European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society · 2026
Neurocognitive and autism spectrum profiles associated with dystrophin isoform disruption in childhood dystrophinopathies: insights from a Brazilian cohort.
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Albuquerque Marco Antônio Veloso, Dias Sarah Leonardo, Lima Karla Danielle, Kok Fernando, Zanoteli Edmar
Аннотация
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) and related dystrophinopathies.
METHOD: In this retrospective cohort study (2014-2025), 161 boys with genetically confirmed dystrophinopathy (145 DMD, 14 Becker muscular dystrophy, and 2 intermediate muscular dystrophy) were classified according to predicted involvement of the brain-expressed dystrophin isoforms Dp427, Dp140, and Dp71. Cognitive function was assessed using standardized intelligence measures (WISC-IV or WASI), complemented by comprehensive neuropsychological evaluation. ASD was diagnosed according to 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. An 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 childhood dystrophinopathies and correlate closely with disruption of brain-expressed dystrophin isoforms, particularly Dp140 and Dp71. Integrating genetic and neuropsychological assessment into routine clinical care is essential for early recognition and timely intervention.
METHOD: In this retrospective cohort study (2014-2025), 161 boys with genetically confirmed dystrophinopathy (145 DMD, 14 Becker muscular dystrophy, and 2 intermediate muscular dystrophy) were classified according to predicted involvement of the brain-expressed dystrophin isoforms Dp427, Dp140, and Dp71. Cognitive function was assessed using standardized intelligence measures (WISC-IV or WASI), complemented by comprehensive neuropsychological evaluation. ASD was diagnosed according to 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. An 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 childhood dystrophinopathies and correlate closely with disruption of brain-expressed dystrophin isoforms, particularly Dp140 and Dp71. Integrating genetic and neuropsychological assessment into routine clinical care is essential for early recognition and timely intervention.