Influence of Dystrophin Isoform Deficiency on Motor Development in Duchenne Muscular Dystrophy

In Duchenne muscular dystrophy (DMD), lack of the shorter dystrophin isoforms Dp140 and Dp71 is associated with increased central nervous system (CNS) involvement. We aimed to investigate how CNS involvement affects motor development in young DMD boys.

Three hundred and forty-two DMD boys aged 3-6 years were subdivided according to DMD mutation expected effects on isoform expression: Group 1 (Dp427 absent, Dp140/Dp71 present, n = 170); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 154) and Group 3 (Dp427/Dp140/Dp71 absent, n = 18). Mixed effects logistic regression was used to investigate relationships between isoform group and the odds of achieving higher North Star Ambulatory Assessment (NSAA) subitem scores for 15 subitems, adjusting for age at visit and glucocorticoid exposure.

The odds of achieving a full score of 2 were significantly lower for 11 NSAA subitems in Group 2 compared to Group 1, 5 NSAA subitems in Group 3 compared to Group 1, and 2 NSAA subitems in Group 3 compared to Group 2. The odds of achieving a score of 2 or 1 compared to 0 were significantly lower in Group 2 compared to Group 1 for the 2 NSAA subitems studied using this comparison.

We found strong and significant associations between the odds of achieving higher NSAA subitem scores and expected patterns of dystrophin isoform involvement, with a cumulative effect of loss of isoforms. This suggests an important relationship between dystrophin isoforms in the brain and the ability to carry out gross motor milestones.