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Objective: Nemaline myopathy (NM) is a rare neuromuscular condition with clinical and genetic heterogeneity. To establish disease natural history, we performed a cross-sectional study of NM, complemented by longitudinal assessment and exploration of pilot outcome measures., Methods: Fifty-seven individuals with NM were recruited at 2 family workshops, including 16 examined at both time points. Participants were evaluated by clinical history and physical examination. Functional outcome measures included the Motor Function Measure (MFM), pulmonary function tests (PFTs), myometry, goniometry, and bulbar assessments., Results: The most common clinical classification was typical congenital (54%), whereas 42% had more severe presentations. Fifty-eight percent of individuals needed mechanical support, with 26% requiring wheelchair, tracheostomy, and feeding tube. The MFM scale was performed in 44 of 57 participants and showed reduced scores in most with little floor/ceiling effect. Of the 27 individuals completing PFTs, abnormal values were observed in 65%. Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure. Genotypes included mutations in ACTA1 (18), NEB (20), and TPM2 (2). Seventeen individuals were genetically unresolved. Patients with pathogenic ACTA1 and NEB variants were largely similar in clinical phenotype. Patients without genetic resolution had more severe disease., Conclusion: We present a comprehensive cross-sectional study of NM. Our data identify significant disabilities and support a relatively stable disease course. We identify a need for further diagnostic investigation for the genetically unresolved group. MFM, PFTs, and the slurp test were identified as promising outcome measures for future clinical trials., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To investigate the efficacy of N -acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies ( RYR1 -RM)., Methods: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance., Results: When compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment ( p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] -1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI -5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study., Conclusion: In ambulatory RYR1 -RM-affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane., Classification of Evidence: This study provides Class I evidence that, for people with RYR1 -RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane., Clinicaltrialsgov Identifier: NCT02362425., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs)., Methods: Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts., Results: Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year ( p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% ( p < 0.05) and 2.55% ( p < 0.01). Range-of-motion measurements decreased by 3.21° ( p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° ( p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% ( p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed., Conclusion: Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs., (© 2019 American Academy of Neurology.)

Objective: The aim of this study was to measure musculoskeletal disorders and occupational risk factors among railroad maintenance-of-way (MOW) workers., Methods: Four thousand eight hundred sixteen active, retired, and disabled members of the Brotherhood of Maintenance of Way Employes Division (BMWED) completed a survey., Results: Compared with U.S. employed men, adjusting for age, race, and region, active male MOW workers were more likely to report "repeated lifting, pushing, pulling, or bending" at work (74.6% vs 46.9%), not enough staff (88.1% vs 65.2%), and a diagnosis of carpal tunnel syndrome (7.9% vs 3.6%). They were less likely to report management priority on workplace health and safety (59.37% vs 94.8%), ability to make job decisions on their own (68.4% vs 87.7%), and supervisor support (60.3% vs 90.8%) (all comparisons, P < 0.001)., Conclusion: Prevention programs should address risk of musculoskeletal disorders and occupational hazards faced by MOW workers.

Background: Fibro-elastic deficiency (FED) and diffuse myxomatous degeneration (DMD) are phenotypes of degenerative mitral valve disease defined morphologically. Whether physiological differences in annular and valvular dynamics exist between these phenotypes remains unknown., Methods and Results: We performed triple quantitation of cardiac remodeling and of mitral regurgitation severity and of annular and valvular dimensions by real-time 3-dimensional-transesophageal-echocardiography. Forty-nine patients with degenerative mitral valve disease classified as FED (n=31) and DMD (n=18) by surgical observation showed no difference in age (65±10 versus 59±13; P=0.5), body surface area (2.0±0.2 versus 2.0±0.2 m(2); P=0.5), left ventricular and atrial dimensions (all P>0.55), and mitral regurgitation regurgitant orifice (P=0.62). On average, annular dimensions were larger in DMD versus FED, but height was similar resulting in lower saddle shape. Dynamically, annular DMD versus FED display poorer contraction and saddle-shape accentuation in early systole and abnormal enlargement, particularly intercommissural, in late-systole (all P<0.05). Valvular dynamics showed stable valvular area in systole in FED versus considerable systolic increased area in DMD (P<0.001). Prolapse height and volume increased little throughout systole in FED versus marked increase in DMD (P<0.001)., Conclusions: Our novel observations show that FED and DMD, although both labeled myxomatous, display considerable physiological phenotypic differences. In DMD, the annular increased size and profoundly abnormal dynamics demonstrate DMD-specific annular degeneration compared with the enlarged but relatively normal FED annulus. DMD does not incur more severe mitral regurgitation, despite larger prolapse and valve redundancy, underscoring potential compensatory role of tissue redundancy of DMD (or aggravating role of tissue paucity of FED) on mitral regurgitation severity., (© 2015 American Heart Association, Inc.)