Aim: To examine the association between dystrophin isoform disruption and cognitive and behavioral outcomes, including autism spectrum disorder (ASD), in a large cohort of boys with Duchenne muscular dystrophy (DMD).
Method: In this retrospective cohort (2014–2025), 161 boys with genetically confirmed DMD were classified according to predicted involvement of the brain-expressed dystrophin isoforms Dp427, Dp140, and Dp71. Cognitive function was assessed using standardized intelligence scales (WISC-IV or WASI) and comprehensive neuropsychological evaluation. ASD was diagnosed using DSM-5 criteria and confirmed through multidisciplinary assessment.
Results: Intellectual disability (ID) was identified in 63 of 161 patients (39.1%), including 47 (29.1%) with mild and 16 (10.0%) with moderate ID. ASD was diagnosed in 16 patients (10%), and in 81% of cases, ASD identification preceded or coincided with the diagnosis of dystrophinopathy.
A clear isoform-dependent gradient was observed: patients with mutations restricted to exons 1–44 (Dp427-only) showed the highest frequency of normal cognition, whereas those with mutations affecting Dp140 or Dp71 exhibited progressively higher rates of ID and ASD.
Interpretation: Cognitive impairment and ASD are frequent non-muscular manifestations of DMD and correlate closely with disruption of brain-expressed dystrophin isoforms, particularly Dp140 and Dp71. Integrating genetic and neuropsychological assessment into routine care is essential for early recognition and timely intervention.