The Multiple Facets of Brain Involvement In Duchenne Muscular Dystrophy

Objectives: Boys with Duchenne muscular dystrophy not only lack dystrophin in muscle, but, depending on the site of the DMD mutation, also to produce shorter isoforms important for brain function. We assessed the effect of the deficiency of different dystrophin isoforms on cognitive and neurobehavioural comorbidities, and motor outcome in DMD. Methods: We performed deep phenotyping in a large DMD population, subdivided in 3 groups based on the site of the DMD mutations: group 1, mutations only affecting full length (Dp427) isoform; group 2 mutations also affecting the brain isoform Dp140; group 3, mutations affecting all isoforms (Dp71+Dp427+Dp140). Results: Boys only lacking Dp427 had normal cognitive function, while boys deficient for all isoforms (group 3) had significant learning disability (mean IQ52) and those in group 2 had a mean IQ of 75. The neurobehavioural comorbidities were more evenly spread across genotypes, although the probability of multiple comorbidities (i.e. ASD, ADHD, internalising and externalising problems) increased in groups 2 and 3. We also documented a pathological startle response the threat in DMD boys, present in boys in group 1, and more severe in group 2. Finally, we demonstrated a clear relationship between motor functional outcome and site of the mutations, with better performance in boys in group 1 than groups 2 and 3. Conclusion: Our results highlight the importance of considering effects of DMD mutations both for cognitive and behavioural comorbidities, but also motor impairment, suggesting a previously unappreciated relationship between dystrophin isoforms expressed in the brain and DMD motor function.