Association study of GBA1 variants with MSA based on comprehensive sequence analysis -Pitfalls in short-read sequence analysis depending on the human reference genome.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar ataxia. To elucidate variants associated with MSA, we have been conducting short-read-based whole-genome sequence analysis. In the process of the association studies, we initially focused on GBA1, a previously proposed susceptibility gene for MSA, to evaluate whether GBA1 variants can be efficiently identified despite its extraordinarily high homology with its pseudogene, GBA1LP. To accomplish this, we conducted a short-read whole-genome sequence analysis with alignment to GRCh38 as well as Sanger sequence analysis and compared the results. We identified five variants with inconsistencies between the two pipelines, of which three variants (p.L483P, p.A495P-p.V499V, p.L483_M489delinsW) were the results of misalignment due to minor alleles in GBA1P1 registered in GRCh38. The miscalling events in these variants were resolved by alignment to GRCh37 as the reference genome, where the major alleles are registered. In addition, a structural variant was not properly identified either by short-read or by Sanger sequence analyses. Having accomplished correct variant calling, we identified three variants pathogenic for Gaucher disease (p.S310G, p.L483P, and p.L483_M489delinsW). Of these variants, the allele frequency of p.L483P (0.003) in the MSA cases was higher than that (0.0011) in controls. The meta-analysis incorporating a previous report demonstrated a significant association of p.L483P with MSA with an odds ratio of 2.92 (95% CI; 1.08 - 7.90, p = 0.0353).

The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.

Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

Recent advances in CGG repeat diseases and a proposal of fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculophryngodistal myopathy (FNOP) spectrum disorder.

While whole genome sequencing and long-read sequencing have become widely available, more and more focuses are on noncoding expanded repeats. Indeed, more than half of noncoding repeat expansions related to diseases have been identified in the five years. An exciting aspect of the progress in this field is an identification of a phenomenon called repeat motif-phenotype correlation. Repeat motif-phenotype correlation in noncoding repeat expansion diseases is first found in benign adult familial myoclonus epilepsy. The concept is extended in the research of CGG repeat expansion diseases. In this review, we focus on newly identified CGG repeat expansion diseases, update the concept of repeat motif-phenotype correlation in CGG repeat expansion diseases, and propose a clinical concept of FNOP (fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculopharyngodistal myopathy)-spectrum disorder, which shares clinical features and thus probably share some common disease pathophysiology, to further facilitate discussion and progress in this field.

Muscle Transcriptomics Shows Overexpression of Cadherin 1 in Inclusion Body Myositis.

OBJECTIVE: This study aimed to elucidate the molecular features of inclusion body myositis (IBM). METHODS: We performed RNA sequencing analysis of muscle biopsy samples from 67 participants, consisting of 58 myositis patients with the pathological finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class I (43 IBM, 6 polymyositis, and 9 unclassifiable myositis), and 9 controls. RESULTS: Cluster analysis, principal component analysis, and pathway analysis showed that differentially expressed genes and pathways identified in IBM and polymyositis were mostly comparable. However, pathways related to cell adhesion molecules were upregulated in IBM as compared with polymyositis and controls (p < 0.01). Notably, CDH1, which encodes the epidermal cell junction protein cadherin 1, was overexpressed in the muscles of IBM, which was validated by another RNA sequencing dataset from previous publications. Western blotting confirmed the presence of mature cadherin 1 protein in the muscles of IBM. Immunohistochemical staining confirmed the positivity for anti-cadherin 1 antibody in the muscles of IBM, whereas there was no muscle fiber positive for anti-cadherin 1 antibody in immune-mediated necrotizing myopathy, antisynthetase syndrome, and controls. The fibers stained with anti-cadherin 1 antibody did not have rimmed vacuoles or abnormal protein accumulation. Experimental skeletal muscle regeneration and differentiation systems showed that CDH1 is expressed during skeletal muscle regeneration and differentiation. INTERPRETATION: CDH1 was detected as a differentially expressed gene, and immunohistochemistry showed that cadherin 1 exists in the muscles of IBM, whereas it was rarely seen in those of other idiopathic inflammatory myopathies. Cadherin 1 upregulation in muscle could provide a valuable clue to the pathological mechanisms of IBM. ANN NEUROL 2022;91:317-328.

A Novel de novo KIF1A Mutation in a Patient with Ataxia, Intellectual Disability and Mild Foot Deformity.

Early-onset ataxias are often difficult to diagnose due to the genetic and phenotypic heterogeneity of patients. Whole exome sequencing (WES) is a powerful method for determining causative mutations of early-onset ataxias. We report a case in which a novel de novo KIF1A mutation was identified in a patient with ataxia, intellectual disability and mild foot deformity.A patient presented with sporadic forms of ataxia with mild foot deformity, intellectual disability, peripheral neuropathy, pyramidal signs, and orthostatic hypotension. WES was used to identify a novel de novo mutation in KIF1A, a known causative gene of neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment syndrome (NESCAVS).We report a novel phenotype of NESCAVS that is associated with a novel de novo missense mutation in KIF1A, which provides valuable information for the diagnosis of NESCAVS even in the era of WES. Early rehabilitation of patients with NESCAVS may prevent symptom worsening and improve the disease course.

History of familial adult myoclonus epilepsy/benign adult familial myoclonic epilepsy around the world.

Familial adult myoclonus epilepsy/benign adult familial myoclonic epilepsy (FAME/BAFME) has emerged as a specific and recognizable epilepsy syndrome with autosomal dominant inheritance found around the world. Here, we trace the history of this syndrome. Initially, it was likely conflated with other familial myoclonus epilepsies, especially the progressive myoclonus epilepsies. As the progressive myoclonus epilepsies became better understood clinically and genetically, this group began to stand out and was first recognized as such in Japan. Subsequently, families were recognized around the world and there was debate as to whether they represented one or multiple disorders. Clarification came with the identification of pentanucleotide repeats in Japanese families, and FAME/BAFME was quickly shown to be due to pentanucleotide expansions in at least six genes. These have geographic predilections and appear to have been caused by historically ancient initial mutations. Within and between families, there is some variation in the phenotype, explained in large part by expansion size, but whether there are features specific to individual genes remains uncertain.

Insights into familial adult myoclonus epilepsy pathogenesis: How the same repeat expansion in six unrelated genes may lead to cortical excitability.

Familial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular localizations and very different functions, which poses the issue of what causes the neurobiological disturbances that lead to the clinical phenotype. Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects. FAME expansions, contrary to the same expansion in DAB1 causing spinocerebellar ataxia type 37, seem to have no or limited impact on their recipient gene expression, which suggests a pathophysiological mechanism independent of the gene and its function. Current hypotheses include toxicity of the RNA molecules carrying UUUCA repeats, or toxicity of polypeptides encoded by the repeats, a mechanism known as repeat-associated non-AUG translation. The analysis of postmortem brains of FAME1 expansion (in SAMD12) carriers has revealed the presence of RNA foci that could be formed by the aggregation of RNA molecules with abnormal UUUCA repeats, but evidence is still lacking for other FAME subtypes. Even when the expansion is located in a gene ubiquitously expressed, expression of repeats remains undetectable in peripheral tissues (blood, skin). Therefore, the development of appropriate cellular models (induced pluripotent stem cell-derived neurons) or the study of affected tissues in patients is required to elucidate how FAME repeat expansions located in unrelated genes lead to disease.

Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions.

Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade-off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models.

Clinical features of a family with late-onset distal hereditary motor neuropathy harboring p.Pro39Leu variant of HSPB1.

BACKGROUND AND AIMS: Pathogenic variants of HSPB1, the gene encoding the small heat shock protein 27, have been reported to cause autosomal dominant distal hereditary motor neuropathy (dHMN) type II and autosomal dominant Charcot-Marie-Tooth (CMT) disease with minimal sensory involvement (CMT2F). This study aimed to describe the clinical features of patients in a family with late-onset dHMN carrying the Pro39Leu variant of HSPB1. METHODS: Whole-exome sequence analysis identified a heterozygous pathogenic variant (Pro39Leu) of HSPB1 in the proband. The presence of the HSPB1 Pro39Leu variant in two affected individuals was confirmed using direct nucleotide sequence analysis. RESULTS: Both patients exhibited distal muscle weakness with lower extremity predominance and no obvious sensory deficits, leading to a clinical diagnosis of late-onset dHMN. Nerve conduction studies (NCSs) revealed a subclinical complication of sensory disturbance in one of the patients. The clinical and electrophysiological findings of patients with the HSPB1 Pro39Leu variant in this study and previous reports are summarized. INTERPRETATION: This study suggests that the clinical spectrum of patients carrying HSPB1 Pro39Leu variants, especially the disease onset, might be broader than expected, and HSPB1 variants should be considered in patients diagnosed with late-onset dHMN. Furthermore, patients with dHMN may have concomitant sensory deficits that should be evaluated using NCSs.

Noncanonical splice-site variant in peripheral myelin protein 22 gene (PMP22) in a patient with hereditary neuropathy with liability to pressure palsies.

AIM: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral neuropathy with autosomal dominant inheritance. Diagnosis can be made from the characteristic abnormalities determined by nerve conduction studies (NCS), including subclinical deficits at physiological compression sites. Heterozygous deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein 22 gene (PMP22) is the cause in the majority of cases. However, the loss of function of PMP22 due to frameshift-causing insertion/deletion, missense, nonsense, or splice-site disrupting variants cause HNPP in some patients. We report a case of a patient diagnosed with HNPP on the basis of clinical features and the results of NCS. No deletions of PMP22 were detected by fluorescence in situ hybridization. METHODS: We performed direct nucleotide sequence analysis and identified a heterozygous variant, c.78 + 3G > T, in PMP22. Since this variant is located outside the canonical splice site at the exon 2-intron 2 junction, we investigated whether the variant causes aberrant splicing and leads to the skipping of exon 2 of PMP22 by in vitro minigene splicing assay. RESULTS: We demonstrated that the c.78 + 3G > T variant causes the skipping of exon 2 and leads to loss of function of the mutant allele. CONCLUSION: Searching for sequence variants located outside the canonical splice sites should also be considered even when deletion of PMP22 is not found in a patient with a clinical diagnosis suggesting HNPP.

Management of treatment-resistant nocturnal enuresis.

Nocturnal enuresis is defined as intermittent urinary incontinence during sleep in children 5 years of age and older, occurring at least once a month for at least 3 months. In Japan, pediatricians who do not specialize in nocturnal enuresis have become more proactive in treating the condition since 2016, when the guidelines for treating it were revised for the first time in 12 years. For monosymptomatic nocturnal enuresis, the first step is lifestyle guidance, with a focus on the restriction of fluid intake at night; however, if lifestyle guidance does not decrease the frequency of nocturnal enuresis, aggressive treatment should be added. The first choice of aggressive treatment is oral desmopressin, an antidiuretic hormone preparation, or alarm therapy. However, there remain patients whose wet nights do not decrease with oral desmopressin or alarm therapy. In such cases, it is necessary to reconfirm the method of desmopressin administration and check for factors that may decrease the efficacy of desmopressin. If alarm therapy does not increase the number of dry nights, it is possible that the patient is fundamentally unsuitable for alarm therapy. If dry nights do not increase with oral desmopressin or alarm therapy, the next treatment strategy should be considered immediately to keep the patient motivated for treatment.

Comparison of the characteristics and factors influencing hospital visits among children with nocturnal enuresis in Japan: The Hirakata-Urayasu population-based cohort study.

OBJECTIVES: The aim of this study was to compare the demographic characteristics of school-aged children with nocturnal enuresis and factors influencing hospital visits between two regions in Japan. METHODS: A cross-sectional survey was conducted in Hirakata City, Osaka Prefecture, and Urayasu City, Chiba Prefecture. An anonymous online questionnaire was administered to all public elementary and junior high school students (aged 6-16 years) or their guardians. Questions included age, gender, perinatal history, frequency of nocturnal enuresis, frequency of bowel movements, comorbidities, and hospital visits for nocturnal enuresis. RESULTS: The survey response rates were 15.4% in Hirakata City and 37.0% in Urayasu City. In total, 426 children with nocturnal enuresis in Hirakata City and 270 in Urayasu City were included in the final analysis. In both cities, the boy-girl ratio was approximately 2:1, and the prevalence of nocturnal enuresis gradually decreased with age. Multivariate analysis revealed that children aged ≥11 years had a significantly higher proportion of hospital visits (OR, 2.61; 95% CI: 1.49-4.56; p = 0.001; OR, 2.72; 95% CI: 1.12-6.64; p = 0.027, respectively). However, the frequency of nocturnal enuresis did not affect hospital visits. CONCLUSIONS: The findings of this study suggest that parents with school-aged children have low awareness that nocturnal enuresis is a health problem and therefore subject to medical consultation. Although the proportion of hospital visits increases for children aged ≥11 years, children and families suffering from nocturnal enuresis should be encouraged to see a doctor instead of adopting a "wait and see attitude," even at a young age.

CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a devastating genetic disease presenting myoclonus, epilepsy, ataxia, and dementia. DRPLA is caused by the expansion of a CAG repeat in the ATN1 gene. Aggregation of the polyglutamine-expanded ATN1 protein causes neuro-degeneration of the dentatorubral and pallidoluysian systems. The expanded CAG repeats are unstable, and ongoing repeat expansions contribute to disease onset, progression, and severity. Inducing contractions of expanded repeats can be a means to treat DRPLA, for which no disease-modifying or curative therapies exist at present. Previously, we characterized a small molecule, naphthyridine-azaquinolone (NA), which binds to CAG slip-out structures and induces repeat contraction in Huntington's disease mice. Here, we demonstrate that long-term intracerebroventricular infusion of NA leads to repeat contraction, reductions in mutant ATN1 aggregation, and improved motor phenotype in a murine model of DRPLA. Furthermore, NA-induced contraction resulted in the modification of repeat-length-dependent dysregulation of gene expression profiles in DRPLA mice. Our study reveals the therapeutic potential of repeat contracting small molecules for repeat expansion disorders, such as DRPLA.

A clinical and genetic study of SPG31 in Japan.

SPG31 is an autosomal dominant hereditary spastic paraplegia caused by pathogenic variants in the receptor expression-enhancing protein 1 (REEP1) gene. We analyzed 488 DNA samples from unrelated HSP patients collected by Japan Spastic Paraplegia Research Consortium and found 15 Japanese SPG31 families. We investigated each family and found a total of 25 individuals with REEP1 variants (comprising 22 patients and three asymptomatic carriers). Fourteen REEP1 variants (five missense, three nonsense, four frameshift, one splice site, and one large deletion) including 11 novel ones were detected. Seventy percent of the patients (14 of 20) showed a pure form and the others (6 of 20) showed a complicated form with peripheral neuropathy. Fifty percent of the patients had neurological symptoms before the age of 10 and 20% of them at age 41-50. The mean age of onset was 19.6 ± 18.7 (from 5 to 67, n = 15) years for males and 32.8 ± 24.7 (from 4 to 60, n = 5) years for females. Although the difference was not statistically significant (p = 0.38, Mann-Whitney U test), males tended to have an earlier age of onset. Moreover, all three asymptomatic carriers were female. We investigated additional factors as to phenotypic appearance in one family with apparent intrafamilial variability in age at onset and clinical severity, but no additional factors including gene variants could be found. This is the first report of clinical and genetic findings of SPG31 in Japan, which may lead to further studies of the genotype-phenotype correlation of SPG31.

Chédiak-Higashi syndrome presenting as a hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by weakness and leg spasticity. LYST is responsible for Chédiak-Higashi syndrome (CHS), which exhibits partial oculocutaneous albinism, primary immunodeficiency, and bleeding tendency in childhood. Although neurological symptoms of CHS also appear in adulthood, a phenotype of spastic paraplegia has rarely been reported in CHS. In this study, we investigated LYST mutations in 387 HSP patients through the Japan Spastic Paraplegia Research Consortium to clarify the frequency of LYST mutations in HSP, finding six adult patients with LYST mutations in four HSP families. They exhibited intellectual disability, cerebellar ataxia, neuropathy, and pyramidal signs. Meanwhile, only 15 patients with CHS in childhood have been revealed in a decade by a nationwide survey in Japan. Thus, LYST mutations might indicate a HSP phenotype in a considerable number of adult patients with CHS.

Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments.

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

An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families.

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

The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy.

BACKGROUND: The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. OBJECTIVE: To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology. METHODS: We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. RESULTS: The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. CONCLUSIONS: This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Quantitative Evaluation of Cerebellar Function in Multiple System Atrophy with Transcranial Magnetic Stimulation.

Objective evaluation of cerebellar dysfunction in neurodegenerative disorders is often difficult because of other overlapping symptoms. Cerebellar inhibition (CBI) tested by dual-coil transcranial magnetic stimulation (TMS) is anticipated as a promising measure to estimate cerebellar function. Cerebellar TMS inhibits the primary motor cortex (M1), which can be measured as the decrease of motor evoked potential (MEP) elicited by a single-pulse TMS over the M1. This study was conducted to quantify cerebellar dysfunction using CBI in cerebellar type multiple system atrophy (MSA-C) patients. First, CBI was measured using MEP elicited from a hand muscle by stimulating the hand motor area of M1. The amount of CBI was defined as the degree of decrease in the MEP amplitude in the presence of cerebellar stimulation compared with the condition of M1 stimulation alone. Results of the MSA-C patients were compared with those of healthy volunteers. Correlation between amounts of CBI and a clinical scale of ataxia, the International Cooperative Ataxia Scale Rating (ICARS), was assessed. Healthy volunteers showed more inhibition than MSA-C patients. Moreover, ICARS showed that the CBI amount in the patients is correlated with the degree of ataxia significantly. Results suggest that CBI can be a good marker of disease progression in MSA-C patients.