DMD/BMD - GENETICS: EP.112 Genotype-phenotype correlation for cognitive and neurodevelopmental comorbidities in Duchenne and Becker muscular dystrophy

Abstract

Although intellectual disability was included in the first description of Duchenne muscular dystrophy (DMD), the cognitive and neurodevelopmental (ND) components of DMD and Becker muscular dystrophy (BMD) remain overshadowed by their motor, cardiac, and pulmonary manifestations. To assess the ND comorbidity burden in dystrophinopathy patients at Le Bonheur Children's Hospital neuromuscular clinic, abstraction of the electronic medical record was performed for 46 patients. Diagnoses of ADHD, epilepsy, autism spectrum, obsessive compulsive, oppositional defiant, mood, anxiety, and sleep disorders, along with discussion of any cognitive difficulties, shyness, or other maladaptive behaviors, were recorded for each patient. Patients were stratified into groups based on their genetic alteration and DMD isoforms predicted to be affected: 1) exons 1-29 (Dp427 impacted alone), 2) exons 30-50 (Dp427 through untranslated region of Dp140 impacted), and 3) exons 51-79 (Dp427 through Dp40 impacted). Mention of cognitive difficulties, spanning from repeating grades to specific learning disorders to severe intellectual disability, and other behavioral problems not meeting a formal diagnosis (including aggression, self-injurious behavior, emotional lability) were present for 74% (34/46) and 61% (28/46) of patients, respectively. The number of patients affected by any type of cognitive difficulty in Group 1 versus 3 was statistically significant (p = 0.01; Fisher exact test) with all members of Group 3 having some cognitive difficulty. Similarly, there is a statistically significant difference in the number of comorbidities between Groups 1 and 3 (p = 0.002; Mann-Whitney U test) with a stair-step increase in comorbidity burden as more isoforms are disrupted. These findings highlight that learning difficulties and behavior problems may be encountered more frequently than previously reported and that distal genotypes merit more extensive and earlier neuropsychological evaluation.