Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study, long-read whole-genome sequencing and repeat-primed PCR were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)₆₉ repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyglycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion-related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases.

Background Lipid-storage myopathy (LSM), defined by triglyceride accumulation in muscle fibres, is a heterogeneous group of lipid metabolic disorders predominantly affecting skeletal muscle. In the past 15 years, more than 200 cases of LSM have been reported in the Chinese literature, but the accurate pathogenic mechanisms are still unknown. Objective In order to gain more insight into the metabolic and genetic dysfunctions of LSM, the authors described a group of Chinese patients with LSM who were very responsive to isolated riboflavin treatment (riboflavin responsive LSM, RR-LSM). Methods Nineteen consecutive LSM patients collected during 1995–2007 in our Neuromuscular Laboratory who were dramatically responsive to riboflavin and presented with proximal muscle weakness, exercise intolerance and elevated serum CK but without episodic encephalopathy were subjected to pathological, biochemical and molecular analysis. Results On the basis of muscle pathology, all 19 patients were diagnosed as LSM. Seventeen patients were suspected of having multiple acyl-coenzyme A dehydrogenase deficiency (MADD) according to blood acylcarnitine profiles and urine organic acid analysis. Genetic analysis identified 19 novel mutations in ETFDH gene in 18 patients, among which one was homozygote, 16 were compound heterozygotes, and one was a single heterozygote. No pathogenic mutation was detected in ETFA or ETFB genes. Western blot analysis showed there was no significant decrease in ETF:QO expression except for one patient. Conclusions The research findings suggest that the majority of Chinese patients with RR-LSM are caused by a mild type of MADD with unique myopathy which is due to ETFDH gene mutation.

Recently, an astrocytic aquaporin 4-dependent drainage system, that is, the glymphatic system, has been identified in the live murine and human brain. Growing evidence suggests that glymphatic function is impaired in patients with several neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. As the third most common neurodegenerative disease, although animal studies have indicated that early glymphatic dysfunction is likely an important pathological mechanism underpinning amyotrophic lateral sclerosis (ALS), no available study has been conducted to thoroughly assess glymphatic function in vivo in ALS patients to date, particularly in early-stage ALS patients. Thus, using DTI analysis along the perivascular space (ALPS) index, an approximate measure of glymphatic function in vivo, we aimed to explore whether glymphatic function is impaired in early-stage ALS patients and the diagnostic performance of the ALPS index in distinguishing between early-stage ALS patients and healthy subjects. We also aimed to identify the relationships between glymphatic dysfunction and clinical disabilities and sleep problems in early-stage ALS patients. In this retrospective study, King’s stage 1 ALS patients were defined as early-stage ALS patients. We enrolled 56 early-stage ALS patients and 32 age- and sex-matched healthy controls (HCs). All participants completed clinical screening, sleep assessment, and ALPS index analysis. For the sleep assessment, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and polysomnography were used. Compared with HCs, early-stage ALS patients had a significantly lower ALPS index after family-wise error correction (p < 0.05). Moreover, receiver operating characteristic analysis showed that the area under the curve for the ALPS index was 0.792 (95% confidence interval 0.700-0.884). Partial correlation analyses showed that the ALPS index was significantly correlated with clinical disability and sleep disturbances in early-stage ALS patients. Multivariate analysis showed that sleep efficiency (r = 0.419; p = 0.002) and periodic limb movements in sleep index (r = -0.294; p = 0.017) were significant predictive factors of the ALPS index in early-stage ALS patients. In conclusion, our study continues to support an important role for glymphatic dysfunction in ALS pathology, and we provide additional insights into the early diagnostic value of glymphatic dysfunction and its correlation with sleep disturbances in vivo in early-stage ALS patients. Moreover, we suggest that early improvement of glymphatic function may be a promising strategy for slowing the neurodegenerative process in ALS. Future studies are needed to explore the diagnostic and therapeutic value of glymphatic dysfunction in individuals with presymptomatic-stage neurodegenerative diseases.

Objective: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases with various subtypes, myositis-specific antibodies, and affect multiple systems. The treatment of IIMs remains challenging, especially for refractory myositis. In addition to steroids and traditional immunosuppressants, rituximab (RTX), a B cell-depleting monoclonal antibody, is emerging as an alternative treatment for refractory myositis. However, the therapeutic response to RTX remains controversial. This meta-analysis aimed to systematically evaluate the efficacy and safety of RTX in patients with IIMs, excluding sporadic inclusion body myositis.Methods: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and WanFang Data were searched for relevant studies. The overall effective rate, complete response rate, and partial response rate were calculated to assess the efficacy of RTX. The incidences of adverse events, infection, severe adverse events, severe infection, and infusion reactions were collected to evaluate the safety of RTX. Subgroup analyses were performed using IIM subtypes, affected organs, continents, and countries. We also performed a sensitivity analysis to identify the sources of heterogeneity.Results: A total of 26 studies were included in the quantitative analysis, which showed that 65% (95% confidence interval [CI]: 54%, 75%) of patients with IIMs responded to RTX, 45% (95% CI: 22%, 70%) of patients achieved a complete response, and 39% (95% CI: 26%, 53%) achieved a partial response. Subgroup analyses indicated that the overall efficacy rates in patients with refractory IIMs, dermatomyositis and polymyositis, as well as anti-synthetase syndrome were 62%, 68%, and 62%, respectively. The overall efficacy rates for muscle, lungs, and skin involvement were 59%, 65%, and 81%, respectively. In addition, studies conducted in Germany and the United States showed that patients with IIMs had an excellent response to RTX, with an effective rate of 90% and 77%, respectively. The incidence of severe adverse events and infections was 8% and 2%, respectively.Conclusion: RTX may be an effective and relatively safe treatment choice in patients with IIMs, especially for refractory cases. However, further verification via randomized controlled trials is warranted.