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ObjectiveTo define the clinicopathologic features and diagnostic utility associated with anti-cytosolic 5'-nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs).MethodsAnti-NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases.ResultsOf 593 patients, anti-NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases patients. Among patients with IBM, anti-NT5C1A antibody seropositive patients had more cytochrome oxidase-negative fibers compared with anti-NT5C1A antibody seronegative patients. Among 14 IBM patients initially negative for anti-NT5C1A antibody, three patients (21%) converted to positive. Anti-NT5C1A antibody seropositivity did not correlate with malignancy, interstitial lung disease, response to treatments in dermatomyositis, antisynthetase syndrome, and IMNM, or survival in IIMs.InterpretationAnti-NT5C1A antibody is associated with IBM. However, the seropositivity can also be seen in non-IBM IIMs and it does not correlate with any prognostic factors or survival.

Dominant mutations in the HSP70 cochaperone DNAJB6 cause a late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease mutations reside within the G/F domain of DNAJB6, but the molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, and mouse models of LGMDD1, we found that the toxicity associated with disease-associated DNAJB6 required its interaction with HSP70 and that abrogating this interaction genetically or with small molecules was protective. In skeletal muscle, DNAJB6 localizes to the Z-disc with HSP70. Whereas HSP70 normally diffused rapidly between the Z-disc and sarcoplasm, the rate of diffusion of HSP70 in LGMDD1 mouse muscle was diminished, probably because it had an unusual affinity for the Z-disc and mutant DNAJB6. Treating LGMDD1 mice with a small-molecule inhibitor of the DNAJ-HSP70 complex remobilized HSP70, improved strength, and corrected myopathology. These data support a model in which LGMDD1 mutations in DNAJB6 are a gain-of-function disease that is, counterintuitively, mediated via HSP70 binding. Thus, therapeutic approaches targeting HSP70-DNAJB6 may be effective in treating this inherited muscular dystrophy.

Polymyositis and dermatomyositis are inflammatory myopathies that differ in their clinical features, histopathology, response to treatment, and prognosis. Although their clinical pictures differ, they both present with symmetrical, proximal muscle weakness. Treatment relies mainly upon empirical use of corticosteroids and immunosuppressive agents. A deeper understanding of the molecular pathways that drive pathogenesis, careful phenotyping, and accurate disease classification will aid clinical research and development of more efficacious treatments. In this review we address the current knowledge of the epidemiology, clinical characteristics, diagnostic evaluation, classification, pathogenesis, treatment, and prognosis of polymyositis and dermatomyositis.

OBJECTIVE: Exon-skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker muscular dystrophy (BMD) by altering pre-mRNA splicing to restore an open reading frame, allowing translation of an internally deleted and partially functional dystrophin protein. The most common single exon deletion-exon 45 (Δ45)-may theoretically be treated by skipping of either flanking exon (44 or 46). We sought to predict the impact of these by assessing the clinical severity in dystrophinopathy patients. METHODS: Phenotypic data including clinical diagnosis, age at wheelchair use, age at loss of ambulation, and presence of cardiomyopathy were analyzed from 41 dystrophinopathy patients containing equivalent in-frame deletions. RESULTS: As expected, deletions of either exons 45 to 47 (Δ45-47) or exons 45 to 48 (Δ45-48) result in BMD in 97% (36 of 37) of subjects. Unexpectedly, deletion of exons 45 to 46 (Δ45-46) is associated with the more severe DMD phenotype in 4 of 4 subjects despite an in-frame transcript. Notably, no patients with a deletion of exons 44 to 45 (Δ44-45) were found within the United Dystrophinopathy Project database, and this mutation has only been reported twice before, which suggests an ascertainment bias attributable to a very mild phenotype. INTERPRETATION: The observation that Δ45-46 patients have typical DMD suggests that the conformation of the resultant protein may result in protein instability or altered binding of critical partners. We conclude that in DMD patients with Δ45, skipping of exon 44 and multiexon skipping of exons 46 and 47 (or exons 46-48) are better potential therapies than skipping of exon 46 alone.

Objective: To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). Methods: We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross‐sectional observational study using previously validated patient‐reported outcome assessments (ACTIVLIM, PROMIS‐57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. Results: A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5‐1 lb/year). Cross‐sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. Interpretation: This study is the largest description of LGMDD1 patients to date and highlights potential genotype‐dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients. [ABSTRACT FROM AUTHOR]

Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD., Mutations in the DMD gene result in either the more severe Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy (BMD). The phenotype generally depends on whether the mutation [...]