The relationship between deficit in digit span and genotype in nonsense mutation Duchenne muscular dystrophy

OBJECTIVETo evaluate the relationship between deficit in digit span and genotype in nonsense mutation (nm) Duchenne muscular dystrophy (DMD) (nmDMD). METHODSWe investigated the relationship between normalized digit-span forward (d-sf) and digit-span backward (d-sb) scores to the location of nmDMD mutations in 169 participants ≥5 to ≤20 years who participated in a phase 2b clinical trial. Because alternative promoters are found upstream of DMD exons 30, 45, and 63, we correlated d-sf and d-sb to the specific nmDMD mutation location. RESULTSParticipants with nm downstream of exon 30, downstream of exon 45, and downstream of exon 63 had significantly lower normalized d-sf scores (p < 0.0001). Participants with nm downstream of exon 45 in addition had significantly lower normalized d-sb score (p < 0.04). There was no significant difference in the normalized d-sb score in participants with mutations upstream or downstream of DMD exon 30 or upstream or downstream of DMD exon 63. CONCLUSIONOur data provide evidence that specific cognitive deficits correlate to genotype in individuals with nmDMD, highlighting the critical role of brain-specific dystrophin isoforms in the neurobiological manifestations of this disease. CLINICALTRIALS.GOV IDENTIFIERNCT02090959.