Autism Spectrum Disorder in Duchenne Muscular Dystrophy

Background: Duchenne Muscular Dystrophy (DMD) is a recessive, X-linked muscle disease caused by a mutation in the dystrophin gene, which codes for the protein dystrophin. Dystrophin is an important structural component in muscle tissue, but is also expressed in the brain, and neurodevelopmental disturbance is common in people with DMD.  Preliminary evidence suggests that autism spectrum disorder (ASD) may be highly prevalent in DMD, alongside difficulties with executive function and intellectual development. Furthermore, clinical observations suggest that the location of a person’s mutation in the dystrophin gene may affect their risk of developing ASD and other neurodevelopmental problems.  Specifically, we suggest that the further down the dystrophin gene the mutation, the more likely an individual is to have neurodevelopmental problems. Mutations downstream of exon 63 have the greatest impact on the production of forms of dystrophin that are expressed in the brain.

Objectives: To asses formally the prevalence of ASD in a sample of young people with DMD; and to test the hypothesis that mutations further downstream in the dystrophin gene carry the greatest risk of causing neurodevelopmental disturbance.

Methods: Participants were 112 (mean age = 9.5 years) boys with DMD, attending the neuromuscular outpatient departments at Great Ormond Street Hospital (London) and Gemelli Hospital (Rome). Parents completed the Social and Communication Disorders Checklist (SCDC) as a screen for ASD. Targeted neuropsychological assessments included: (1) Wechsler Intelligence Scale for Children-IV (WISC-IV); (2) the Dimensional, Diagnostic and Developmental Interview (3Di); (3) the Conners-3; and (4) the Child Behaviour Checklist. Within this sample 39 had a mutation upstream of exon 30 of the dystrophin gene; 85 had a mutation between exons 31 and 62; and 12 had mutations downstream of exon 62.

Results: Forty per cent of the sample scored above the cut-off for probable ASD caseness on the SCDC screening measure. Subsequent detailed and rigorous assessment using the 3Di suggested a prevalence for ASD of 24% within this sample. Estimated rates of ADHD (35%) and internalising problems (30%) were also high. In addition general intellectual disability was found in 28% of the boys with DMD tested using the WISC-IV. SCDC score and intellectual ability were both associated with genotype: children who had a mutation downstream of exon 62 were most severely affected.

Conclusions: Rates of neurodevelopmental difficulties, including ASD, are elevated in DMD compared to general paediatric samples. Boys with mutations downstream of exon 62 have the highest risk of neurodevelopmental disorder, including autistic social communication impairment. Our findings highlight the need to clarify the role of dystrophin in neurodevelopment, and to investigate whether the gene-protein-brain-behaviour pathway we describe has relevance to cases of ASD outside of DMD.