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Background: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far. Objective: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy. Methods: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point. Results: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was –0.1 kg (–2.1 to 2.0) in the SA-ER group and –5.1 kg (–10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (–0.3 to 9.9; P = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed. Conclusions: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan.

This study aimed to characterize dysphagic patients with inclusion body myositis (IBM) with cricopharyngeal bar (CPB) (n = 17; IBM-CPB(+)) by comparing their swallowing function and muscle magnetic resonance imaging data with IBM patients without CPB (n = 28; IBM-CPB(-)). IBM-CPB(+) patients were older at diagnosis and had more frequent obstruction-related dysphagia and stronger knee extension than IBM-CPB(-) patients. IBM-CPB(+) patients also had less intramuscular fatty infiltration than IBM-CPB(-) patients on T1-weighted magnetic resonance images of the rectus femoris (2.6% versus 10.3%, p0.05), vastus lateralis (27.8% versus 57.1%, p0.01), vastus intermedius (17.6% versus 43.5%, p0.01), vastus medialis (14.1% versus 39.1%, p0.01), deltoid (5.5% versus 18.7%, p0.05), biceps (6.6% versus 21.1%, p0.001), and triceps (12.9% versus 33.0%, p0.05). These findings suggest that IBM-CPB(+) patients were older, frequently exhibited obstruction-related dysphagia, had stronger knee extension, and had less fatty infiltration of the limb muscles compared to IBM-CPB(-) patients, and provide valuable information on the clinical subset of IBM-CBP(+) patients in order to expand the knowledge of the clinical heterogeneity in IBM.

Background Developmental disorders associated with Becker muscular dystrophy (BMD), possibly resulting from a lack of dystrophin in the brain, have been reported, but their importance is not fully understood. We report a case of a BMD patient who had been socially withdrawn due to mental retardation and autism spectrum disorder and could not receive appropriate medical services, resulting in delayed detection of severe cardiomyopathy and embolic strokes which developed as complications of BMD. Case report: The case is a 41-year-old male. In elementary school, he was the slowest runner in his class and had poor grades. He started missing school due to bullying in junior high school and had been socially withdrawn for 24 years. He developed difficulty walking due to progressive muscle weakness in the extremities and lost ambulation at age 36. At age 41, he was referred to our hospital by public health support services to address his social withdrawal. Muscle biopsy led to the diagnosis of BMD. Psychological examination revealed mild mental retardation and autism spectrum disorder, which may have resulted in social isolation. He had severe cardiomyopathy and asymptomatic cerebral infarction due to heart failure. Conclusion In BMD patients, developmental disorders can potentially hinder access to appropriate medical treatment. BMD is an important differential diagnosis for physically disabled children with developmental disorders. Early intellectual and psychological interventions and evaluation of complications are important for improving patient prognosis and quality of life.

Lewy body-related α-synucleinopathy (Lewy pathology) has been reported in patients with myotonic dystrophy (DM) type 1 (DM1), but no detailed report has described the prevalence and extent of its occurrence. We studied consecutive full autopsy cases of DM1 at the National Center of Neurology and Psychiatry (NCNP) Brain Bank for intractable psychiatric and neurological disorders. Thirty-two cases, genetically determined to be DM1 (59.0 ± 8.7 years), obtained from the NCNP Brain Bank, were compared with control cases obtained from the Brain Bank for Aging Research (BBAR) in Japan. The investigated anatomical sites followed the Dementia with Lewy Bodies Consensus Guideline, expanding to the peripheral autonomic nervous system, temporal pole, and occipital cortex, in addition to the olfactory epithelium and spinal cord. Of the 32 patients, 11 (34.4%) had Lewy pathology, with a significantly higher prevalence than that in the control cases from the BBAR (20.1%). Lewy pathology detected in DM1 was widespread, but no macroscopic depigmentation of the substantia nigra was observed in any DM1 case; this was commensurate with the microscopic paucity of Lewy pathology in the substantia nigra and amygdala. Lewy pathology in DM1 does not appear to follow either Braak's ascending paradigm or the olfactory-amygdala extension. Lewy neurites and dots in DM1 were very sparse in the cerebral cortex and distinct from those observed in BBAR control cases. This study was the first demonstration of unique Lewy pathology in DM1 and may contribute to the understanding of the protein propagation hypothesis of Lewy pathology.

Extraordinary Measures is a 2010 film about parents who tried to develop a drug with a glycobiology scientist to save their children suffering from a milder subtype of infantile Pompe disease (non-classic infantile-onset form), which can be said as an intermediate type between infantile onset and late-onset types. This movie is based on a nonfiction book The Cure by Geeta Anand. Pompe disease (glycogen storage disease type 2) is a myopathy, that affects the diaphragm. Infantile Pompe disease presents cardiomyopathy and hepatomegaly. Enzyme replacement therapy for Pompe disease with Myozyme was approved by FDA in 2006. Activities of the patients and their families association, including fund-raising, were pictured in the film, as well as (1) negotiation with a venture capital firm, (2) management of a pharmaceutical company for an orphan drug development for a rare genetic disorder, and conflicts of the father who works for the pharmaceutical company and desperately wants to provide the products to his own children.

Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy. This report aims to describe two unrelated male patients showing mild manifestations of the disease. A 39-year-old man presented with a 10-year history of elevated serum creatine kinase levels with slowly progressive muscle weakness. Muscle pathology showed autophagic vacuoles with sarcolemmal features. Genetic testing revealed a hemizygous mutation in exon 9b, an alternatively spliced exon, of lysosome-associated membrane protein-2 (LAMP-2) (c.1097_1098delAA). Cardiac testing showed asymptomatic mild left ventricular hypertrophy. He had borderline intelligence. Early stage of retinopathy was detected. Another male patient, currently 53-year-old, had asymptomatic supraventricular extrasystole and muscle weakness but no intellectual disability, harboring the same mutation. He also had retinopathy. The present patients commonly carry a mutation in exon 9b of LAMP-2, suggesting that mutations in the exon are associated with a mild form of Danon disease.

DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T>A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70 and DNAJB4 predominantly in type 1 fibers. Both Dnajb4- F90L knock-in and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.

BackgroundA number of clinical trials targeting GNE myopathy patients have been conducted. However, useful clinical parameters for postmarketing surveillance and long-term clinical observation have not yet been established.ObjectiveWe conducted a 5-year observational follow-up natural history study to identify evaluation parameters, which may be useful for the long-term observation of GNE myopathy patients.MethodsThirty-three genetically confirmed GNE myopathy patients were recruited and evaluated at study entry (baseline) and yearly in a 5-year follow-up. Hand-held dynamometer measurements of knee extension strength, grip power and pinch power, summed Manual Muscle Testing (MMT) score of 17 muscles, Gross Motor Function Measure (GMFM), 6 min walk test, percent vital capacity and percent forced vital capacity (%FVC), lean body mass (whole body, arms and legs), creatine kinase, Barthel Index, modified Rankin Scale and 36-item Short Form Survey national standard scores were examined.ResultsOf the 33 patients, 22 (66%) completed evaluations for the entire 5-year follow-up period. These patients had a significant reduction in summed MMT score (p=0.005), GMFM (p=0.005), pinch power (pConclusionsMMT, GMFM, pinch power and %FVC are useful parameters for the long-term evaluation of GNE myopathy patients.

SummaryFacioscapulohumeral muscular dystrophy (FSHD) can be subdivided into two types: FSHD1, caused by contraction of the D4Z4 repeat on chromosome 4q35, and FSHD2, caused by mild contraction of the D4Z4 repeat plus aberrant hypomethylation mediated by genetic variants in SMCHD1, DNMT3B, or LRIF1. Genetic diagnosis of FSHD is challenging because of the complex procedures required. Here, we applied Nanopore CRISPR/Cas9-targeted resequencing for the diagnosis of FSHD by simultaneous detection of D4Z4 repeat length and methylation status at nucleotide level in genetically-confirmed and suspected patients. We found significant hypomethylation of contracted D4Z4 repeats in FSHD1 and strong correlation between methylation rate and patient phenotype. This finding can explain how repeat contraction contributes to disease pathogenesis by activating DUX4 expression.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in all cases analyzed. Exonization of intronic sequences was observed in 15 cases and exon skipping in one case; 13 single nucleotide variants and three structural rearrangements were identified as causal genomic variations. DMD transcripts were aberrantly spliced and polyadenylated in two cases in which chromosome rearrangements were detected. In one case, DMD transcripts were terminated due to nucleotide repeat expansion. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed, because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in 19 of 20 cases; Exonization of intronic sequences in 15 cases, exon skipping in one case, aberrantly spliced and polyadenylated transcripts in two cases and transcription termination in one case. Intronic single nucleotide variants, chromosomal rearrangements and nucleotide repeat expansion were identified in DMD gene as pathogenic causes of transcript alteration. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

Background Anti-mitochondrial antibody (AMA)–associated myopathy is known to be concomitant with primary biliary cirrhosis and to cause both skeletal muscle disorders and arrhythmias, myocardium disorders, and respiratory muscle disorders. We report a case of AMA-associated myopathy in which the bradycardia-related symptoms preceded the skeletal muscle symptoms. Case summary A 59-year-old woman visited the emergency room in our hospital following a syncopal event. The patient was bradycardiac (45 bpm) with a junctional rhythm resulting from sick sinus syndrome (SSS) and was suffering from heart failure. Blood tests revealed elevated creatinine kinase (CK) and hepatic enzymes. She underwent permanent pacemaker implantation. However, it proved difficult to detect the electrical potential in the right atrium. Although successful atrial pacing was achieved at the lower right atrial septum, the atrial threshold was markedly high and she depended on ventricular pacing. One year later, neurological examination and muscle biopsy confirmed the diagnosis of AMA-associated myopathy. Following this diagnosis, steroid pulse therapy was initiated. Steroid administration relieved her symptoms and lowered the CK levels but the atrial standstill persisted. The patient takes low-dose prednisolone and has had an uneventful course for 3 years. Discussion To the best of our knowledge, this is the first case of AMA-associated myopathy diagnosed by the first symptom related to bradycardia due to SSS. Patients with AMA-associated myopathy can experience a variety of cardiac symptoms, including arrhythmias, and initially complain of cardiac symptoms without symptoms of skeletal myopathy. This disease should be considered when diagnosing patients with arrhythmia and elevated CK.

Background Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 (nSMase2/Smpd3) hydrolyzes sphingomyelin in lipid rafts. This protein thus modulates inflammatory responses, cell survival or apoptosis pathways, and the secretion of extracellular vesicles in a Ca2+-dependent manner. However, its roles in dystrophic pathology have not yet been clarified. Methods To investigate the effects of the loss of nSMase2/Smpd3 on dystrophic muscles and its role in the abnormal behavior observed in DMD patients, we generated mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice). Results Young mdx:Smpd3 DKO mice exhibited reduced muscular degeneration and decreased inflammation responses, but later on they showed exacerbated muscular necrosis. In addition, the abnormal stress response displayed by mdx mice was improved in the mdx:Smpd3 DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus. Conclusions nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.

To determine the prevalence and characteristics of the cricopharyngeal bar (CPB), defined as marked protrusion with lacking relaxation and stricture of the upper esophageal sphincter on videofluoroscopy, in patients with inclusion body myositis (IBM). We conducted a case–control study of comprehensive series of adult healthy individuals and consecutive patients with neuropsychiatric disorders aged over 45 (52 versus 2486). A standard videofluoroscopy was performed. Overall, 47 individuals with CPB were identified. Of the individuals with CPB, 36% were IBM followed by neurodegenerative disorders, muscular disorders, neuromuscular disorders, and others (32%, 21%, 2.1%, and 8.5%, respectively), indicating the heterogeneity of the etiologies. Against muscular disorders, the sensitivity and specificity of the CPB for IBM were 33% (= 17/52; 95% confidence interval [CI], 20–45%) and 96% (= 264/274; 95% CI, 94–99%), respectively. IBM with CPB showed a higher frequency of obstruction-related dysphagia (88% versus 22%, p

Background: Few studies have examined respiratory dysfunction in patients with Becker muscular dystrophy (BMD). Objective: This study aimed to examine the characteristics of respiratory dysfunction in patients with BMD. Methods: The present retrospective study assessed respiratory parameters of adult BMD patients using medical records and compared these parameters with various patient characteristics to identify correlations. BMD patients aged 17 years and older who had been diagnosed genetically and/or pathologically were included in the analysis. Results: Of the source population of 133 patients, respiratory function was assessed in 85. Two of these patients had no symptoms, and eight had died. Mean % forced vital capacity (% FVC) was 94.2+/–21.7% (median, 96.1%; range, 5.1–134.1%). In 16 (19%) of the 85 patients, % FVC was

Becker muscular dystrophy (BMD) is caused by specific mutations in the DMD gene that causes progressive muscle weakness and primarily affects skeletal and cardiac muscle. Although cardiac involvement is a significant cause of mortality in BMD, the genetic–phenotype correlation for skeletal and cardiac muscles has not been elucidated. Here, we described a 39-year-old man with BMD, who presented with subtle skeletal muscle weakness in the right leg in his 20s and underwent left ventricular restoration for severe dilated cardiomyopathy at the age of 29. He had difficulty climbing stairs after the age of 35. Neither duplication nor deletion of exons was detected by multiplex ligation-dependent probe amplification. A hemizygous c.264 + 1G>A mutation in intron 4 of the DMD was identified by next-generation sequencing. Furthermore, exon 4 skipping of the DMD was confirmed in both skeletal and cardiac muscles evaluated by reverse transcriptase PCR. Endomyocardial and skeletal muscle biopsies revealed dystrophic pathology characterized by muscle fiber atrophy and hypertrophy with a mild degree of interstitial fibrosis. Interestingly, dystrophin immunohistochemistry demonstrated patchy and faint staining of the skeletal muscle membranes but almost normal staining of the cardiac muscle membranes. Western blot analysis revealed a decreased amount of truncated dystrophin in skeletal muscle but surprisingly almost normal amount in cardiac muscle. This case indicates that BMD patients may have severe cardiac dysfunction despite preserved cardiac truncated dystrophin expression.

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5′ UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

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

Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy.We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2).The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy.Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.

BackgroundA number of clinical trials targeting GNE myopathy patients have been conducted. However, useful clinical parameters for post-marketing surveillance and long-term clinical observation have not yet been established. ObjectiveWe conducted a 5-year observational follow-up natural history study to identify evaluation parameters which may be useful for the long-term observation of GNE myopathy patients. MethodsThirty-three genetically-confirmed GNE myopathy patients were recruited and evaluated at study entry (baseline) and yearly in a 5-year follow-up. Hand-held dynamometer measurements of knee extension strength, grip power, and pinch power, summed Manual Muscle Testing (MMT) score of 17 muscles, Gross Motor Function Measure (GMFM), 6-minute walk test, percent vital capacity and percent force vital capacity (%FVC), lean body mass (whole body, arms, and legs), creatine kinase (CK), Barthel Index, modified Rankin Scale, and SF-36 national standard scores were examined. ResultsOf the 33 patients, 22 (66%) completed evaluations for the entire 5-year follow-up period. These patients had a significant reduction in summed MMT score (p=0.001), GMFM (p=0.001), grip power (p=0.013), pinch power (pp=0.030), %FVC (pp=0.040), and the Physical Functioning subscale score of the SF-36 (p=0.015) at the 5th year evaluation relative to baseline. Among these parameters, summed MMT score, GMFM, pinch power, and %FVC showed significant changes even in non-ambulant patients.ConclusionsMMT, GMFM, pinch power, CK, %FVC, lean body mass, and Physical Functioning subscale score of the SF-36 are useful parameters for the long-term evaluation of GNE myopathy patients.

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.

BackgroundOculopharyngodistal 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.ObjectivesTo identify and to clinicopathologically characterize OPDM patients who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC).MethodsTwo hundred eleven 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 the identified OPDM_NOTCH2NLC patients were re-reviewed. Intra-myonuclear inclusions were further evaluated by immunohistochemistry and electron microscopy.ResultsSeven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically had ptosis, ophthalmoplegia, dysarthria, and muscle weakness, and myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which are diagnostic of NIID typically on skin biopsy, in addition to rimmed vacuoles. Sample for electron microscopy was available only from one patient, which showed intranuclear inclusions of 12.6 ± 1.6 nm in diameter.ConclusionsWe identified seven OPDM_NOTCH2NLC patients. Our patients had various additional central and/or peripheral nervous system involvement, albeit all being clinicopathologically compatible; thus, diagnosed as having OPDM, expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

The degradation of cellular components plays an essential role in homeostasis. However, the known degradation pathways cannot account for the levels of proteolysis in cells. Here, we demonstrate that cytosolic proteins are imported into lysosomes in an ATP-dependent manner for degradation through a direct uptake mechanism distinct from any known pathway. SIDT2, a lysosomal membrane protein previously reported as an RNA transporter, translocates substrate proteins across the lysosomal membrane. Furthermore, we identify a dominant-negative mutation in SIDT2 that causes neuropathy and distal myopathy with rimmed vacuoles, a protein aggregation disease in humans. We generate Sidt2 knockout mice, recapitulating the characteristic features of this disease. Our results reveal a novel degradation pathway and illustrate its crucial role in cellular proteostasis, physiology, and pathophysiology.One Sentence SummaryDiscovery of a novel proteolytic pathway in cells, the dysfunction of which leads to protein aggregation disease in humans.

Importance Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, setting, and participants This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main outcomes and measures Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and relevance This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

Nemaline myopathy commonly presents with symmetrical proximal weakness. Here we report two cases of nemaline myopathy presenting with distal dominant involvement with prominent asymmetry. Case 1 was a 37-year-old man who recalled frequently falling down and had right calf atrophy since he was 3-years-old. He had right calf muscle atrophy and weakness and steppage gait; his cardiopulmonary function was normal. Case 2 was a 35-year-old man with right calf muscle atrophy and weakness since childhood. He had right dominant distal leg weakness and atrophy together with respiratory failure and started noninvasive positive pressure ventilation. He also developed cardiomyopathy and died from acute respiratory failure due to pneumonia at age 39. Both cases harbored compound heterozygous nebulin (NEB) mutations with c.20131 C>T:p.Arg6711Trp and a nonsense mutation. Nemaline myopathy associated with NEB mutations can present as distal dominant myopathy with prominent asymmetry.

Introduction: Little is known about the frequency of cardiopulmonary failure in limb-girdle muscular dystrophy type 2A (calpainopathy) patients, although some studies have reported severe cardiomyopathy or respiratory failure. Methods: To clarify the frequency of cardiopulmonary dysfunction in this patient population, we retrospectively reviewed the respiratory and cardiac function of 43 patients with calpainopathy. Results: Nine of the 43 patients had forced vital capacity (FVC)

Introduction: Little is known about the frequency of cardiopulmonary failure in limb‐girdle muscular dystrophy type 2A (calpainopathy) patients, although some studies have reported severe cardiomyopathy or respiratory failure. Methods: To clarify the frequency of cardiopulmonary dysfunction in this patient population, we retrospectively reviewed the respiratory and cardiac function of 43 patients with calpainopathy. Results: Nine of the 43 patients had forced vital capacity (FVC)

ObjectiveTo elucidate the prevalence of Japanese ADSSL1 myopathy and determine the clinicopathologic features of the disease.MethodsWe searched for ADSSL1 variants in myopathic patients from January 1978 to March 2019 in our repository and assessed the clinicopathologic features of patients with variants.ResultsWe identified 63 patients from 59 families with biallelic variants of ADSSL1. Among the 7 distinct variants identified, c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other 5 were novel. Most of the identified patients displayed more variable muscle symptoms, including symptoms in the proximal and/or distal leg muscles, tongue, masseter, diaphragm, and paraspinal muscles, in adolescence than previously reported patients. Dysphagia with masticatory dysfunction developed in 26 out of 63 patients; hypertrophic cardiomyopathy developed in 12 out of 48 patients; and restrictive ventilatory insufficiency developed in 26 out of 34 patients in later stages. Radiologically, fat infiltration into the periphery of vastus lateralis, gastrocnemius, and soleus muscles was observed in all patients. Pathologically, nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy. This finding revealed that ADSSL1 myopathy is the most frequent among all genetically diagnosable nemaline myopathies in our center.ConclusionsADSSL1 myopathy is characterized by more variable manifestations than previously reported. It is the most common among all genetically diagnosable nemaline myopathies in our center, although mildly increased lipid droplets are also constantly observed features.

Background X‐linked myotubular myopathy (XLMTM) is a form of the severest congenital muscle diseases characterized by marked muscle weakness, hypotonia, and feeding and breathing difficulties in male infants. It is caused by mutations in the myotubularin gene (MTM1). Methods Evaluation of clinical history and examination of muscle pathology of three patients and comprehensive genome analysis on our original targeted gene panel system for muscular diseases. Results We report three patients, each of whom presents distinct muscle pathological features. The three patients have novel hemizygous MTM1 variants, including c.527A>G (p.Gln176Arg), c.595C>G (p.Pro199Ala), or c.688T>C (p.Trp230Arg). Conclusions All variants were assessed as “Class 4 (likely pathogenic)” on the basis of the guideline of American College of Medical Genetics and Genomics. These distinct pathological features among the patients with variants in the second cluster of PTP domain in MTM1 provides an insight into microheterogeneities in disease phenotypes in XLMTM.

Introduction: Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon. Case presentation: We report a family with a history of PC accompanied by persistent distal hand dominant muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. Cases within the family harbor the prevalent PC causative mutation, T1313M, in the SCN4A gene. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy. Conclusions: PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness.

The patient was an 81-year-old woman. At age 73, she developed difficulties in climbing stairs and swallowing, and became unable to open bottles at age 74. She had been walking with a cane since age 76. Accidental chest X-ray findings showed bilateral hilar lymphadenopathy at age 78. Angiotensin converting enzyme (ACE) was elevated. Lymphocyte proliferation was prominent in bronchoalveolar lavage fluid. Sarcoidosis was suspected, but she was followed without treatment due to lack of respiratory symptoms. She became unable to walk without assistance at age 80 and visited our hospital with a complaint of gait disturbance at age 81. Moderate diffuse muscle atrophy in extremities was evident. Muscle weakness of finger flexion and knee extension were remarkable. The muscle involvement pattern was similar to sporadic inclusion body myositis (sIBM). However, radiographically, rectus femoris and semitendinosus muscles are selectively preserved. This radiogaphic finding was consistent with chronic sarcoid myopathy (CSM). We reached a final diagnosis of CSM based on the presence of granulomas in the muscle biopsy specimen, BHL in fluorodeoxyglucose positron-emission tomography, the previous finding of elevated ACE, and bronchoscopy results. In conclusion, CSM is a treatable disease and should thus be differentiated from sIBM. This should not be done solely based on clinical findings, but instead, muscle biopsy should be performed. Moreover, muscle selectivity may be useful in distinguishing between CSM and sIBM.

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Objective. Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies. Methods. We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies. Results. We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled. Conclusion.Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy.

Introduction We retrospectively reviewed respiratory and cardiac function in patients with dysferlinopathy, including 2 autopsy cases with respiratory dysfunction. Methods Subjects included 48 patients who underwent respiratory evaluation (n = 47), electrocardiography (n = 46), and echocardiography (n = 23). Results Of the 47 patients, 10 had reduced percent forced vital capacity (%FVC), and 4 required non-invasive positive pressure ventilation. %FVC was significantly correlated with disease duration, and mean %FVC was significantly lower in non-ambulatory patients, as well as in those aged ≥65 years with normal creatine kinase levels. On electrocardiography, QRS complex duration was prolonged in 19 patients, although no significant association with age, disease duration, or respiratory function was found. Echocardiography indicated no left ventricular dysfunction in any patient. Histopathology of autopsied cases revealed mild cardiomyopathy and moderate diaphragm involvement. Conclusion Patients with dysferlinopathy may develop severe respiratory failure and latent cardiac dysfunction. Both respiratory and cardiac function should be monitored diligently. Muscle Nerve 53: 394–401, 2016

Sporadic late onset nemaline myopathy (SLONM) associated with monoclonal gammopathy of undetermined significance (MGUS) is an adult onset myopathy with poor clinical outcomes, requiring high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM-SCT). Here we report two cases of SLONM associated with MGUS in which improvements were achieved only with immunotherapy. A 39-year-old woman had a two-year history of dropped head syndrome and progressive proximal weakness. On admission, she was able to walk with assistance and had lordosis with camptocormia. Combination therapy with plasmapheresis and intravenous immunoglobulin in addition to intravenous methylprednisolone pulse therapy ameliorated camptocormia and proximal weakness after one year. A 51-year-old man had difficulty in raising his arms and required walking assistance prior to visiting our hospital. He had proximal weakness and atrophy, winged scapulae, and gait disturbance. After combination immunotherapy, no progression was observed for 13 years. In both cases, patients did not desire to undergo HDM-SCT, and IgG kappa monoclonal protein was positive, of which the levels were normalized after immunotherapy. Combination immunotherapy can be a possible alternative to HDM-SCT in patients with SLONM. Both patients showed myogenic changes with abundant fibrillation, and needle EMG revealed positive sharp waves. Case 1 showed high signal intensities in MRI STIR/T2WI in muscles showing weakness. These findings are commonly observed in patients with myositis, suggesting that, without muscle biopsy, SLONM may be misdiagnosed as myositis. Muscle biopsy revealed scattered fibers with nemaline bodies without type 2B deficiency, which are important pathological findings that differentiate SLONM from congenital nemaline myopathy.

To show the predictive risk factors for aspiration pneumonia and prognostic importance of a cricopharyngeal bar (CPB) on videofluoroscopic examination of swallowing (VFS) in inclusion body myositis (IBM).In this retrospective study, we examined a consecutive series of 37 patients with clinico-pathologically defined IBM based on the European Neuromuscular Center diagnostic criteria for IBM from 2013. The Swallowing Disturbance Questionnaire was used for the evaluation of dysphagia. A standard VFS was performed at diagnosis. The primary outcome was aspiration pneumonia. Secondary outcomes included IBM Functional Rating Scale score, forced vital capacity (FVC), and body mass index.Aspiration pneumonia occurred in 10 of 37 IBM patients (27%). Based on univariate analysis, 4 factors increased aspiration pneumonia risk: BMI 18.5 (n = 5; hazard ratio [HR], 10.7; 95% CI, 2.50-46.0; p = .001); aspiration (n = 7; HR, 7.57; 95% CI, 1.82-31.6; p = .005); insufficient opening of the upper esophageal sphincter (n = 11; HR, 4.53; 95% CI, 1.12-18.3; p = .03); and CPB presence (n = 15; HR, 11.6; 95% CI, 1.46-91.8; p = .02). Clinical features of IBM-CPB(+) were elderly onset, obstruction-related dysphagia, and mild decreases in FVC, resulting in aspiration pneumonia in 1.3 years (interquartile range, 0.9-5.2); 67% of IBM-CPB(+) patients underwent interventional procedures for dysphagia. IBM-CPB(+) patients had a lower FVC than IBM-CPB(-).A CPB in IBM largely contributes to obstruction-related dysphagia and is a risk factor that predicts aspiration pneumonia and refractory dysphagia requiring aggressive therapy.

The majority of patients with Duchenne muscular dystrophy (DMD) have electrocardiographic abnormalities, but the clinical significance of conduction disturbances remains unclear. This study aimed to evaluate age-dependent cardiac conduction disturbances by electrocardiogram (ECG) to identify risks of complete atrioventricular (AV) block in this patient population. In total, 47 patients with DMD (age, ≥20 ys) who recorded ECGs at our hospital from July 2015 to June 2016 were included in this study. The PR interval and QRS duration in their previous ECGs were analyzed retrospectively. Associations between ECG findings and left ventricular (LV) systolic function obtained from the latest echocardiography were examined. The mean age of patients was 27.6 ± 6.0 years, and the mean observation period was 9.8 ± 3.7 years. The PR interval gradually increased with age, but no ECGs showed an abnormally prolonged PR interval. On the other hand, the QRS duration tended to increase progressively with age, and some patients had an abnormally prolonged QRS duration. The QRS duration was not correlated with LV systolic function (P = 0.867). One patient who developed a complete AV block had a drastically prolonged QRS duration before the onset of the disorder. The QRS duration tended to increase progressively with age, irrespective of LV systolic function in patients with DMD. Attention should be paid to the QRS duration as an indicator of risk for complete AV block in older patients.

We report a 62-year-old woman with a history of Basedow's disease and Sjogren's syndrome who presented with slowly progressive limb muscle weakness over the course of ten years. On physical examination, she had dry eye and mouth, but was otherwise normal. Neurological examination revealed symmetrical proximal dominant muscle weakness. Polymyositis was suspected at initial diagnosis due to her clinical course, physical examination, and autoimmune disease. However, the final diagnosis based on a muscle biopsy was the chronic myopathic type of sarcoid myopathy. Among 25 definite sarcoid myopathy cases in the National Center of Neurology and Psychiatry muscle repository from 2010 to 2015, 6/25 had autoimmune diseases. All 6 patients were female and had the chronic myopathic type of sarcoid myopathy. The number of patients with Sjogren's syndrome, thyroid disease, autoimmune hepatitis, and idiopathic thrombocytopenia were 4, 1, 1, and 1, respectively. Only the present case had both thyroid disease and Sjogren's syndrome. In conclusion, the chronic myopathic type of sarcoid myopathy is one possibility to consider in patients who present with progressive myopathy together with autoimmune diseases.