To test the hypothesis that DMD mutations expected to differentially impact dystrophin isoform expression could differentially affect the pattern of motor impairment in Duchenne muscular dystrophy (DMD).

DMD is caused by DMD mutations leading to loss of dystrophin protein. In addition to the universal involvement of the Dp427 isoform, different mutations might lead to the additional involvement of isoforms Dp140 and Dp71 expressed in brain. Severity of central nervous system involvement (CNS) increases with cumulative loss of Dp140 and Dp71.

The North star ambulatory assessment motor function scale has 17 subitems scored 0 (unable), 1 (completes with modifications) or 2 (completes without modifications). Subitem scores for 621 DMD participants aged 5.0 to 7.9 years were classified by dystrophin isoform involvement; group 1 (Dp427 absent, Dp140/Dp71 present, n=246), group 2 (Dp427/Dp140 absent, Dp71 present, n=195) and group 3 (Dp427/Dp140/Dp71 absent, n=32). Multiple logistic regression, including age as a co-variate, was used to investigate differences in subitem scores between isoform groups. P<0.003 was considered significant via Bonferroni correction for multiple testing.

Subitem scores were lower in those lacking Dp140 and Dp71, with a cumulative effect of loss of isoforms, for stand right/left, climb right/left, descend right/left, jump, hop right/left and run (p<0.003 for all). For example, amongst 6.0-6.9 year olds, percentage achieving 2 for stand on left leg was 59% (group 1), 52% (group 2) and 13% (group 3) and for jump was 72% (group 1), 64% (group 2) and 33% (group 3). 

In addition to the known CNS phenotype, DMD boys lacking Dp140 and Dp71 exhibit remarkably worse scores for multiple NSAA subitems with a cumulative effect of loss of isoforms. Certain subitems are more impacted than others and the pattern of involvement varies with age. It is crucial to consider dystrophin isoform involvement in DMD clinical practice and trial design.