The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.

Introduction-Acid maltase deficiency (AMD) (Pompe disease) is an inherited myopathic disorder of glycogen degradation. Diagnosis is often delayed. Muscle ultrasound could improve diagnosis.

ATLIS was more sensitive to change than ALSFRS-R or VC and could decrease sample size requirements by approximately one-third. The ability of ATLIS to detect prefunctional change has potential value in early trials. Muscle Nerve 56: 710-715, 2017.

Background: Duchenne muscular dystrophy (DMD) is a rare x-linked recessive genetic disorder affecting 1 in every 5000–10000 [1, 2]. This disease leads to a variable but progressive sequential pattern of muscle weakness that eventually leads to loss of important functional milestones such as the ability to walk. With promising drugs in development to ameliorate the effects of muscle weakness, these treatments must be associated with a clinically meaningful functional change. Objective: The objective of this analysis is to determine both distribution, minimal detectable change (MDC), and anchor-based, minimal clinically important difference, (MCID) of 12 month change values in standardized time function tests (TFT) used to monitor disease progression in DMD. Method: This is a retrospective analysis of prospectively collected data from a multi-center prospective natural history study with the Cooperative International Neuromuscular Research Group (CINRG). This study calculated MDC and MCID values for 3 commonly used timed function tests typically used to monitor disease progression; supine to stand (STS), 10 meter walk/run(10MWT), and 4 stair climb(4SC). MDC used standard error of measurement (SEM) while MCID measurements used the Vignos scale as an anchor to determine clinical change in functional status. Results: All 3 TFT were significantly important clinical endpoints to detect MDC and MCID changes. MDC and MCID 12 month changes were significant in 10MWT(–0.138, –0.212), Supine to Stand (–0.026, –0.023) and 4 stair climb (–0.034, –0.035) with an effect size greater or close to 0.2. Conclusion: The 3 TFT are clinically meaningful endpoints used to establish change in DMD. MCID values were higher than MDC values indicating that an anchor-based approach using Vignos as a clinically meaningful loss of lower extremity abilities is appropriate to assess change in boys with DMD.

Objective:To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM.Methods:Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS).Results:Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning.Conclusions:The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.