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

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

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

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

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

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

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

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

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

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

DOI： 10.1016/j.celrep.2024.114734

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BACKGROUND: Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations. CASE PRESENTATION: A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser. CONCLUSIONS: The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

DOI： 10.1186/s12883-024-03823-9

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Language：Japanese   Publisher：(株)日本プランニングセンター  

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BACKGROUND: Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity. METHODS: We screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion. RESULTS: In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5'-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%-1.26%). CONCLUSIONS: FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.

DOI： 10.1136/jnnp-2024-333541

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DOI： 10.1007/s00401-024-02738-6

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Language：Japanese   Publisher：(一社)日本高次脳機能学会  

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Nogo-Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS.

DOI： 10.1038/s41420-023-01758-7

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Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, autosomal recessive neurodegenerative disorder caused by biallelic AAGGG/ACAGG repeat expansion (AAGGG-exp/ACAGG-exp) in RFC1. The recent identification of patients with CANVAS exhibiting compound heterozygosity for AAGGG-exp and truncating variants supports the loss-of-function of RFC1 in CANVAS patients. We investigated the pathological changes in two autopsied patients with CANVAS harboring biallelic ACAGG-exp and AAGGG-exp. RNA fluorescence in situ hybridization of the two patients revealed CCTGT- and CCCTT-containing RNA foci, respectively, in neuronal nuclei of tissues with neuronal loss. Our findings suggest that RNA toxicity may be involved in the pathogenesis of CANVAS. This article is protected by copyright. All rights reserved.

DOI： 10.1002/ana.26848

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

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

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

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

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

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

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

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

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients.

DOI： 10.1038/s10038-023-01170-0

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

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BACKGROUND: The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. We have recently found biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD). METHODS: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using XL-PCRs and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. RESULTS: Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10 % (0.23-3.18 %; 95 % confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40 - 48 years and their disease course had been unremarkable apart from the early onset. CONCLUSIONS: Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine, if our findings are specific to the Finnish population.

DOI： 10.1111/ene.15717

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This study aimed to test our hypothesis that the cerebellum plays an important role in the generation of the optical-geometric illusion known as the Poggendorff illusion, the mechanism of which has been explained by accumulated experience with natural scene geometry. A total of 79 participants, comprising 28 patients with isolated cerebellar stroke, 27 patients with isolated cerebral stroke and 24 healthy controls, performed Poggendorff illusion tasks and 2 different control tasks. We also investigated core brain regions underpinning changes in the experience of the illusion effect using multivariate lesion-symptom mapping. Our results indicate that patients with isolated cerebellar stroke were significantly less likely to experience the Poggendorff illusion effect than patients with isolated cerebral stroke or healthy controls (74.6, 90.5 and 89.8%, respectively; F(2,76) = 6.675, P = 0.002). However, there were no inter-group differences in the control tasks. Lesion-symptom mapping analysis revealed that the brain lesions associated with the reduced frequency of the Poggendorff illusion effect were mainly centred on the right posteromedial cerebellar region, including the right lobules VI, VII, VIII, IX and Crus II. Our findings demonstrated, for the first time, that patients with cerebellar damage were significantly less likely to experience the Poggendorff illusion effect and that right posteromedial cerebellar lesions played an important role in this effect. These results provide new insight into alterations of a geometric illusion effect in patients with cerebellar disorders and pave the way for future clinical use of the illusion task to detect cerebellar abnormalities.

DOI： 10.1093/braincomms/fcad053

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

Siponimod, which is approved to treat active secondary progressive multiple sclerosis, acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P1) and an agonist of S1P5. S1P1 antagonization, which inhibits lymphocyte egress from lymphoid tissues and subsequent infiltration into the central nervous system (CNS), is considered the main therapeutic mechanism of siponimod. In addition, siponimod's direct effects on CNS glial cells are another potential neuroprotective mechanism because siponimod can penetrate the blood-brain barrier and CNS glial cells express S1P receptors. However, it remains uncertain whether siponimod directly affects CNS glial cells. In this study, we investigated siponimod's effects on astrocytes using mouse primary cultures. Siponimod suppressed nuclear factor kappa B activation and pro-inflammatory cytokine production. Using antagonists for S1P1 and S1P5, we found that siponimod partially exerts its anti-inflammatory effects via S1P1, but not via S1P5. Moreover, siponimod also inhibited histone deacetylase, suggesting that siponimod exerts broad anti-inflammatory effects via S1P1 antagonization and histone deacetylase inhibition. Siponimod might suppress disease progression in multiple sclerosis in part via direct inhibition of astroglial CNS neuroinflammation.

DOI： 10.1016/j.neures.2022.08.003

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BackgroundEndovascular treatment (EVT) for acute large vessel occlusion has proven to be effective in randomized controlled trials. We conducted a prospective cohort study to evaluate the real-world efficacy of EVT in a metropolitan area with a large number of comprehensive stroke centers and to compare it with the results of other registries and RCTs.MethodsWe analyzed the Kanagawa Intravenous and Endovascular Treatment of Acute Ischemic Stroke registry, a prospective, multicenter observational study of patients treated by EVT and/or intravenous tissue-type plasminogen activator (tPA). Of the 2488 patients enrolled from January 2018 to June 2020, 1764 patients treated with EVT were included. The primary outcome was a good outcome, which was defined as a modified Rankin Scale (mRS) of 0 to 2 at 90 days. Secondary analysis included predicting a good outcome using multivariate logistic regression analysis.ResultsThe median age was 77 years and the median National Institute of Health Stroke Scale (NIHSS) score was 18. Pretreatment mRS score 0-2 was 87%, and direct transport was 92%. The rate of occlusion in anterior circulation was 90.3%. Successful recanalization was observed in 88.7%. The median time from onset to recanalization was 193 minutes. Good outcomes at 90 days were 43.3% in anterior circulation and 41.9% in posterior circulation. Overall mortality was 12.6%. Significant predictors for a good outcome were: age, male, direct transfer, NIHSS score, Alberta Stroke Program Early Computed Tomography Score, intravenous tPA, and successful recanalization.ConclusionsEVT in routine clinical use in a metropolitan area showed comparable good outcomes and lower mortality compared to previous studies, despite the high proportion of patients with older age, pretreatment mRS score of > 2, posterior circulation occlusion, and higher NIHSS. Those results may have been associated with more direct transport and faster onset-to-recanalization times.

DOI： 10.1177/17474930221138014

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We developed a diagnostic method for repeat expansion diseases using a long-read sequencer to improve currently available, low throughput diagnostic methods. We employed the real-time target enrichment system of the nanopore GridION sequencer using the adaptive sampling option, in which software-based target assignment is available without prior sample enrichment, and built an analysis pipeline that prioritized the disease-causing loci. Twenty-two patients with various neurological and neuromuscular diseases, including 12 with genetically diagnosed repeat expansion diseases and 10 manifesting cerebellar ataxia, but without genetic diagnosis, were analyzed. We first sequenced the 12 molecularly diagnosed patients and accurately confirmed expanded repeats in all with uniform depth of coverage across the loci. Next, we applied our method and a conventional method to 10 molecularly undiagnosed patients. Our method corrected inaccurate diagnoses of two patients by the conventional method. Our method is superior to conventional diagnostic methods in terms of speed, accuracy, and comprehensiveness.

DOI： 10.1038/s41525-022-00331-y

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

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

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

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

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

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

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

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

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

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

In amyotrophic lateral sclerosis (ALS), neurodegeneration is characterized by distal axonopathy that begins at the distal axons, including the neuromuscular junctions, and progresses proximally in a “dying back” manner prior to the degeneration of cell bodies. However, the molecular mechanism for distal axonopathy in ALS has not been fully addressed. Semaphorin 3A (Sema3A), a repulsive axon guidance molecule that phosphorylates collapsin response mediator proteins (CRMPs), is known to be highly expressed in Schwann cells near distal axons in a mouse model of ALS. To clarify the involvement of Sema3A–CRMP signaling in the axonal pathogenesis of ALS, we investigated the expression of phosphorylated CRMP1 (pCRMP1) in the spinal cords of 35 patients with sporadic ALS and seven disease controls. In ALS patients, we found that pCRMP1 accumulated in the proximal axons and co-localized with phosphorylated neurofilaments (pNFs), which are a major protein constituent of spheroids. Interestingly, the pCRMP1:pNF ratio of the fluorescence signal in spheroid immunostaining was inversely correlated with disease duration in 18 evaluable ALS patients, indicating that the accumulation of pCRMP1 may precede that of pNFs in spheroids or promote ALS progression. In addition, overexpression of a phospho-mimicking CRMP1 mutant inhibited axonal outgrowth in Neuro2A cells. Taken together, these results indicate that pCRMP1 may be involved in the pathogenesis of axonopathy in ALS, leading to spheroid formation through the proximal progression of axonopathy.

DOI： 10.3389/fneur.2022.994676

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We report two patients with autosomal dominant neuronal intranuclear inclusion disease (NIID) harboring the biallelic GGC repeat expansion in NOTCH2NLC to uncover the impact of repeat expansion zygosity on the clinical phenotype. The zygosity of the entire NOTCH2NLC GGC repeat expansion and DNA methylation were comprehensively evaluated using fluorescent amplicon length PCR (AL-PCR), Southern blotting and targeted long-read sequencing, and detailed genetic/epigenetic and clinical features were described. In AL-PCR, we could not recognize the wild-type allele in both patients. Targeted long-read sequencing revealed that one patient harbored a homozygous repeat expansion. The other patient harbored compound heterozygous repeat expansions. The GGC repeats and the nearest CpG island were hypomethylated in all expanded alleles in both patients. Both patients harboring the biallelic GGC repeat expansion showed a typical dementia-dominant NIID phenotype. In conclusion, the biallelic GGC repeat expansion in two typical NIID patients indicated that NOTCH2NLC-related diseases could be completely dominant.

DOI： 10.1016/j.ygeno.2022.110469

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A 39-year-old man exhibited ocular flutter and cerebellar ataxia following a subacute disturbance of consciousness and partial seizure. He was diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy by tissue- and cell-based antibody assays. Brain single-photon emission computed tomography detected a significant increase in blood flow in the fastigial nucleus, a critical region for eye saccade control. Immunotherapies diminished the ocular flutter and reduced hyperperfusion in the fastigial nucleus. This case suggests that autoimmune GFAP astrocytopathy can cause ocular flutter and provides strong imaging evidence supporting the hypothesis that ocular flutter is caused by hyperactivity or disinhibition of the fastigial nucleus.

DOI： 10.1016/j.clineuro.2022.107307

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BACKGROUND: Ultrasonography (US) is a noninvasive and patient-friendly tool for the evaluation of peripheral nerves. In motor neuron diseases, amyotrophic lateral sclerosis (ALS) has been reported to show the atrophy of peripheral nerves on US. However, the US findings are still unclear in spinal and bulbar muscular atrophy (SBMA), an adult-onset lower motor neuron disease caused by an abnormal CAG repeat expansion in the androgen receptor gene. METHODS: We prospectively recruited and evaluated 11 patients with genetically confirmed SBMA and 9 patients with ALS diagnosed according to the revised El Escorial ALS criteria or the Awaji electrodiagnostic criteria. The C5-C7 cervical nerve roots and the median and ulnar nerves were evaluated ultrasonographically. RESULTS: The cross-sectional areas (CSAs) of the C6 and C7 nerve roots, the median nerve in the upper arm and forearm, and the ulnar nerve in the upper arm were smaller in patients with SBMA than those in patients with ALS (p < 0.05), whereas the CSAs of the C5 nerve root and the ulnar nerve in the forearm were not smaller. CONCLUSIONS: US showed that the peripheral nerves in patients with SBMA were thinner than those in patients with ALS despite similar degrees of weakness and motor neuron loss. Possible causes include additional sensory nerve involvement and longer disease duration in patients with SBMA than those in patients with ALS.

DOI： 10.1007/s10072-022-05969-1

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Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

DOI： 10.1111/cge.14133

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Spinocerebellar ataxia type 2 (SCA2) is caused by mutations in the ATXN2 gene in which toxic effects are triggered by expanded polyglutamine repeats within ataxin-2. SCA2 is accompanied by motor neuron degeneration as occurs in amyotrophic lateral sclerosis (ALS). We investigated the distribution patterns of ataxin-2 and transactivation-responsive DNA-binding protein 43 (TDP-43), a major disease-related protein in ALS, in the CNS of 3 SCA2 patients. Phosphorylated TDP-43 (pTDP-43)-positive lesions were widely distributed throughout the CNS and generally overlapped with 1C2 (expanded polyglutamine)-immunoreactive lesions. This distribution pattern is different from the pattern in limbic-predominant age-related TDP-43 encephalopathy. In SCA2, double immunostaining of TDP-43 and 1C2 in motor neurons revealed 3 staining patterns: cytoplasmic 1C2 and nuclear TDP-43, nucleocytoplasmic 1C2 and nuclear TDP-43, and nuclear 1C2 and cytoplasmic TDP-43, which reflect the early, active, and final stages of pathological change, respectively. The translocation of TDP-43 from the nucleus to the cytoplasm along with the translocation of 1C2 in the opposite direction indicates that nuclear accumulation of the disease-specific protein ataxin-2 affects the intracellular dynamics of TDP-43. Such a close interrelationship between mutant ataxin-2 and TDP-43 in the cell might account for the similarity of their distribution in the CNS of patients with SCA2.

DOI： 10.1093/jnen/nlac032

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Guillain-Barré syndrome (GBS) has occasionally occurred in people who have received coronavirus disease 2019 (COVID-19) vaccines. Dysgeusia is rare symptom of GBS. We herein report a rare case of sensory ataxic GBS with dysgeusia just after the second dose of the Pfizer-BioNTech COVID-19 vaccine. Although autoantibodies against glycolipids were not detected, immunotherapy with intravenous immunoglobulin and methylprednisolone pulse therapy effectively ameliorated the symptoms. Our report suggests that the COVID-19 vaccine may induce various clinical subtypes of GBS, including a rare variant with sensory ataxia and dysgeusia.

DOI： 10.2169/internalmedicine.8967-21

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Language：Japanese   Publisher：(一社)日本遺伝カウンセリング学会  

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522→Ala) knockin (Crmp1ki/ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knockout (Crmp1 -/-) mice, respectively. Crmp1ki/ki/SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1-/-/SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki/ki/SOD1G93A mice but not in Crmp1-/-/SOD1G93A mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions were comparatively well-preserved in Crmp1ki/ki/SOD1G93A mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1ki/ki/SOD1G93A and Crmp1-/-/SOD1G93A mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.Significance StatementCollapsin response mediator protein 1 (CRMP1) is an intracellular molecule that mediates semaphorin 3A (Sema3A) signaling. Phosphoproteomic analysis showed that the Semaphorin Neuronal Repulsive Signaling Pathway, which includes Crmp1 phosphorylation at Ser522, is upregulated in SOD1G93A mice that serve as a model of amyotrophic lateral sclerosis (ALS). While deleting both copies of the Crmp1 gene (Crmp1-/- ) leads to deterioration of motor function in SOD1G93A mice, phospho-null Crmp1 (Crmp1ki/ki ) improves motor function while preventing motor neuron loss and denervation of neuromuscular junctions. Among the Sema3A-mediated axon guidance pathways, we propose that CRMP1 phosphorylation is a potential therapeutic target for ALS.

DOI： 10.1523/ENEURO.0133-22.2022

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Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

DOI： 10.1093/brain/awab363

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Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder, characterized by the presence of eosinophilic inclusions (NIIs) within nuclei of central and peripheral nervous system cells. This study aims to identify the components of NIIs, which have been difficult to analyze directly due to their insolubility. In order to establish a method to directly identify the components of NIIs, we first analyzed the huntingtin inclusion-rich fraction obtained from the brains of Huntington disease model mice. Although the sequence with expanded polyglutamine could not be identified by liquid-chromatography mass spectrometry, amino acid analysis revealed that glutamine of the huntingtin inclusion-rich fraction increased significantly. This is compatible with the calculated amino acid content of the transgene product. Therefore, we applied this method to analyze the NIIs of diseased human brains, which may have proteins with compositionally biased regions, and identified a serine-rich protein called hornerin. Since the analyzed NII-rich fraction was also serine-rich, we suggested hornerin as a major component of the NIIs. A specific distribution of hornerin in NIID was also investigated by Matrix-assisted laser desorption/ionization imaging mass spectrometry and immunofluorescence. Finally, we confirmed a variant of hornerin by whole-exome sequencing and DNA sequencing. This study suggests that hornerin may be related to the pathological process of this NIID, and the direct analysis of NIIs, especially by amino acid analysis using the NII-rich fractions, would contribute to a deeper understanding of the disease pathogenesis.

DOI： 10.1186/s40478-022-01333-8

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INTRODUCTION: The basal ganglia and related dopaminergic cortical areas are important neural systems underlying motor learning and are also implicated in impulse control disorders (ICDs). Motor learning impairments and ICDs are frequently observed in Parkinson's disease (PD). Nevertheless, the relationship between motor learning ability and ICDs has not been elucidated. METHODS: We examined the relationship between motor learning ability and gambling propensity, a possible symptom for prodromal ICDs, in PD patients. Fifty-nine PD patients without clinical ICDs and 43 normal controls (NC) were administered a visuomotor rotation perturbation task and the Iowa Gambling Task (IGT) to evaluate motor learning ability and gambling propensity, respectively. Participants also performed additional cognitive assessments and underwent brain perfusion SPECT imaging. RESULTS: Better motor learning ability was significantly correlated with lower IGT scores, i.e., higher gambling propensity, in PD patients but not in NC. The higher scores on assessments reflecting prefrontal lobe function and well-preserved blood perfusion in prefrontal areas were correlated with lower IGT scores along with better motor learning ability. CONCLUSIONS: Our findings suggest that better motor learning ability and higher gambling propensity are based on better prefrontal functions, which are in accordance with the theory that the prefrontal cortex is one of the common essential regions for both motor learning and ICDs.

DOI： 10.1080/13803395.2022.2083083

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An intronic expansion (AAGGG)exp in the RFC1 gene has recently been shown to cause recessively inherited cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and, furthermore, a few patients with ataxia and parkinsonism have been reported. We investigated 569 Finnish patients with medicated parkinsonism for RFC1 and found biallelic (AAGGG)exp in three non-consanguineous patients with clinically confirmed Parkinson's disease without ataxia suggesting that RFC1-related disorders include Parkinson's disease as well.

DOI： 10.1038/s41531-021-00275-7

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DOI： 10.1016/j.ensci.2021.100377

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BACKGROUND: GGC repeat expansions in NOTCH2NLC are associated with neuronal intranuclear inclusion disease. Very recently, asymptomatic carriers with NOTCH2NLC repeat expansions were reported. In these asymptomatic individuals, the CpG island in NOTCH2NLC is hypermethylated, suggesting that two factors repeat length and DNA methylation status should be considered to evaluate pathogenicity. Long-read sequencing can be used to simultaneously profile genomic and epigenomic alterations. We analyzed four sporadic cases with NOTCH2NLC repeat expansion and their phenotypically normal parents. The native genomic DNA that retains base modification was sequenced on a per-trio basis using both PacBio and Oxford Nanopore long-read sequencing technologies. A custom workflow was developed to evaluate DNA modifications. With these two technologies combined, long-range DNA methylation information was integrated with complete repeat DNA sequences to investigate the genetic origins of expanded GGC repeats in these sporadic cases. RESULTS: In all four families, asymptomatic fathers had longer expansions (median: 522, 390, 528 and 650 repeats) compared with their affected offspring (median: 93, 117, 162 and 140 repeats, respectively). These expansions are much longer than the disease-causing range previously reported (in general, 41-300 repeats). Repeat lengths were extremely variable in the father, suggesting somatic mosaicism. Instability is more frequent in alleles with uninterrupted pure GGCs. Single molecule epigenetic analysis revealed complex DNA methylation patterns and epigenetic heterogeneity. We identified an aberrant gain-of-methylation region (2.2 kb in size beyond the CpG island and GGC repeats) in asymptomatic fathers. This methylated region was unmethylated in the normal allele with bilateral transitional zones with both methylated and unmethylated CpG dinucleotides, which may be protected from methylation to ensure NOTCH2NLC expression. CONCLUSIONS: We clearly demonstrate that the four sporadic NOTCH2NLC-related cases are derived from the paternal GGC repeat contraction associated with demethylation. The entire genetic and epigenetic landscape of the NOTCH2NLC region was uncovered using the custom workflow of long-read sequence data, demonstrating the utility of this method for revealing epigenetic/mutational changes in repetitive elements, which are difficult to characterize by conventional short-read/bisulfite sequencing methods. Our approach should be useful for biomedical research, aiding the discovery of DNA methylation abnormalities through the entire genome.

DOI： 10.1186/s13148-021-01192-5

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OBJECTIVE: Simultanagnosia is a rare neuropsychological symptom characterized by difficulty recognizing global structures while preserving perception of local detail. The condition is classified into ventral and dorsal types. Clinical presentation of ventral simultanagnosia includes a reduced ability to recognize multiple visual stimuli rapidly, that is, part-by-part recognition. Here, we report a case of ventral simultanagnosia with a unique presentation; when short-duration visual stimuli were presented, the patient could perform global recognition by improving his part-by-part approach. To investigate the relationship between local and global perception bias and the duration of the present stimulus, we conducted a visual perception test using hierarchically organized Navon figures. METHODS/RESULTS: The patient was a 62-year-old right-handed man who suffered from cerebral infarction in the right occipitotemporal lobe. He had no language dysfunction but exhibited left unilateral neglect, prosopagnosia, and ventral-type simultanagnosia. We conducted a visual perception test using the Navon figures and control figures as a visual stimulus. We randomly presented the figures for intervals of 0.2 or 20 s and let the patient report all the letters (global and/or local element) that he recognized. Global elements of the Navon letter were recognized a rate of 0% and 78.3% at intervals of 20 and 0.2 s, respectively, indicating that shorter presentation made the part-by-part approach less likely to manifest. CONCLUSIONS: We assumed that the simultanagnosia in this case was caused by failure to maintain the initially perceived global information for a long period of time during visual presentation, due to right occipitotemporal damage.

DOI： 10.1093/arclin/acab088

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BACKGROUND: The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. PATIENTS AND METHODS: All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. RESULTS: A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. CONCLUSIONS: Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

DOI： 10.1186/s12883-021-02409-z

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BACKGROUND: Anticoagulation therapy, especially using heparin or recently developed oral direct factor Xa inhibitors (DiXals), is recommended as first-line treatment for cancer-related venous thromboembolism (VTE). However, the preventive efficacy of these anticoagulants for cancer-associated ischemic stroke is still unknown. We retrospectively investigated the efficacy of subcutaneous unfractionated heparin (UFH) and DiXals for preventing the recurrence of cancer-associated cryptogenic ischemic stroke with VTE. METHODS: We retrospectively studied consecutive patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE who received subcutaneous UFH or oral DiXaIs at 9 hospitals. RESULT: Fifty-three patients (24 treated with UFH and 29 treated with DiXaIs) were enrolled. Of these, 47 demonstrated systemic metastasis (cancer stage IV). During 30-day follow-up after initiation of anticoagulation therapy, recurrent ischemic stroke was observed in only 1 patient (4%) in the UFH group and in 9 patients (31%) in the DiXal group. The incidence of major bleeding complications was similar between the 2 groups (4% and 10%, respectively). The cumulative risk of ischemic stroke recurrence within 30 days was lower with UFH than with DiXals (competing risk analysis, p = 0.008). In the DiXal group, patients who experienced recurrence showed significantly higher D-dimer levels than those without recurrence. CONCLUSION: In patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE, UFH demonstrated a lower rate of recurrent ischemic stroke than DiXaIs, and there were no differences in bleeding risk between the 2 treatments. D-dimer levels at stroke onset increased the risk of recurrence in the DiXal group but not in the UFH group.

DOI： 10.1016/j.thromres.2021.08.016

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PURPOSE: Recently, various magnetic resonance imaging (MRI) modalities have been developed to easily detect carotid and aortic plaques, but these techniques are time-consuming and vulnerable to motion artifacts. We investigated the utility of a gradient echo MRI technique known as liver acquisition with volume acceleration flexible (LAVA-Flex) to detect carotid and aortic atherosclerotic plaques. METHODS: Ten patients who underwent carotid endarterectomy (CEA) were assessed regarding the correspondence between LAVA-Flex findings and the histopathology of excised carotid plaques. In addition, 47 patients with cryptogenic ischemic stroke underwent LAVA-Flex and transesophageal echocardiography (TEE) for detection of embolic sources in the thoracic aorta. We analyzed the relationship between the thickness of the aortic plaque measured by TEE and the presence of high-intensity lesions on LAVA-Flex. RESULTS: Nine of 10 patients (90.0%) who underwent CEA showed a high-intensity carotid lesion on LAVA-Flex, which corresponded pathologically to plaques containing large lipid cores and hemorrhage. Twenty-four (51.1%) of 47 cryptogenic stroke patients showed a high-intensity lesion in the thoracic aorta on LAVA-Flex; of these, 21 (87.5%) also demonstrated a large plaque (thickness ≥4 mm) on TEE. Twenty-two (95.7%) of 23 patients without a high-intensity lesion on LAVA-Flex demonstrated no large plaque on TEE. LAVA-Flex had a sensitivity of 95.5% and a specificity of 88.0% in patients with large plaques. CONCLUSION: This study showed that LAVA-Flex successfully detected carotid and aortic plaques. This imaging technique may be useful to rapidly diagnose and evaluate carotid and aortic plaques, which are critical risk factors for aortogenic stroke.

DOI： 10.1007/s00234-021-02812-w

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DOI： 10.1093/brain/awab183

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BACKGROUND: Mild cognitive impairment (MCI) in Parkinson's disease (PD) is considered a risk factor for PD with dementia (PDD). Verbal fluency tasks are widely used to assess executive function in PDD. However, in cases of PD with MCI (PD-MCI), the relative diagnostic accuracy of different qualitative verbal fluency measures and their related neural mechanisms remain unknown. OBJECTIVE: This study aimed to investigate the relative diagnostic accuracy of qualitative (clustering and switching) verbal fluency strategies and their correlates with functional imaging in PD-MCI. METHODS: Forty-five patients with PD (26 with MCI and 19 without MCI) and 25 healthy controls underwent comprehensive neurocognitive testing and resting-state functional magnetic resonance imaging. MCI in patients with PD was diagnosed according to established clinical criteria. The diagnostic accuracy of verbal fluency measures was determined via receiver operating characteristic analysis. Changes in brain functional connectivity between groups and across clinical measures were assessed using seed-to-voxel analyses. RESULTS: Patients with PD-MCI generated fewer words and switched less frequently in semantic and phonemic fluency tasks compared to other groups. Switching in semantic fluency showed high diagnostic accuracy for PD-MCI and was associated with reduced functional connectivity in the salience network. CONCLUSION: Our results indicate that reduced switching in semantic fluency tasks is a sensitive and specific marker for PD-MCI. Qualitative verbal fluency deficits and salience network dysfunction represent early clinical changes observed in PD-MCI.

DOI： 10.3233/JPD-202473

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A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype-phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype-phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.

DOI： 10.1093/brain/awab021

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Neuroinflammation by activated microglia and astrocytes plays a critical role in progression of amyotrophic lateral sclerosis (ALS). Interleukin-19 (IL-19) is a negative-feedback regulator that limits pro-inflammatory responses of microglia in an autocrine and paracrine manner, but it remains unclear how IL-19 contributes to ALS pathogenesis. We investigated the role of IL-19 in ALS using transgenic mice carrying human superoxide dismutase 1 with the G93A mutation (SOD1G93A Tg mice). We generated IL-19-deficient SOD1G93A Tg (IL-19-/-/SOD1G93A Tg) mice by crossing SOD1G93A Tg mice with IL-19-/- mice, and then evaluated disease progression, motor function, survival rate, and pathological and biochemical alternations in the resultant mice. In addition, we assessed the effect of IL-19 on glial cells using primary microglia and astrocyte cultures from the embryonic brains of SOD1G93A Tg mice and IL-19-/-/SOD1G93A Tg mice. Expression of IL-19 in primary microglia and lumbar spinal cord was higher in SOD1G93A Tg mice than in wild-type mice. Unexpectedly, IL-19-/-/SOD1G93A Tg mice exhibited significant improvement of motor function. Ablation of IL-19 in SOD1G93A Tg mice increased expression of both neurotoxic and neuroprotective factors, including tumor necrosis factor-α (TNF-α), IL-1β, glial cell line-derived neurotrophic factor (GDNF), and transforming growth factor β1, in lumbar spinal cord. Primary microglia and astrocytes from IL-19-/-/SOD1G93A Tg mice expressed higher levels of TNF-α, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms.

DOI： 10.1186/s13041-021-00785-8

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Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral-pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.

DOI： 10.1186/s13041-021-00770-1

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Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

DOI： 10.1126/sciadv.abd2368

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Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.

DOI： 10.1002/humu.24129

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We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.

DOI： 10.1002/humu.24130

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BACKGROUND: Foreign accent syndrome (FAS) is a rare acquired speech disorder wherein an individual's spoken accent is perceived as "foreign." Most reported cases involve left frontal brain lesions, but it is known that various other lesions can also cause FAS. To determine whether heterogeneous FAS-causing lesions are localized to a common functional speech network rather than to a single anatomical site, we employed a recently validated image analysis technique known as "lesion network mapping." METHODS: We identified 25 published cases of acquired neurogenic FAS without aphasia, and mapped each lesion volume onto a reference brain. We next identified the network of brain regions functionally connected to each FAS lesion using a connectome dataset from normative participants. Network maps were then overlapped to identify common network sites across the lesions. RESULTS: Classical lesion overlap analysis showed heterogeneity in lesion anatomical location, consistent with prior reports. However, at least 80% of lesions showed network overlap in the bilateral lower and middle portions of the precentral gyrus and in the medial frontal cortex. The left lower portion of the precentral gyrus is suggested to be the location of lesions causing apraxia of speech (AOS), and the middle portion is considered to be a larynx-specific motor area associated with the production of vowels and stop/nasal consonants and with the determination of pitch accent. CONCLUSIONS: The lesions that cause FAS are anatomically heterogeneous, but they share a common functional network located in the bilateral posterior region of the frontal lobe. This network specifically includes not only the lower portion of the central gyrus, but also its middle region, which is referred to as the larynx motor cortex and is known to be associated with phonation. Our findings suggest that disrupted networks in FAS might be anatomically different from those in AOS.

DOI： 10.1016/j.nicl.2021.102760

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RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (POLR3A). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A>G (p.M852V) and c.2668G>T (p.V890F) in the POLR3A gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.

DOI： 10.3389/fneur.2021.622355

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Takotsubo cardiomyopathy (TCM) is a stress-induced cardiomyopathy triggered by critical illness including severe neurological disorders. However, an association between TCM and Bickerstaff brainstem encephalitis (BBE) has rarely been described. During the current coronavirus disease 2019 (COVID-19) pandemic, growing evidence indicates that COVID-19 often leads to various neurological disorders, but there are few reports of an association between COVID-19 and BBE. Here we report a case of TCM associated with BBE triggered by COVID-19, which subsided with immunotherapy for BBE. Both transthoracic echocardiography and electrocardiography led to early and accurate diagnosis of TCM. Sustained hemodynamic instability due to TCM was immediately lessened with immunotherapy whereas additional plasmapheresis and immunotherapy were required to treat BBE. This case indicates that BBE might follow COVID-19 and TCM should be considered when hemodynamic status remains unstable in a patient with BBE.

DOI： 10.3389/fneur.2021.822247

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Here we report three cases of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) mimicking multiple sclerosis in which seropositivity for anti-MOG antibodies occurred during disease-modifying drug dimethyl fumarate (DMF) treatment. These patients developed relapses with anti-MOG antibody seroconversion after switching from fingolimod or steroid pulse therapy to DMF, which was associated with peripheral lymphocyte recovery. MOGAD is considered a humoral immune disease, and DMF reportedly enhances Th2-skewed humoral immune activity. Therefore, we suggest that DMF, but not fingolimod, may exacerbate humoral immune imbalance and enhance autoantibody production, leading to aggravation of MOGAD.

DOI： 10.3389/fimmu.2021.625465

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Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC. We aimed to identify and to clinicopathologically characterize patients with OPDM who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Note that 211 patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of identified patients with OPDM_NOTCH2NLC were re-reviewed. Intra-myonuclear inclusions were evaluated using immunohistochemistry and electron microscopy (EM). Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically demonstrated ptosis, ophthalmoplegia, dysarthria and muscle weakness; they myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which were diagnostic of NIID (typically on skin biopsy), in addition to rimmed vacuoles. The sample for EM was available only from one patient, which demonstrated intranuclear inclusions of 12.6 ± 1.6 nm in diameter. We identified seven patients with OPDM_NOTCH2NLC. Our patients had various additional central and/or peripheral nervous system involvement, although all were clinicopathologically compatible; thus, they were diagnosed as having OPDM and expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

DOI： 10.1186/s40478-020-01084-4

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

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We herein report a 33-year-old woman who was an asymptomatic hepatitis B virus (HBV) carrier and presented with distal muscle weakness in the legs and asymmetrical paresthesia in the distal extremities. A nerve biopsy specimen revealed fibrinoid necrosis associated with inflammatory infiltration in the perineural space, and deposition of hepatitis B core antigen and C4d complement was detected in the vascular endothelial cells as well as around the vessels. She was diagnosed with HBV-related vasculitic neuropathy and treated with intravenous immunoglobulin (IVIG). Her symptoms completely subsided after eight weeks. Vasculitic neuropathy rarely develops in the chronic inactive stages of HBV infection. This is the first report of an HBV-inactive carrier with vasculitic neuropathy successfully treated with IVIG.

DOI： 10.2169/internalmedicine.4498-20

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BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

DOI： 10.1136/jmedgenet-2020-106896

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INTRODUCTION: Variants of CACNA1G, which encodes CaV3.1, have been reported to be associated with various neurological disorders. METHODS: Whole-exome sequencing of genomic DNA from 348 Japanese patients with neurodevelopmental disorders and their parents was conducted, and de novo variants of CACNA1G were extracted. The electrophysiological properties of each mutant channel were investigated by voltage-clamp and current-clamp analyses of HEK293T cells overexpressing these channels. RESULTS: Two patients diagnosed with Rett syndrome and West syndrome were found to have known pathological CACNA1G mutations reported in cerebellar ataxia cohorts: c.2881G > A, p.Ala961Thr and c.4591A > G, p.Met1531Val, respectively. One patient with Lennox-Gastaut syndrome was revealed to harbor a previously unreported heterozygous variant: c.3817A > T, p.Ile1273Phe. Clinical symptoms of the two patients with known mutations included severe developmental delay without acquisition of the ability to walk independently. The patient with a potentially novel mutation showed developmental delay, intractable seizures, and mild cerebral atrophy on MRI, but the severity of symptoms was milder than in the former two cases. Electrophysiological study using HEK293T cells demonstrated significant changes of T-type Ca2+ currents by p.Ala961Thr and p.Met1531Val SNVs, which were likely to enhance oscillation of membrane potential at low frequencies. In contrast, p.Ile1273Phe showed no significant effects in our electrophysiological evaluations, with its pathogenesis remaining undetermined. CONCLUSION: De novo variants of CACNA1G explain some neurodevelopmental disorders. Our study further provides information to understand the genotype-phenotype correlations of patients with CACNA1G mutations.

DOI： 10.1016/j.jns.2020.117047

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DOI： 10.1002/ana.25819

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It remains controversial whether circulating monocytes expressing CCR2 infiltrate the central nervous system (CNS) and contribute to pathogenicity of amyotrophic lateral sclerosis (ALS). A previous report used conventional immunohistochemistry to show that CCR2 is exclusively expressed by astrocytes, but not infiltrating monocytes/microglia or neurons, in the spinal cords of ALS model mice. In this study, we assessed the cellular distribution of CCR2 in the CNS of ALS mice using CCR2-reporter mice (Ccr2rfp/+-Cx3cr1gfp/+-SOD1G93A Tg mice), a more sophisticated method for directly detecting the distribution of CCR2 protein. We found that infiltration of CCR2+ monocytes in the lumbar spinal cord increased over the course of disease progression. Moreover, from the middle stage of disease, CCR2 was partially distributed in microglia and neurons, but not astrocytes, in striking contrast to the previous findings. These novel observations suggested that CCR2+ monocyte infiltration leads to CNS environmental deterioration due to toxic conversion of microglia and neurons, creating a vicious cycle of neuroinflammation and leading to acceleration of ALS pathology. Our findings also show that this reporter mouse is a useful and powerful tool for obtaining new insights into the pathomechanisms of ALS.

DOI： 10.1186/s13041-020-00607-3

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Recently, a recessively inherited intronic repeat expansion in replication factor C1 (RFC1) was identified in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Here, we describe a Japanese case of genetically confirmed CANVAS with autonomic failure and auditory hallucination. The case showed impaired uptake of iodine-123-metaiodobenzylguanidine and 123I-ioflupane in the cardiac sympathetic nerve and dopaminergic neurons, respectively, by single-photon emission computed tomography. Long-read sequencing identified biallelic pathogenic (AAGGG)n nucleotide repeat expansion in RFC1 and heterozygous benign (TAAAA)n and (TAGAA)n expansions in brain expressed, associated with NEDD4 (BEAN1). Enrichment of the repeat regions in RFC1 and BEAN1 using a Cas9-mediated system clearly distinguished between pathogenic and benign repeat expansions. The haplotype around RFC1 indicated that the (AAGGG)n expansion in our case was on the same ancestral allele as that of European cases. Thus, long-read sequencing facilitates precise genetic diagnosis of diseases with complex repeat structures and various expansions.

DOI： 10.1038/s10038-020-0733-y

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Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet's disease, and myositis. Here we present the first report of anti-signal recognition particle antibody-associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.

DOI： 10.3389/fimmu.2020.595480

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Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed polymerase chain reaction for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Furthermore, we found 1 case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. ANN NEUROL 2019;86:962-968.

DOI： 10.1002/ana.25586

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BACKGROUND: We encountered two unrelated individuals suffering from neurological disorders, including epilepsy and scoliosis. CASE PRESENTATION: Whole-exome sequencing identified the same recurrent, de novo, pathogenic variant in NUS1 [NM_138459.4:c.691 + 1C > A] in both individuals. This variant is located in the conserved cis-prenyltransferase domain of the nuclear undecaprenyl pyrophosphate synthase 1 gene (NUS1), which encodes the Nogo-B receptor, an essential catalyst for protein glycosylation. This variant was confirmed to create a new splice donor site, resulting in aberrant RNA splicing resulting in a 91-bp deletion in exon 3 in both individuals. The mutant mRNA was partially degraded by nonsense mediated mRNA decay. To date, only four de novo variants and one homozygous variant have been reported in NUS1, which cause developmental and epileptic encephalopathy, early onset Parkinson's disease, and a congenital disorder of glycosylation. Seven patients, including our two patients, have presented with epileptic seizures and intellectual disabilities. CONCLUSIONS: Our study strongly supports the finding that this recurrent, de novo, variant in NUS1 causes developmental and epileptic encephalopathy with involuntary movement, ataxia and scoliosis.

DOI： 10.1186/s12883-019-1489-x

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Exosomes contain many proteins associated with neurodegenerative diseases. To identify new candidate biomarkers and proteins associated with amyotrophic lateral sclerosis (ALS), we performed liquid chromatography-tandem mass spectrometry proteomic analysis of exosome-enriched fractions isolated from cerebrospinal fluid (CSF) of sporadic ALS patients using gel filtration chromatography. Proteomic data revealed that three proteins were increased and 11 proteins were decreased in ALS patients. The protein with the greatest increase in exosome-enriched fractions of CSF derived from ALS was novel INHAT repressor (NIR), which is closely associated with nucleolar function. By immunohistochemical analysis, we found that NIR was reduced in the nucleus of motor neurons in ALS patients. Our results demonstrate the potential utility of our methodology for proteomic analysis of CSF exosomes and suggest that nucleolar stress might play a role in sporadic ALS pathogenesis through the dysfunction of NIR.

DOI： 10.1016/j.neures.2019.10.010

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DOI： 10.1212/CPJ.0000000000000599

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Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

DOI： 10.1016/j.nbd.2019.104516

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A 24-year-old Japanese man exhibited slowly progressive gait disturbance from childhood to young adulthood. Physical and physiological examinations showed the involvement of both upper and lower motor neurons, fulfilling the diagnostic criteria for amyotrophic lateral sclerosis (ALS). Mild cognitive impairment and subclinical sensory involvement were also observed. A genetic analysis revealed novel compound heterozygous mutations, c.767C>T (p.Thr256Ile) and c.800A>G (p.Asp267Gly), in the vaccinia-related kinase 1 gene (VRK1). This is the first report of a Japanese patient with a motor neuron disease phenotype caused by VRK1 mutations. This diagnosis should be considered in atypical cases of juvenile-onset and slowly progressive types of motor neuron disease.

DOI： 10.2169/internalmedicine.2126-18

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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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Fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor and is widely used for relapsing-remitting multiple sclerosis (MS). Here we report the first case of non-traumatic acute epidural hematoma in a relapsing-remitting MS patient treated with fingolimod. Fingolimod might increase the risk of hemorrhage by enhancing vasospasm and causing vascular disruption. Switching fingolimod to other disease-modifying drugs, including dimethyl fumarate, should be considered when non-traumatic hemorrhage is observed in MS patients.

DOI： 10.3389/fneur.2019.00763

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OBJECTIVE: Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2-related disorders. COL4A1/COL4A2 encode type IV collagen α1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20 to 30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2-related disorders. METHODS: Whole exome sequencing was performed in 2 families with suspected COL4A1/COL4A2-related disorders. We validated the role of COLGALT1 variants by constructing a 3-dimensional structural model, evaluating collagen β (1-O) galactosyltransferase 1 (ColGalT1) protein expression and ColGalT activity by Western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments. RESULTS: Exome sequencing demonstrated biallelic variants in COLGALT1 encoding ColGalT1, which was involved in the post-translational modification of type IV collagen in 2 unrelated patients: c.452 T > G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G > C (p.Ala154Pro) and c.1129G > C (p.Gly377Arg) in Patient 2. Three-dimensional model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild type. INTERPRETATION: Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2-related disorders. Ann Neurol 2018;84:843-853.

DOI： 10.1002/ana.25367

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Spinocerebellar ataxia type 21 (SCA21) is a rare subtype of autosomal dominant cerebellar ataxias, which was first identified in a French family and has been reported almost exclusively in French ancestry so far. We here report the first Japanese family with SCA21, in which all affected members examined carried a heterozygous c.509C > T:p.Pro170Leu variant in TMEM240. Their clinical features were summarized as a slowly progressive ataxia of young-adult onset (5-48 years) associated with various degree of psychomotor retardation or cognitive impairment. The MR images revealed atrophy in the cerebellum, but not in the cerebrum or brainstem. These clinical findings were consistent with those in the original French families with SCA21. Neuropathological findings in one autopsied patient showed a prominent decrease of cerebellar Purkinje cells, but no specific abnormalities outside the cerebellum.

DOI： 10.1007/s12311-018-0941-6

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Steroid pulse therapy with methylprednisolone (mPSL) succinate ester is the most common treatment for neuromyelitis optica (NMO); no cases of anaphylaxis have been reported to date. Here, we report two cases of anaphylactic shock induced by mPSL pulse therapy in patients with NMO and concurrent systemic lupus erythematosus. Both patients had received several courses of mPSL pulse therapy without any problems previously. Repeated mPSL pulse therapy and comorbid humoral autoimmune disease might increase the risk of anaphylaxis. Corticosteroids without succinate esters should be considered as an alternative therapy to prevent anaphylaxis.

DOI： 10.1177/1352458518763099

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DOI： 10.1111/cen3.12469

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DOI： 10.1111/cen3.12470

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DOI： 10.1111/cge.13369

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Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom‐designed gene panel. We selected 55 leukoencephalopathy‐related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.

DOI： 10.1111/cge.13371

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DOI： 10.1002/mdc3.12614

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Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

DOI： 10.1038/s10038-017-0408-5

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BACKGROUND: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. METHODS: CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. RESULTS: Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CONCLUSIONS: CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.

DOI： 10.1186/s12974-018-1084-x

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BACKGROUND: In dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), it is still debated whether white matter hyperintensities (WMH) on MRI reflect atherosclerotic cerebrovascular changes or Alzheimer's disease (AD)-related pathology such as cerebral amyloid angiopathy. To examine AD-related pathology in DLB and PDD, we compared the severity of WMH and medial temporal lobe atrophy among patients with DLB, PDD, non-demented PD (PDND), and AD. METHODS: We retrospectively studied sex- and age-matched outpatients with AD, DLB, PDD, and PDND, as well as subjects without central nervous system disorders as normal controls (n=50 each). All subjects underwent 1.5-T MRI examinations, and WMH detected by T2-weighted images or fluid-attenuated inversion recovery images were semiquantified according to the Fazekas method. Medial temporal lobe atrophy (MTA) was visually assessed by the MTA score. RESULTS: WMH were more prominent in AD, DLB, and PDD patients than in PDND patients and normal controls (NCs). DLB as well as AD showed more severe WMH than PDD. Visual assessment of medial temporal lobe atrophy showed that AD patients had the most severe atrophy, followed by DLB, PDD, and PDND patients, and NC subjects in that order. MTA scores showed significant correlations with WMH severity. CONCLUSION: Our results indicated that DLB was more similar to AD than to PDD in terms of MRI findings, suggesting that WMH in DLB may reflect mainly AD-related pathology rather than atherosclerotic cerebrovascular changes.

DOI： 10.1016/j.jns.2017.12.018

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Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA-binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43-negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43-positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43-positive NCIs.

DOI： 10.1016/j.ajpath.2017.10.007

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DOI： 10.11253/ninchishinkeikagaku.20.89_2

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DOI： 10.1038/srep35236

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Recent new sequencing techniques allow the identification of novel responsible genes for autosomal recessive spinocerebellar ataxias (ARCAs). However, the same phenotypes are sometimes attributed to the different responsible genes in ARCAs. On the contrary, the same responsible genes may cause heterogeneous phenotypes with respect to the age at onset, symptoms, and the severity of the disease progression. In addition, it is an important issue to clarify whether the gene mutations identified in Caucasian patients with infantile-onset ARCAs are also observed in Japanese patients with adult-onset ARCAs. In this article we review the characteristics of several ARCAs, the existence of which has been recently identified or confirmed in Japan.

DOI： 10.5692/clinicalneurol.cn-000879

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DOI： 10.1007/s00415-015-7948-4

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DOI： 10.1038/jhg.2015.86

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DOI： 10.1001/jamaneurol.2015.0610

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DOI： 10.1186/s40478-015-0202-6

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DOI： 10.1038/jhg.2015.7

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DOI： 10.1038/srep07132

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DOI： 10.1038/jhg.2014.75

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DOI： 10.1007/s10048-013-0375-8

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DOI： 10.1002/ajmg.a.35983

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DOI： 10.1002/mds.25296

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DOI： 10.1002/humu.22257

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J04871&link_issn=&doc_id=20130311230006&doc_link_id=1390283684968595968&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390283684968595968&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

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DOI： 10.1038/jhg.2012.117

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DOI： 10.1002/ana.23736

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Corticobasal syndrome (CBS) is associated with different pathologies including FTLD-tau (corticobasal degeneration; CBD, progressive supranuclear palsy, and Pick disease), FTLD-TDP, Alzheimer disease, Creutzfeldt-Jakob disease, and Parkinson disease/dementia with Lewy bodies. Genetic causes of CBS are also various reflecting diverse pathology. In familial and sporadic FTLD, MAPT, GRN and C9ORF72 mutations are three major causes of the disease. A part of patients harboring these mutations could exhibit CBS. In addition, the patients with TARDBP, FUS, LRRK2 or CSF1R mutations also have potential to exhibit CBS. In sporadic cases, H1 haplotype of MAPT is known to be associated with FTLD-tau, including CBS/CBD. Despite major advances in recent years, the majority of familial and sporadic CBS cases are genetically unsolved. In particular, little is known about both familial and sporadic cases of CBS in Japanese. Further studies are needed to unveil the genetic background of CBS.

DOI： 10.5692/clinicalneurol.53.1026

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DOI： 10.2169/internalmedicine.52.0252

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DOI： 10.1038/jhg.2012.105

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DOI： 10.1007/s10048-012-0337-6

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DOI： 10.1111/j.1528-1167.2012.03548.x

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DOI： 10.1002/ana.23620

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DOI： 10.1016/j.braindev.2011.07.004

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DOI： 10.1007/s00439-011-1105-7

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DOI： 10.1111/j.1399-0004.2011.01733.x

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DOI： 10.1038/ng.2219

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DOI： 10.1212/WNL.0b013e318249f71f

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DOI： 10.1111/j.1399-0004.2010.01575.x

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DOI： 10.1136/jmg.2010.083535

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DOI： 10.1111/j.1399-0004.2011.01721.x

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DOI： 10.1016/j.ajhg.2011.07.012

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DOI： 10.1038/jhg.2011.16

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DOI： 10.1016/j.ajhg.2010.11.012

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DOI： 10.1093/nar/gkq1162

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DOI： 10.1016/j.neures.2009.10.004

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DOI： 10.5692/clinicalneurol.50.641

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DOI： 10.1074/jbc.M705306200

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J-GLOBAL

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

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

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

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

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

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

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

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

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

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

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

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

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

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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

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Language：English   Publisher：(一社)日本てんかん学会  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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

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

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J-GLOBAL

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

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

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

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Language：Japanese   Publisher：(株)日本プランニングセンター  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J03334&link_issn=&doc_id=20181128410005&doc_link_id=%2Fag4nbzta%2F2018%2F002409%2F006%2F0021-0025%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag4nbzta%2F2018%2F002409%2F006%2F0021-0025%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

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

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

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

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

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

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

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Language：Japanese   Publisher：(株)南江堂  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00974&link_issn=&doc_id=20180830130055&doc_link_id=10.15106%2Fj_naika122_564&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_naika122_564&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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

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

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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Language：Japanese   Publisher：日本神経免疫学会  

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J-GLOBAL

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

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

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

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

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

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

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

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J-GLOBAL

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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J-GLOBAL

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

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

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

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

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

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

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

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Language：Japanese   Publisher：The Japan Stroke Society  

DOI： 10.3995/jstroke.32.351

CiNii Books

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.99.1656

CiNii Books

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Language：Japanese   Publisher：日本臨床社  

CiNii Books

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

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

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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

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

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

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