Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophy (LGMD2C, LGMD2D, LGMD2E, and LGMD2F) that are caused, respectively, by mutations in the SGCG, SGCA, SGCB, and SGCD genes. Knowledge about the clinical and genetic features of sarcoglycanopathies in Chinese patients is limited. The aims of this study were to investigate in detail the clinical manifestations, sarcoglycan expression, and gene mutations in Chinese patients with sarcoglycanopathies and to identify possible correlations between them. Of 3638 patients for suspected neuromuscular diseases (1733 with inherited myopathies, 1557 with acquired myopathies, and 348 unknown), 756 patients had next-generation sequencing (NGS) diagnostic panel. Twenty-five patients with sarcoglycanopathies (11.5%) were identified from 218 confirmed LGMDs, comprising 18 with LGMD2D, 6 with LGMD2E, and one with LGMD2C. One patient with LGMD2D also had Charcot-Marie-Tooth 1A. The clinical phenotypes of the patients with LGMD2D or LGMD2E were markedly heterogeneous. Muscle biopsy showed a dystrophic pattern in 19 patients and mild myopathic changes in 6. The percentage of correct prediction of genotype based on expression of sarcoglycan was 36.0% (4 LGMD2D, 4 LGMD2E, and one LGMD2C). There was a statistically significant positive correlation between reduction of α-sarcoglycan level and disease severity in LGMD2D. Thirty-five mutations were identified in SGCA, SGCB, SGCG, and PMP22, 16 of which were novel. Exon 3 of SGCA was a hotspot region for mutations in LGMD2D. The missense mutation c.662G > A (p.R221H) was the most common mutation in SGCA. Missense mutations in both alleles of SGCA were associated with a relative benign disease course. No obvious clinical, sarcoglycan expression, and genetic correlation was found in LGMD2E. This study expands the clinical and genetic spectrum of sarcoglycanopathies in Chinese patients and provides evidence that disease severity of LGMD2D may be predicted by α-sarcoglycan expression and SGCA mutation.

Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that has been reported in different ethnic populations which carry different common mutations of the acid alpha-glucosidase (GAA) gene. The GAA mutation pattern in mainland Chinese patients with late-onset Pompe disease is still not well understood. We presented the clinical and genetic characteristics of 27 mainland Chinese late-onset Pompe patients from 24 families. GAA mutation analysis revealed 26 different mutations, including 10 that were novel. The allelic frequency of c.2238G > C (p.W746C) was found to be 27.08% in this patient group. Respiratory dysfunction was diagnosed in 10 of 11 patients who underwent pulmonary function evaluation, although only four required ventilator support at night. Our findings indicate that c.2238G > C (p.W746C) is the most common mutation in mainland Chinese late-onset Pompe patients, as observed in Taiwanese patients. The novel mutations identified in this study expand the genetic spectrum of late-onset Pompe disease, and the prevalence of respiratory dysfunction highlights the importance of monitoring pulmonary function in late-onset Pompe patients.

Objective: We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes.Methods: The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up.Results: Thirty‐five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb‐girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha‐dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long‐term use in patients with COLQ or AGRN mutations.Interpretation: The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb‐girdle myasthenic syndrome, tubular aggregates, and decreased alpha‐dystroglycan were indicative of the specific subtypes. Based on the follow‐up findings, we suggest cautious evaluation of the long‐term efficacy of therapeutic agents in congenital myasthenic syndrome.

Objective: To quantitatively evaluate cerebral small vessel disease (CSVD) in brain magnetic resonance imaging (MRI) and its correlation with disease burden and markers in Fabry disease, a rare X-linked lysosomal storage disease. Methods: We collected brain MRI data from seventy-one Chinese patients with Fabry disease. CSVD was evaluated using an age-related white matter change rating scale, Fazekas scale, enlarged perivascular spaces grading scale, lacunar infarction scale, Microbleed Anatomical Rating Scale, global cortical atrophy scale, and small-vessel disease score. Factors associated with MRI lesions, including sex, clinical subtype, disease severity, disease burden, genotype, and biomarkers, were also analyzed. Results: Of 71 patients, 16 (22.5%) experienced ischemic stroke. The incidences of lacunar infarctions, white matter hyperintensities, and cerebral microbleeds were 55%, 62%, and 33%, respectively. The abnormal MRI group had later disease onset, longer disease duration, and a higher Mainz Severity Score Index (p < 0.05) than the normal MRI group. Patients with more severe clinical phenotypes also had higher CVSD-related scores. Sex and GLA mutational type were not closely associated with brain MRI lesions. Of the disease markers, the Mainz Severity Score Index and plasma globotriaosylsphingosine (Lyso-Gb₃) were closely correlated with the majority of the MRI scores, whereas α-galactosidase A activity was not. Conclusion: Brain MRI revealed progressive lacunar infarctions, white matter hyperintensities, and decreased brain volume in patients with Fabry disease. Brain MRI lesions were closely related to onset-age; disease duration, severity, burden; and plasma Lyso-Gb₃. However, they were not associated with sex, α-galactosidase A activity, or GLA mutation type.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), usually referred to as hereditary diffuse leukoencephalopathy with spheroids or pigmentary orthochromatic leukodystrophy, is genetically caused by CSF1R mutations. AARS2 was recently confirmed to be another causative gene in a series of CSF1R-negative ALSP cases. We report a case of adult-onset leukoencephalopathy with ALSP with AARS2 variants. A 34-year-old woman presented with 2 years of motor and cognitive deterioration with severely impaired cortical functions and rigid spasticity. Brain magnetic resonance imaging showed a confluent, patchy, and predominantly frontoparietal, periventricular pattern of white matter lesions, with relatively preserved subcortical U-fibers. Brain biopsy revealed axonal spheroids, severe demyelination and pigmented macrophages. Genetic analyses revealed compound heterozygous c.1691T>C and c.179C>A variants in the AARS2 gene. CSF1R mutation testing was negative. Our findings proved adult-onset leukoencephalopathy with spheroids and pigmented glia to be a genetically heterogeneous disease entity. The selective brain involvement without ovarian failure might be a new subtype in AARS2 mutations related to ALSP.

Objective: This study aimed to investigate mitochondrial changes and the mitochondrial antiviral‐signaling protein (MAVS)‐type I interferon (IFN1) signaling pathway in the muscles of anti‐melanoma differentiation gene 5(MDA5) dermatomyositis (DM) patients.Methods: Eleven anti‐MDA5 DM and ten antibody‐negative DM patients were included. Muscle biopsies were performed in all patients. Muscle pathology and mitochondrial morphology in particular were compared between two groups. The expression of MDA5, MAVS, interferon (IFN) regulatory factor 7, and IFN‐stimulated gene 15, which are components of the MAVS‐IFN1 signaling pathway, was measured in muscle specimen. The correlation between MAVS expression in muscles and disease phenotypes and muscle pathology were analyzed.Results: Anti‐MDA5 DM showed a significantly lower incidence of the characteristic DM pathology (P < 0.05) than antibody‐negative DM, including perifascicular fiber atrophy, inflammation, and vasculopathy. Mitochondrial abnormalities in anti‐MDA5 patients revealed a high incidence of (8/11,72.7%) and different pattern from that in antibody‐negative DM. MDA5, MAVS, IFN regulatory factor 7, and IFN stimulated gene 15 expression levels in the muscles of anti‐MDA5 DM patients were higher than those of the controls (P < 0.05) but lower than those of antibody‐negative DM patients (P < 0.05). The MAVS levels negatively correlated with manual muscle test 8 scores (r = 0.701, P = 0.016).Conclusions: Compared to antibody‐negative DM, we presented a different distribution of the mitochondrial pathology and less severe morphology in anti‐MDA5 DM. We also revealed the enhanced but less intensive MAVS‐IFN1 signaling pathway activity in muscles of anti‐MDA5 DM. Such disparity suggested the potentially different mechanism of muscle injury in two DM groups.