis with rarefaction. Cell bodies in the choroid plexuses were eosinophilic and swollen. Electron microscopic examination revealed that these cells contained numerous abnormal mitochondria. Whole-exome sequencing revealed the 2-base deletion in C12orf65. CONCLUSIONS: We report an autopsy case of the C12orf65 mutation, and findings suggest that mitochondrial dysfunction may underlie the unique clinical presentations.

DOI： 10.1212/NXG.0000000000000171

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Authorship：Lead author   Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.106.1598

Authorship：Lead author   Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<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

Authorship：Lead author   Language：Japanese   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.34.6_S136

Language：Japanese   Publisher：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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Language：Japanese   Publisher：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

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Language：English   Publisher：The Japanese Society of Internal Medicine  

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

DOI： 10.2169/internalmedicine.2943-23

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

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

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

Language：Japanese   Publisher：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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Language：Japanese   Publisher：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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Language：Japanese   Publisher：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

Language：English   Publisher：The Japan Neurosurgical Society  

<p>Herein, we report a case of carotid artery stenting with proximal flow protection for severe stenosis of the left internal carotid artery using transbrachial and transradial artery approaches. Because an abdominal aortic aneurysm was present, we avoided the transfemoral approach. The procedure was successfully performed with a combination of an 8-Fr balloon guide catheter and microballoon catheter on separate axes. No complications such as pseudoaneurysm, thrombosis, or dissection were observed at the puncture site. The patient was discharged without complications and showed good outcomes at 3 months. This technique may offer a useful alternative for patients with severe stenosis who cannot be treated using a femoral artery approach.</p>

DOI： 10.2176/jns-nmc.2023-0071

PubMed

Language：Japanese   Publisher：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

Language：English   Publisher：(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。

Language：English   Publisher：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。

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

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

Language：English   Publisher：Scientific Reports  

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

DOI： 10.1038/s41598-023-45011-8

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PubMed

Language：English   Publisher：(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。

Language：English   Publisher：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。

Language：English   Publisher：The Japanese Society of Internal Medicine  

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

DOI： 10.2169/internalmedicine.0061-22

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PubMed

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

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

Language：Japanese   Publisher：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

Language：Japanese   Publisher：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

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

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

DOI： 10.1136/jnnp-2022-330769

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PubMed

Language：English   Publisher：(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。

Language：English   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.0969-22

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PubMed

Language：English   Publisher：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

Language：English   Publisher：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

Language：Japanese   Publisher：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

Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<p>The discovery and approval of novel treatments and vaccines are altering the trajectory of neuroinfectious illnesses.</p><p>As for bacterial meningitis, the pneumococcal vaccine and Haemophilus influenzae type b vaccine have reduced the incidence of bacterial meningitis in children. The pneumococcal vaccine is now routinely administered to adults as well to prevent pneumonia, but problems of serotype substitution have arisen, including for children. Additionally, recently approved medications for the treatment of systemic myasthenia gravis and neuromyelitis optica spectrum diseases, such as eculizumab and labulizumab, increase the risk of meningococcal infection in adults and may result in meningitis. As a result, it is critical to immunize patients against meningococcal meningitis before administration and to describe the risks to the patient and family.</p><p>For tetanus, additional immunization with absorbed tetanus toxoid or concomitant use of human tetanus immune globulin should be taken into account, depending on the condition of the wound. According to an evaluation of contamination, wound depth, and consequences from neuropathy or ischemia, aggressive debridement should be taken into consideration for non–open wounds.</p><p>Vaccines for shingles have been approved for patients over 50 years of age, both live attenuated vaccines and genetically engineered vaccines. Given that both are successful in avoiding the disease's start, it is important to recognize the benefits and drawbacks of each and employ them appropriately.</p><p>The Japanese encephalitis virus, a flavivirus, is subject to routine vaccination in childhood, but it is known that the antibody retention rate declines in adults, and additional vaccination should be considered for those who work in rural areas in endemic areas. Although Japan has not licensed a vaccine for the tick–borne encephalitis virus, the administration should be taken into account if the individual will be living in an area where it is common or will be visiting a forest.</p><p>There is also disagreement over the effectiveness of long–term SARS–CoV–2 vaccines, and further understanding of the etiology is preferred.</p>

DOI： 10.15082/jsnt.40.2_99

Language：Japanese   Publisher：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

Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>Pathogenic variants in<i> Gap Junction Protein Beta 1</i> (<i>GJB1)</i> 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.173 C>A (p. P58H), in the <i>GJB1</i> gene. Patients with variants at codon 58 in <i>GJB1</i> showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of <i>GJB1</i> variants. </p>

DOI： 10.2169/internalmedicine.1403-22

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PubMed

Language：Japanese   Publisher：Societas Neurologica Japonica  

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

DOI： 10.5692/clinicalneurol.cn-001822

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PubMed

Language：English   Publisher：The Japanese Society of Internal Medicine  

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

DOI： 10.2169/internalmedicine.1713-23

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PubMed

Language：Japanese   Publisher：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

Language：Japanese   Publisher：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

Language：English   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.2704-23

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PubMed

Language：Japanese   Publisher：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

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

DOI： 10.34397/jsnd.28.1_1

Language：Japanese   Publisher：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

Language：Japanese   Publisher：Clinical and Experimental Neuroimmunology  

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

DOI： 10.1111/cen3.12764

Scopus

Language：English   Publisher：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

Language：Japanese   Publisher：Societas Neurologica Japonica  

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

DOI： 10.5692/clinicalneurol.cn-001870

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PubMed

Language：Japanese   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.40.6_s199

Language：Japanese   Publisher：Societas Neurologica Japonica  

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

DOI： 10.5692/clinicalneurol.cn-001915

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PubMed

Language：Japanese   Publisher：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

Language：Japanese   Publisher：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

Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

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

DOI： 10.15082/jsnt.40.5_707

Language：Japanese   Publisher：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

Language：Japanese   Publisher：The Japanese Society of Child Neurology  

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

DOI： 10.11251/ojjscn.55.448

Scopus

Publisher：医歯薬出版  

DOI： 10.32118/ayu283101038

Language：Japanese   Publisher：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

Language：English   Publisher：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

Language：Japanese   Publisher：株式会社医学書院  

DOI： 10.11477/mf.1416202227

PubMed

Language：English   Publisher：(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。

Language：Japanese   Publisher：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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Language：Japanese   Publisher：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

Language：English   Publisher：(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。

Language：English   Publisher：(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。

Language：Japanese   Publisher：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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Language：Japanese   Publisher：Neurology and Clinical Neuroscience  

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

DOI： 10.1111/ncn3.12660

Scopus

Language：Japanese   Publisher：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

Scopus

PubMed

Language：Japanese   Publisher：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

Language：English   Publisher：Nature Publishing Group  

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

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

Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

DOI： 10.3390/biomedicines10071546

Scopus

PubMed

Language：Japanese   Publisher：The Japanese Congress on Neurological Emergencies  

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

DOI： 10.11170/jjsnecc.34.2_21

Language：English   Publisher：(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。

Language：English   Publisher：Nature Publishing Group  

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

Language：English   Publisher：(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。

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

BACKGROUND: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. METHODS: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. RESULTS: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

DOI： 10.1002/acn3.51555

Scopus

PubMed

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214347

Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>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 fluid-attenuated 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. </p>

DOI： 10.2169/internalmedicine.9326-22

Scopus

PubMed

Language：Japanese   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.39.4_540

Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

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

DOI： 10.15082/jsnt.39.5_773

Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<p>Medical scientists are asked to make various judgments when new diseases emerge, such as COVID–19, but even for these experts, their judgments are often incorrect. Experts always attempt to convince the public using a term “science–based evidence” but, in many cases, without real solid evidence. There are massive of unexplained diseases and pathogenicity in neurology. In order to discover and elucidate new diseases and their pathophysiological conditions, it is important to carefully examine and investigate each patient, followed by a persistent tracing sincerely and deeply. Medicine is still developing, and to make the neurology more practical and useful for the world, I would like to expect flexibility, innovation, and conscience from doctors with neurological expertise.</p>

DOI： 10.15082/jsnt.39.1_3

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

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

DOI： 10.3389/fneur.2022.986504

Scopus

PubMed

Language：Japanese   Publisher：The Japanese Society of Child Neurology  

<p>  Transient cerebral manifestations resembling mild encephalopathy with a reversible splenial lesion (MERS) type-2 have been reported in patients with X-linked Charcot-Marie-Tooth disease type-1 (CMTX1). Here, we report the case of two brothers with MERS type-2, who was later diagnosed with CMTX1. The 12-year-old younger brother developed an altered state of consciousness, quadriplesia, and dysarthria after an acute phase of mycoplasma pneumonia. We diagnosed MERS type-2 after diffusion-weighted magnetic resonance imaging revealed transient symmetric hyperintensity lesions in the splenium of the corpus callosum and cerebral white matter. We suspected CMTX1 because his older brother had previously suffered from MERS type-2 and further examination of the lower limbs revealed a persistent absence of deep tendon reflexes, high-arched feet, and “inverted champagne bottle” legs in both mother and brothers. Presence of the <i>GJB1</i> missense mutation—NM_000166.6 (GJB1) : c. 77C>T (p. Ser26Leu) —was later confirmed in the younger brother. In cases of MERS type-2 with cerebral focal sign and without seizure, CMTX1 is considered as an underlying condition, but motor symptoms may be unnoticeable in childhood. Therefore, it is crucial to examine carefully lower limbs signs which can appear as early symptoms, not only in probands but also in their family.</p>

DOI： 10.11251/ojjscn.54.56

Scopus

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

<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Interpretation</h4>l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP.<h4>Trial registration number</h4>UMIN000023854.

DOI： 10.1002/acn3.51715

Scopus

PubMed

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

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

Language：Japanese   Publisher：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

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

Publishing type：Research paper (scientific journal)  

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

Language：English  

DOI： 10.1128/JCM.03230-20

PubMed

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.110.598

Language：Japanese   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.38.3_369

Publisher：株式会社医学書院  

DOI： 10.11477/mf.2425201205

Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>We herein report a 50-year-old man with alcoholic cirrhosis who developed loss of consciousness and tremor of the upper limbs. Magnetic resonance imaging findings were suggestive of limbic encephalitis with bilateral hippocampal damage, and a cerebrospinal fluid (CSF) examination confirmed anti-N-methyl-D-aspartate (NMDA) and anti-glutamate receptor antibodies. Despite initial corticosteroid therapy, meningeal irritation symptoms appeared, owing to the development of cryptococcal meningitis (CM), diagnosed by the detection of cryptococcal capsular polysaccharide antigen in the follow-up CSF analysis. Cerebral infarction with reversible stenosis of major cerebral arteries during the clinical course was also observed. Following administration of antifungals and corticosteroids, the number of cells in the CSF gradually declined, and NMDA receptor antibodies disappeared. Our study demonstrates the unique coexistence of CM with anti-NMDA receptor encephalitis in adults. </p>

DOI： 10.2169/internalmedicine.4629-20

Scopus

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本小児神経学会  

Language：English   Publisher：(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。

Publishing type：Research paper (scientific journal)  

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

Publishing type：Research paper (scientific journal)  

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

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PubMed

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

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

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

Language：English  

DOI： 10.1371/journal.pntd.0008361

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本末梢神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本糖尿病学会  

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

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

DOI： doi.org/10.1111/jns.12369

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

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

Publisher：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。

Publisher：Brain and Development  

DOI： 10.1016/j.braindev.2019.10.008

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PubMed

DOI： 10.1002/ams2.565

PubMed

Publisher：(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。

Language：Japanese   Publisher：Japanese Society of Clinical Neurophysiology  

<p>Previous reports showed that some patients with X-linked Charcot–Marie–Tooth disease type 1 (CMTX1) showed favorable response after intravenous immunoglobulin therapy (IVIg). Immunological vulnerability of the myelin is hypothesized to underlie mechanism of such groups. Here, we report a patient with CMTX1 who responded to IVIg. A 51-year-old male became to be easy to stumble from about 46 years old, and developed subacute progression of gait disturbance three months before admission. Examination revealed hammer toes, muscle weakness in the distal four extremities, diminished tendon reflexes, and sensory ataxia. Nerve conduction study showed demyelinating features, fulfilled the criteria for CIDP. IVIg showed favorable effect. However, his symptom gradually worsened several months after IVIg. His mother also had peripheral neuropathy predominantly in the lower limbs. CMT was suspected and genetic test revealed P70S mutation in <i>GJB1</i>. The diagnosis of CMTX1 was made. His symptom improved again after second IVIg, and then, repeated IVIg maintained his symptoms.</p>

DOI： 10.11422/jscn.48.8

Language：Japanese   Publisher：Japanese Society for Neuroinfectious Diseases  

<p>Background : While Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease, the progression of the disease varies from person to person. While some blood or cerebrospinal fluid biomarkers for rapid progression of HAM/TSP have been reported, no clinical parameter associated with rapid progression of HAM/TSP has been identified except for older age. Purpose : We tried to find the initial symptom associated with rapid progression of the disease using registry data on patients ( n=527 ) enrolled in the Japanese HAM/TSP patient registry "HAM-net." We determined the periods from the onset of HAM/TSP to the age of wheelchair use in daily life of all the patients and compared the periods by their initial symptom. Result : Urinary disturbance as an initial symptom was significantly associated with slowly progression of HAM/TSP. Sensory disturbance as an initial symptom was significantly associated with rapid progression. Conclusion : The result showed that Initial symptoms could suggest the disease course of the patients with HAM/TSP.</p>

DOI： 10.34397/jsnd.25.1_146

Language：Japanese   Publisher：The Japanese Society of Child Neurology  

<p>  <i>SUCLA2</i>-related mitochondrial DNA depletion syndrome is known as Leigh syndrome with methylmalonic aciduria. The patient was a 12-year-old girl with non-consanguineous parents. The clinical features included psychomotor retardation, hypotonia, sensorineural hearing impairment, feeding difficulty, growth retardation, muscular atrophy, external ophthalmoplegia, blepharoptosis, gastroesophageal reflux, recurrent vomiting, sagittal craniosynostosis, peripheral axonal neuropathy, restrictive respiratory failure and kyphoscoliosis. Lactate levels in blood and cerebrospinal fluid were elevated at 8 months of age, and brain MRI showed cerebral atrophy. The MRI at 2 years of age revealed hyperintense areas in the bilateral basal ganglia on T2-weighted imaging. Therefore, the patient was diagnosed with Leigh syndrome. Although the serum acylcarnitine profile revealed slightly elevated propionylcarnitine, urine organic acid analysis was decided as normal. At 9 years of age, exome sequencing for the research of peripheral neuropathy revealed novel compound heterozygous variants, NM_003850.2 (SUCLA2) : c.1300del (p.Asp434Metfs^＊8) ＋c.664-1G＞A. Her parents were heterozygous of each variant. A second analysis of urine organic acid showed mildly elevated methylmalonic acid. Muscle biopsy revealed that the activities of complexes Ⅰ and Ⅳ were at the lower limit of the normal range. Thus, the patient was diagnosed with <i>SUCLA2</i>-related mitochondrial DNA depletion syndrome. It is important to pay attention to elevated serum propionylcarnitine and mildly elevated urinary methylmalonic acid levels in patients with mitochondrial diseases.</p>

DOI： 10.11251/ojjscn.52.318

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Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>We describe an additional patient with spastic paraplegia 48 (SPG48). A 52-year-old woman with gradually increasing gait disturbance was admitted to our hospital. When she was 47 years old, acquaintances noted a shuffling gait. Gait worsening was evident at 48 years. Spastic gait was apparent at 50, and she required a walking stick at 54. Her elder brother had similar gait disturbance. No consanguinity was known. Neurologic examination at 52 disclosed spasticity and moderate weakness in the lower limbs. Spasticity and brisk reflexes in all limbs. Laboratory studies including HTLV-1 titer detected no abnormalities. MRI demonstrated mild corpus callosum narrowing and prominent anterior periventricular hyperintensities in fluid attenuation inversion recovery images. In limb muscles, electromyography (EMG) showed a chronic neurogenic pattern including reduced interference. Gene analysis identified compound homozygosity in exon 7 of adaptor-related protein complex 5 subunit zeta 1 (<i>AP5Z1</i>), including a novel frameshift mutation, c.1662_1672del;p.Glu554Hfs*15 in the patient, and a heterozygous missense mutation in asymptomatic family members, including her mother, two siblings, and a daughter. The frameshift mutation is considered a pathogenic variant according to American College of Medical Genetics and Genomics standards and guidelines. Based on clinical features, imaging findings and genetic abnormalities, we diagnosed this patient with SPG48. Mutations in <i>AP5Z1</i>, which encodes the ζ subunit of AP-5, underlie SPG48. The AP-5 adaptor protein complex, which is mutated in SPG48, binds to both spastizin and spatacsin. While hereditary spastic paraplegias generally are clinically and genetically heterogenous, SPG48, SPG11, and SPG15 are clinically similar.</p>

DOI： 10.5692/clinicalneurol.60.cn-001419

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PubMed

Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>Disaster countermeasures have been implemented by the Japanese Society of Neurology based on the experience of support to the areas affected by the Great East Japan Earthquake on March 11, 2011. The countermeasures activity began at the end of 2011. We, the Committee for Measures Against Disaster, officially started work in 2014. We developed a support network to urgently deal with patients with intractable neurological disease at the time of disaster and strengthen disaster measures, including effective disaster countermeasure training. During the 2016 Kumamoto earthquake, we realized the need to prepare for natural disasters, leading to a state of emergency, at normal times. A list of vulnerable people should be prepared and the individual support plan for disaster should be confirmed during normal times. Furthermore, during disaster, livelihood support is required for patients with intractable neurological disease living in evacuation centers in affected areas. Therefore, we compiled and published the book, titled "The manual of disaster countermeasures," in 2017. The Committee for Measures Against Disaster in the Japanese Society of Neurology has appointed a liaison officer for patients with intractable neurological disease in each prefecture. The liaison's role of is gathering and disseminating information on the disaster-hit areas, arranging medical support, and coordinating health activities, when natural disasters occur. It is hoped that the liaison officer will play an active role both at normal times and during disaster, even unforeseen ones. Although we hope for the best, we aim to be prepared for the worst.</p>

DOI： 10.5692/clinicalneurol.cn-001493

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PubMed

Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>The patient was a 29-year-old male. He took his first steps at two-and-a-half years old, but his physical strength deteriorated and he became non-ambulatory at 12 years old. He had respiratory failure at the age of 20, and finally underwent tracheostomy with invasive positive-pressure ventilation (TPPV). He showed distal dominant muscle weakness and atrophy, including the face. Spinal scoliosis was recognized. He had peripheral predominance of sensory disorders. Nerve conduction studies showed a decrease of compound muscle action potential and a reduction of motor nerve conduction velocity. Sensory nerve action potential was not evoked. In genetic analysis, c.23 C> T (p. T8M) heterozygous mutation was found in the senataxin gene (<i>SETX</i>). Although <i>SETX</i> is a causative gene of familial amyotrophic lateral sclerosis type 4 (ALS4), this case suggests that <i>SETX</i> mutation can also cause motor and sensory polyneuropathy.</p>

DOI： 10.5692/clinicalneurol.60.cn-001415

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PubMed

Language：Japanese   Publisher：THE JAPAN DIABETES SOCIETY  

<p>The patient was a 64-year-old woman with a family history of diabetes mellitus who was diagnosed with focal glomerulosclerosis and diabetes mellitus at 40 and 53 years of age, respectively. Five years previously, the patient had switched from oral hypoglycemic drugs to intensive insulin therapy due to poor glycemic control. Three years later, the patient was diagnosed with progressive memory loss that was thought to be the reason for the deterioration in glycemic control. A neurological examination revealed impairment of the higher brain functions and coordination of arm movements. Bilateral white matter lesions with cerebral, brain stem, and cerebellar atrophy were observed on brain MRI. In addition, a left biceps muscle biopsy revealed myopathy accompanied by ragged red fiber, a characteristic finding of mitochondrial diabetes. The re-examination of the renal biopsy specimen that was obtained at 57 years of age was also suggestive of a mitochondrial-related lesion. Surprisingly, the patient's older sister was also diagnosed with mitochondrial diabetes. There are no previous reports of cases in which mitochondrial diabetes was discovered due to poor control as a result of associated cognitive decline. We describe the present case with consideration of the relevant literature.</p>

DOI： 10.11213/tonyobyo.63.344

Scopus

Language：Japanese   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.37.4_634

Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<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

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

BACKGROUND: Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is characterized by adult onset, a slowly progressive course and autosomal dominant inheritance. It remains unclear whether myopathic changes occur histopathologically. METHODS: We encountered 2 patients in a family with a heterozygous p.P285L mutation in TRK-fused gene (TFG), which is known to cause HMSN-P. The affected individuals developed proximal-dominant muscle weakness in their 40s, which slowly progressed to a motor neuron disease-like phenotype. RESULTS: Muscle biopsy showed myopathic pathology including fiber size variability, increased internal nuclei, fiber splitting, and core-like structures, associated with neurogenic changes: large groups of atrophic fibers and fiber type-grouping. Immunohistochemistry revealed sarcoplasmic aggregates of TFG, TDP-43, and p62 without congophilic material. CONCLUSIONS: The present study demonstrates myopathic changes in HMSN-P. Although the mechanisms underlying the skeletal muscle involvement remain to be elucidated, immunohistochemistry suggests that abnormal protein aggregation may be involved in the myopathic pathology.

DOI： 10.1002/mus.26683

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PubMed

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

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

Publisher：(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

Publisher：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。

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.108.1515

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

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

DOI： 10.1038/s41588-019-0459-y

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the Neurological Sciences  

DOI： 10.1016/j.jns.2019.05.023

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PubMed

Publisher：(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。

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

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>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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PubMed

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

Mutations in the HADHB gene induce dysfunctions in the beta-oxidation of fatty acids and result in a MTP deficiency, which is characterized by clinical heterogeneity, such as cardiomyopathy and recurrent Leigh-like encephalopathy. In contrast, milder forms of HADHB mutations cause the later onset of progressive axonal peripheral neuropathy (approximately 50-80%) and myopathy with or without episodic myoglobinuria. The mechanisms linking neuronal defects in these diseases to the loss of HADHB function currently remain unclear. Drosophila has the CG4581 (dHADHB) gene as a single human HADHB homologue. We herein established pan-neuron-specific dHADHB knockdown flies and examined their phenotypes. The knockdown of dHADHB shortened the lifespan of flies, reduced locomotor ability and also limited learning abilities. These phenotypes were accompanied by an abnormal synapse morphology at neuromuscular junctions (NMJ) and reduction in both ATP and ROS levels in central nervous system (CNS). The Drosophila NMJ synapses are glutamatergic that is similar to those in the vertebrate CNS. The present results reveal a critical role for dHADHB in the morphogenesis and function of glutamatergic neurons including peripheral neurons. The dHADHB knockdown flies established herein provide a useful model for investigating the pathological mechanisms underlying neuropathies caused by a HADHB deficiency.

DOI： 10.1016/j.yexcr.2019.03.040

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PubMed

Language：English   Publisher：Neurology Asia  

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

The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.

DOI： 10.1038/s10038-018-0538-4

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PubMed

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

DOI： 10.1016/j.braindev.2018.08.006

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PubMed

Publisher：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。

Publisher：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。

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

Objective 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. Methods and Patients 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. Results 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 PLEC gene and c.421G>C, p.V141L in the ST3GAL6 gene in all affected siblings. Conclusion A new atypical fALS family with a benign clinical course is herein reported. We identified two candidate gene mutations of PLEC and ST3GAL6 linked to this phenotype.

DOI： 10.2169/internalmedicine.2222-18

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PubMed

Language：Japanese   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.36.6_S154

Publisher：Journal of NeuroVirology  

DOI： 10.1007/s13365-018-0704-7

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<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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Authorship：Last author   Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<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

Publishing type：Research paper (scientific journal)  

DOI： 10.5692/clinicalneurol.cn-001221

PubMed

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

DOI： 10.1111/1346-8138.14336

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PubMed

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

Leucine-rich repeat kinase 2 (LRRK2) is the most common causative gene for autosomal dominant Parkinson's disease (PD) and is also known to be a susceptibility gene for sporadic PD. Although clinical symptoms with LRRK2 mutations are similar to those in sporadic PD, their pathologies are heterogeneous and include nigral degeneration with abnormal inclusions containing alpha-synuclein, tau, TAR DNA-binding protein 43, and ubiquitin, or pure nigral degeneration with no protein aggregation pathologies. We discovered two families harboring heterozygous and homozygous c.4332 G > A; p.R1441H in LRRK2 with consanguinity, sharing a common founder. They lived in the city of Makurazaki, located in a rural area of the southern region, the Kagoshima prefecture, in Kyushu, Japan. All patients presented late-onset parkinsonism without apparent cognitive decline and demonstrated a good response to levodopa. We obtained three autopsied cases that all presented with isolated nigral degeneration with no alpha-synuclein or other protein inclusions. This is the first report of neuropathological findings in patients with LRRK2 p.R1441H mutations that includes both homozygous and heterozygous mutations. Our findings in this study suggest that isolated nigral degeneration is the primary pathology in patients with LRRK2 p.R1441H mutations, and that protein aggregation of alpha-synuclein or tau might be secondary changes.

DOI： 10.1186/s40478-018-0617-y

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DOI： 10.1038/s41598-018-33442-7

PubMed

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

DOI： 10.1186/s12883-018-1131-3

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PubMed

Publisher：(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)

Language：English   Publisher：Elsevier Inc.  

Pyruvate dehydrogenase complex deficiency (PDCD) is a common primary cause of defects in mitochondrial function and also can lead to peripheral neuropathy. Pyruvate dehydrogenase E1 component subunit beta (PDHB) is a subunit of pyruvate dehydrogenase E1, which is a well-known component of PDC. In Drosophila melanogaster, the CG11876 (dPDHB) gene is a homolog of human PDHB. In this study, we established a Drosophila model with neuron-specific knockdown of dPDHB to investigate its role in neuropathy pathogenesis. Knockdown of dPDHB in pan-neurons induced locomotor defects in both larval and adult stages, which were consistent with abnormal morphology of the motor neuron terminals at neuromuscular junctions and mitochondrial fragmentation in brains. Moreover, neuron-specific knockdown of dPDHB also shortened the lifespan of adult flies. In addition, flies with knockdown of dPDHB manifested a rough eye phenotype and aberrant photoreceptor axon targeting. These results with the Drosophila model suggest the involvement of PDHB in peripheral neuropathy.

DOI： 10.1016/j.yexcr.2018.02.035

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

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%

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

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

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

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by severe respiratory failure due to diaphragmatic paralysis and distal muscular weakness in early infancy. After an initial decline in respiratory state and motor function until 1-2years of age, residual capabilities reach a plateau. We report the peripheral neuropathological findings of a patient with SMARD1 at 1year and 1month of age, when his muscle strength and respiratory symptoms had deteriorated and then stabilized for several months. Peripheral nerve biopsy revealed severely progressed axonal degeneration. This finding suggests the rapid progression of peripheral axonal neuropathy in SMARD1 that leads to its characteristic clinical course of respiratory failure and paralysis in the early infantile period.

DOI： 10.1016/j.braindev.2017.08.004

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Publisher：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。

Language：English   Publisher：(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。

Language：English   Publisher：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。

Publisher：Nature Publishing Group  

Axonal Charcot-Marie-Tooth disease (CMT) is most frequently caused by mutations in the MFN2 gene (CMT2A) that can lead to various clinical phenotypes. The age at disease onset varies, but most cases occur before adolescence. We report two Japanese sisters who presented with middle-age-onset peripheral neuropathy with distinct clinical features. In the affected sisters, a homozygous missense mutation, c.1894C&gt
T, p.R632W, corresponding to the transmembrane domain of MFN2 was identified
this mutation was heterozygous in another non-affected sibling, demonstrating co-segregation of the genotype and phenotype. The patients developed adult-onset slowly progressive muscle weakness that was predominant in the calf muscles and sensory disturbance. Magnetic resonance imaging revealed diffuse atrophy of the spinal cord, especially in the thoracic segment, and mild atrophy of the parietal lobe and the cerebellum in both patients. Electron microscopy of the sural nerve revealed clusters of round and swollen mitochondria. This is the first case report of adult-onset CMT2A with an autosomal-recessive inheritance pattern. The phenotype caused by the MFN2 mutation in these cases is very mild, considering that the mutation causes middle-aged-onset Charcot-Marie-Tooth even in the homozygous state. The mechanism of MFN2 mutation-induced toxicity is an interesting theme that awaits further investigations.

DOI： 10.1038/s10038-017-0353-3

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

Language：English   Publisher：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。

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

Seipinopathy is an autosomal dominant neurodegenerative disease caused by mutations of the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene. We report the first Japanese case of seipinopathy with a heterozygous mutation of p.N88S in the BSCL2 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 BSCL2 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.

DOI： 10.2169/internalmedicine.8765-16

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

DOI： 10.1007/978-981-13-0529-0_7

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

<p>A 23-year-old man experienced numbness in the perioral region and right arm, and right leg weakness on the second day after drinking a large amount of alcohol during foreign travel. His symptoms disappeared but then reappeared repetitively. Cerebral MRI performed on the third day after onset showed multiple white matter lesions; however, these lesions disappeared 26 days after onset. Neurological examination and nerve conduction studies revealed demyelinating polyneuropathy. Genetic testing for Charcot-Marie-Tooth disease, X-linked dominant 1 (CMTX1) due to <i>GJB1</i> mutation was conducted based on the symptoms of transient central nervous system lesions and polyneuropathy exhibited by the patient and his mother. As a result, a c.530T>C (p.V177A) substitution in exon 2 of <i>GJB1</i> was identified. CMTX1 patients should be advised to avoid excessive drinking because this could induce central nervous system lesions.</p>

DOI： 10.5692/clinicalneurol.cn-001130

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

<p>A 32-year-old woman showed transient central type facial nerve palsy and bulbar symptoms. Brain MRI revealed high intensity signals in the cerebral white matter, splenium of corpus callosum, and posterior limb of internal capsule. Two elder brothers of the patient had distal dominant peripheral neuropathies in four limbs. In this family, the point mutation of GJB1 gene, encoding connexin 32, was revealed and X-linked Charcot-Marie-Tooth disease (CMTX1) was diagnosed. The presented case was a heterozygote of this mutation. She showed severe transient central nervous system (CNS) symptoms and subclinical demyelinating peripheral neuropathy. The CNS symptoms and alterations of brain images were very similar among three siblings. There are many reports on male patients with CMTX1 who show associated CN symptoms, but female patients are very rare. There has been no previous report of a CMTX1 patient similar to the patient presented here. The trigger factors have been recognized at the onset of transient CN symptoms in these cases. The prevention of these factors is important for the management of such patients.</p>

DOI： 10.5692/clinicalneurol.cn-001138

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Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.35.6_S105

Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>A 43-year-old man without a previous episode of uveitis presented with slowly progressive neurological symptoms that appeared within the past year such as dysarthria, ataxic gait, and behavioral changes. Brain MRI findings showed atrophic lesions in the brainstem and cerebellum. Because these clinical symptoms and abnormal MRI findings indicated spinocerebellar degeneration as the initial diagnosis, he was admitted to our hospital. On admission, we noticed that he had non-neurological manifestations of Behçet disease, such as stomatitis, genital ulcers, and folliculitis. HLA-B51 was positive. He also showed pleocytosis (29 cells/mm³, predominantly mononuclear cells) and elevated cerebrospinal fluid (CSF) IL-6 levels (213 pg/m<i>l</i>), hence he was diagnosed with chronic progressive neuro-Behçet disease (CPNBD). The therapeutic effect of a high-dose intravenous methylprednisolone pulse (1,000 mg/day for 3 days) and methotrexate (maximum dosage, 16 mg/week) was poor against both neurological symptoms and CSF findings. Intravenous infliximab therapy (5 mg/kg, 2 weeks) dramatically decreased CSF IL-6 levels (13 pg/m<i>l</i>) but clinical symptoms remained unchanged. MRI findings of extensive cerebral atrophy and increased CSF IL-6 levels at the pretreatment time point reflected irreversible neurological involvement in CPNBD. For cases with progressive psychiatric symptoms and cerebellar ataxia in the early stage of the disease, skin manifestations should be examined immediately, CSF IL-6 levels measured, and immunosuppressive therapy initiated before CPNBD progresses to brainstem atrophy.</p>

DOI： 10.5692/clinicalneurol.cn-001086

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PubMed

Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

<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

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.107.95

Language：English   Publisher：BIOMED CENTRAL LTD  

Background: Chemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/macrophages and T-lymphocytes, and acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
Results: The results showed that: (1) CCL1 was preferentially expressed in HAM/TSP-derived HTLV-1-infected T-cell lines, (2) CCL1 expression was induced along with Tax expression in the Tax-inducible T-cell line JPX9, (3) transient Tax expression in an HTLV-1-negative T-cell line activated the CCL1 gene promoter, (4) plasma levels of CCL1 were significantly higher in patients with HAM/TSP than in HTLV-1-seronegative patients with multiple sclerosis and HTLV-1-infected asymptomatic healthy carriers, and (5) minocycline inhibited the production of CCL1 in HTLV-1-infected T-cell lines.
Conclusions: The present results suggest that elevated CCL1 levels may be associated with the pathogenesis of HAM/TSP. Although further studies are required to determine the in vivo significance, minocycline may be considered as a potential candidate for the long-term treatment of HAM/TSP via its anti-inflammatory effects, which includes the inhibition of CCL1 expression.

DOI： 10.1186/s12985-017-0902-6

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PubMed

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

Guillain-Barre syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (IgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and IgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (5 points) were associated with an increased risk for mechanical ventilation. Patients with IgG &lt;1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and IgG in GBS are clinically relevant in Japan.

DOI： 10.1111/jns.12234

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DOI： 10.11477/mf.1416200923

PubMed

Publisher：ELSEVIER SCI LTD  

Introduction: Although spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia.
Methods: I-123-metaiodobenzyl guanidine (I-123-MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using I-123-iofiupane (I-123-FP-CIT) were performed for the six patients from three SCA2 families.
Results: I-123-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested. DAT SPECT showed decreased uptake in the striatum in all four patients who were scanned, including one patient without parkinsonism. When patterns of uptake were compared to those with Parkinson's disease, most of the patients had minimal reduction uptake in the putamen.
Conclusion: DAT SPECT is expected to be useful in differentiating SCA2 from Parkinson's disease, making an early diagnosis, and allowing early therapeutic intervention. (C) 2017 Published by Elsevier Ltd.

DOI： 10.1016/j.parkreldis.2017.08.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Detection of specific immune responses against cancer/testis antigen NY-ESO-1 was recently reported in patients with adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-infected asymptomatic carriers (ACs). However, the relationship of the responses with the HTLV-1 proviral load (PVL) and the levels of viral gene expression remain unclear.
Findings: We measured plasma levels of autoantibodies to NY-ESO-1 immunogenic tumor antigen in HTLV-1-infected individuals with different clinical status, and in healthy controls. Data were compared to tax and HBZ mRNA levels, and PVL. Plasma anti-NY-ESO-1 antibody was detectable in 13.7% (7/51) of ACs, 29.2% (38/130) of patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 18.9% (10/53) of patients with ATL. Anti-NY-ESO-1 plasma levels were significantly higher in patients with HAM/TSP than in patients with ATL or ACs. Anti-NY-ESO-1 levels were not associated with PVL or the expression levels of tax and HBZ mRNA among HTLV-1-infected individuals, regardless of clinical status.
Conclusions: The present results indicate the strong humoral immune response against NY-ESO-1 in natural HTLV-1 infection, irrespective of the clinical status. The higher immunoreactivity against NY-ESO-1 is not simply associated with the levels of both HTLV-1 gene expression and the number of infected cells in vivo. Rather, it might reflect chronic and generalized immune activation in infected individuals.

DOI： 10.1186/s12985-017-0802-9

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Publisher：ELSEVIER SCIENCE BV  

Bilateral striatal necrosis (BSN) has many causes and is characterized by unique clinical and neuroradiological features. Herein, we report a clinical and genetic analysis of three BSN cases from two independent Japanese families harboring a mitochondrial DNA (mtDNA) 14459G &gt; A mutation located in a coding region of the NADH dehydrogenase subunit 6 gene. In the first family, two male siblings from non-consanguineous parents exhibited similar phenotypes, with infantile-onset generalized dystonia. A third sporadic case involved a male patient with a comparatively milder phenotype characterized by juvenile-onset mild truncal ataxia and parkinsonism. Cerebral magnetic resonance imaging of these cases revealed abnormal signal intensities along the bilateral putaminal area and enlarged lateral ventricle anterior horns caused by caudate nuclear atrophy, particularly in the sibling pair. The sibling-pair cases shared a homoplasmic 14459G &gt; A mutation, and the sporadic case showed heteroplasmy of the same mutation. Additionally, all three cases harbored the 14605A &gt; G single nucleotide polymorphism, which was previously reported as a rare synonymous variation (4.3%) in a Japanese population. Plasmid sequencing revealed a genetic linkage of these two DNA substitutions, suggesting that the three patients shared a genetic founder. Although our mtDNA analysis was only accessible using leukocytes, clinical severity might be associated with homoplasmy or heteroplasmy. In summary, it is important to evaluate potential mtDNA defects in BSN cases, regardless of familial occurrence. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2017.05.015

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PubMed

Language：English   Publisher：WILEY  

Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system. Neuron-specific knockdown of fat shortened the life span and induced the defect in locomotive abilities of adult flies. In consistent with these phenotypes, defects in synapse structure at neuromuscular junction were observed in neuron-specific fat-knockdown flies. In addition, aberrations in axonal targeting of photoreceptor neuron in third-instar larvae were also observed, suggesting that fat involves in axonal targeting. Taken together, the results indicate that Drosophila fat plays an essential role in formation and/or maintenance of neuron. Both VMS and HS show mental retardation and neuronal defects. We therefore consider that these two rare human diseases could possibly be caused by the defect in FAT4 function in neuronal cells.

DOI： 10.1111/gtc.12500

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PubMed

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

Language：English   Publisher：BIOMED CENTRAL LTD  

Background: Although human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP.
Results: The subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p &lt; 0.001) and s-HAM/TSP (p &lt; 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5 alpha in HAM/TSP patients. The patients with TRIM5 alpha 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/10(4) PBMC, p = 0.003). The patients with the 304L variant of TRIM5 alpha had significantly higher PVLs than those with 304H (1669 vs. 595 copies/10(4) PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors.
Conclusions: Transcontinental subtype is susceptible to HAM/TSP, especially in familial cases. Ten common mutations causing amino acid changes in the HTLV-1 gene were specific to the transcontinental subtype. TRIM5 alpha polymorphisms were associated with PVLs, indicating that TRIM5 alpha could be implicated in HTLV-1 replication.

DOI： 10.1186/s12977-017-0350-9

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

DOI： 10.1016/j.jneuroim

Language：English   Publisher：ELSEVIER SCIENCE BV  

Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/rsp) is believed to be the result of "bystander damage" involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI-CaFe), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to -cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell -cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after 18 h of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system. Published by Elsevier B.V.

DOI： 10.1016/j.jneuroim.2016.09.014

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Context: Toxocara canis is a parasite known to cause visceral larva migrans. The infection rarely affects the central nervous system but there have been several reports of myelitis caused by visceral larva migrans due to Toxocara canis. In previous reported cases, the lesions were located in the thoracic or cervical spinal cord. To the best of our knowledge, this is the first report of a lesion involving the lumbosacral region.
Findings: A 60-year-old man developed weakness and dysesthesia in the lower limbs. The symptoms resolved spontaneously, but recurred after five months. One month later, the patient developed pollakiuria and constipation. He was a dog owner and frequently ate raw chicken meat and beef liver. Sagittal T2-weighted image (T2WI) showed swelling and hyperintensity in the spinal cord from T10 to the lumbosacral region and focal nodular enhancement on the posterior segment of the lumbar spinal cord. Blood cell counts showed slight eosinophilia and elevated serum immunoglobulin E level. Cerebrospinal fluid examination showed slight pleocytosis with eosinophilia. Enzyme-linked immunosorbent assay showed high levels of anti-Toxocara antibodies in the serum and cerebrospinal fluid. In addition, confirmatory test by Western blot was positive. The patient was initially treated with intravenous methylprednisolone with slight improvement in muscle weakness. Albendazole was added with a second course of intravenous methylprednisolone. The muscle weakness in the lower limbs improved considerably, and swelling and hyperintensity on T2WI almost disappeared.
Conclusion: Our results suggest that Toxocara canis myelitis cannot be discounted even if the myelitis involves the lumbosacral region.

DOI： 10.1080/10790268.2015.1114230

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PubMed

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

DOI： 10.1111/cge.13002.

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

DOI： Clinical diversity caused by novel IGHMBP2 variants.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jns.2016.11.074

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PubMed

Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.106.1542

Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>A 45-year-old man presented to us due to slowly progressive muscle weakness and sensory disturbances in his lower limbs since his 40's. He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood, which disappeared by age 20. A nerve conduction study showed peripheral axonal neuropathy and then Charcot-Marie-Tooth disease (CMT) was considered as the most likely diagnosis; however, exome sequencing failed to identify a mutation in the known genes of CMTs. Since age 55, he recurrently developed severe rhabdomyolysis that required hospitalization. On suspicion of lipid metabolism disorders, we performed serum acylcarnitine analysis, and which revealed mildly elevated long-chain fatty acids. We re-examined variants obtained via exome sequencing and found a mutation in <i>HADHB</i>. Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid beta-oxidation caused by <i>HADHA</i> or <i>HADHB</i> mutation. It can be a life-threatening multiorgan disorder with early infantile onset, but it can also present in childhood or adolescence with peripheral neuropathy and recurrent rhabdomyolysis. This case of adult-diagnosed MTP deficiency was characterized by slowly progressive peripheral neuropathy masquerading CMT in addition to muscular symptoms. MTP deficiency should be considered in patients with the combination of peripheral neuropathy and recurrent rhabdomyolysis.</p>

DOI： 10.5692/clinicalneurol.cn-000976

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PubMed

Language：Japanese   Publisher：Societas Neurologica Japonica  

<p>We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of <i>MME</i> gene was detected and thus he was diagnosed as autosomal-recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by <i>MME</i> mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of <i>MME</i> gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient.</p>

DOI： 10.5692/clinicalneurol.cn-001036

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PubMed

Authorship：Last author   Publisher：Societas Neurologica Japonica  

<p>We report a 44 years old man with slowly progressive muscular atrophy of the extremities for over 30 years. He experienced difficulty in walking in his 10's and was diagnosed as hereditary spastic paraplegia (HSP) in his 20's. And then, muscle atrophy of the extremities slowly progressed especially in his distal muscles. Sensory axonal neuropathy was detected with sural nerve biopsy. His father and uncle have been diagnosed as HSP in their early days. His father noticed weakness of his leg in his 20's. He lost motor function of the leg in his 60's. In addition, marked disturbance of thermal sensation, vibration, and sense of position were found by physical examination. Our genetic study detected senataxin (<i>SETX</i>) gene mutation (c.8C>T,p.T3I) in the blood of those two patients, and they had been identified as family cases of amyotrophic lateral sclerosis (ALS) 4. As clinical symptoms of ALS4 would be similar to those of HSP at the onset, we suggest considering ALS4 in seeing patients with HSP without gene diagnosis.</p>

DOI： 10.5692/clinicalneurol.cn-000996

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PubMed

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

DOI： 10.1016/j.jns.2016.10.030.

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DOI： 10.1111/jns.12193

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DOI： 10.1136/jnnp-2015-312646

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DOI： 10.1111/ped.13152

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DOI： 10.1016/S1474-4422(16)30157-0.

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DOI： 10.1016/j.braindev.2016.05.003

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DOI： 10.1186/s12977-016-0263-z.

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DOI： 10.1186/s12974-016-0533-7

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DOI： 10.1002/mus.25067

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Language：English   Publishing type：Doctoral thesis  

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

Language：English  

PubMed

Responsible for pages：237-239   Language：Japanese Book type：Scholarly book

Language：Japanese Book type：Scholarly book

CiNii Books

CiNii Books

Total pages：3000   Responsible for pages：428-433   Language：Japanese Book type：Textbook, survey, introduction

Total pages：278   Responsible for pages：230-237   Language：Japanese Book type：Scholarly book

Total pages：328   Responsible for pages：267-273   Language：Japanese Book type：Scholarly book

Total pages：155   Responsible for pages：29-36   Language：Japanese Book type：Scholarly book

Total pages：155   Responsible for pages：37-40   Language：Japanese Book type：Scholarly book

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J-GLOBAL

Language：English   Publisher：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

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DOI： 10.5692/clinicalneurol.cn-001558

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Authorship：Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Authorship：Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Authorship：Last author   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

J-GLOBAL

Authorship：Last author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher：医学書院  

Authorship：Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Authorship：Corresponding author   Language：Japanese  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Authorship：Corresponding author   Language：Japanese  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Authorship：Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

DOI： 10.1016/j.jns.2019.116623

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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

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

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.108.1515

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

J-GLOBAL

Language：English   Publisher：Journal of Dermatology  

DOI： 10.1111/1346-8138.14336

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PubMed

Publisher：John Wiley & Sons Australia, Ltd  

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

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.35.5_605

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：中外医学社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：科学評論社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本神経治療学会  

DOI： doi.org/10.15082/jsnt.35.4_536

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：中外医学社  

Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.34.4_472

Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.35.4_528

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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

Publisher：Journal of the Neurological Sciences  

DOI： 10.1016/j.jns.2016.11.074

Scopus

PubMed

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese  

J-GLOBAL

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Event date： 2021.9

Venue：WEB開催  

Event date： 2021.8

Event date： 2021.6

Venue：WEB開催  

Event date： 2021.6

Language：Japanese  

Venue：WEB開催  

Event date： 2021.6

Language：Japanese  

Venue：WEB開催  

Event date： 2021.6

Language：Japanese  

Venue：WEB開催