Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full‐length Dp427 is the primary dystrophin isoform expressed in muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS comorbidities is well known, relationships between mutations expected to disrupt Dp140 and Dp71 and motor outcomes are not. Methods Functional outcome data from 387 DMD boys aged 4–15 years were subdivided by DMD mutation expected effects on dystrophin isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n = 201); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 152); and Group 3 (Dp427/Dp140/Dp71 absent, n = 34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10 m walk/run velocities and rise time velocities were explored using regression analysis. Western blot analysis was used to study Dp427, Dp140 and Dp71 production in myogenic cells (control and DMD human), control skeletal muscle, DMD skeletal muscle from the three isoform groups and cerebral cortex from mice (wild‐type and DMD models). Grip strength and rotarod running test were studied in wild‐type mice and DMD mouse models. DMD mouse models were mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD‐null (lacking all isoforms). Results In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in Group 3 than Group 1 (P < 0.01) and 4.9 points lower in Group 3 than Group 2 (P = 0.05). Mean peak NSAA scores were 4.0 points lower in Group 3 than Group 1 (P < 0.01) and 1.6 points lower in Group 2 than Group 1 (P = 0.04). Mean four‐limb grip strength was 1.5 g/g lower in mdx52 than mdx mice (P = 0.003) and 1.5 g/g lower in DMD‐null than mdx mice (P = 0.002). Dp71 was produced in myogenic cells (control and DMD human) and skeletal muscle from humans in Groups 1 and 2 and mdx mice, but not skeletal muscle from human controls, myogenic cells and skeletal muscle from humans in Group 3 or skeletal muscle from wild‐type, mdx52 or DMD‐null mice. Conclusions Our results highlight the importance of considering expected effects of DMD mutations on dystrophin isoform production when considering patterns of DMD motor impairment and the implications for clinical practice and clinical trials. Our results suggest a complex relationship between dystrophin isoforms expressed in the brain and DMD motor function.

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Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full length Dp427 is the primary dystrophin isoform expressed in skeletal muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS co-morbidities is well known, relationships between lack of Dp140 and Dp71 and DMD motor outcomes are not. We have conducted a series of investigations addressing this. Methods Functional outcome data from 387 DMD boys aged 4.0-15.4 years was subdivided by DMD mutation expected effect on isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n=201); group 2 (Dp427/Dp140 absent, Dp71 present, n=152); and group 3 (Dp427/Dp140/Dp71 absent, n=34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10m walk/run and rise times were explored using regression analysis. We used Capillary Western immunoassay (Wes) analysis to study Dp427, Dp140 and Dp71 production in wild-type and DMD skeletal muscle and myogenic cultures. Grip strength was studied in wild-type, mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD-null (lacking all isoforms) mice. Results In DMD boys, we found a strong association between isoform group and motor function. In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in group 3 than group 1 (p<0.01) and 4.9 points lower in group 3 than group 2 (p=0.05). Mean peak NSAA scores were 4.0 points lower in group 3 than group 1 (p<0.01), 2.4 points lower in group 3 than group 2 (p=0.09) and 1.6 points lower in group 2 than group 1 (p=0.04). Average grip strength in peak force at 3 months of age was higher in mdx than mdx52 mice (p=0.01). Dp427, but not Dp71, was produced in normal skeletal muscle; low levels of Dp71 were detected in DMD skeletal muscle. High Dp71 levels were present in wild-type and DMD myogenic cultures. Conclusions DMD boys lacking Dp140 and Dp140/Dp71 displayed worse motor function with a cumulative effect of isoform loss. DMD mouse models lacking Dp427 and Dp140 had lower grip strength than those lacking Dp427 but not Dp140. Our results highlight the importance of considering the effects of dystrophin isoform loss on DMD motor impairment, with important implications for understanding the complex relationship between brain and muscle function in DMD and patient stratification for clinical trials.

Introduction/Aims Spinal muscular atrophy (SMA) type III is a relatively mild form of SMA. Few studies have investigated the changes in both respiratory and upper limb function within this population after loss of ambulation. The aim of this study was to assess change in percentage of predicted forced vital capacity (FVC% predicted) and change in the Revised Upper Limb Module (RULM) score in these patients throughout a 24‐month period after loss of ambulation. Effect of scoliosis and its surgical correction, disease duration since loss of ambulation, weight, and height were also investigated. Methods Retrospective analyses were performed on 24 nonambulant SMA III patients from data collected at two centers in the United Kingdom. Results The FVC% predicted score showed a significant progressive deterioration of 17% over the 24‐month period. Respiratory deterioration correlated significantly with age, weight, disease duration since loss of ambulation, and spinal correctional surgery. Longitudinal RULM data were available for 16 patients; a significant deterioration was observed with a mean decrease in score of 3 over 24 months. Age correlated negatively with RULM score, as did height and time since loss of ambulation. A significant positive correlation between FVC% predicted and RULM was demonstrated. Discussion This study highlights how SMA type III patients have progressive deterioration of respiratory and upper limb function after loss of ambulation. Combining data from these assessments could provide insight into clinical progression, inform clinical trials, and provide assistance in managing disease progression expectations for patients.