Genotype-phenotype correlation of neurodevelopmental disorders in patients with dystrophinopathies

Abstract

Objective  Neurodevelopmental disorders are frequently and heterogeneously diagnosed among patients with dystrophinopathies. The authors aimed to evaluate how the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD), Obsessive-Compulsive Disorder (OCD), or Autism Spectrum Disorder (ASD), and genotype are related to DMD genotype.

Methods  In an observational cross-sectional study, standardized instruments were applied to 50 participants and their caregivers, mainly from a reference center for rare diseases in Southern Brazil (n = 38) or other Brazilian centers (n = 12). Participants were divided according to genotype and affected dystrophin isoforms.

Results  The overall diagnostic rate of symptoms of ASD was 34 %, similar to OCD (35.5 %), with half of the participants (51.4 %) having symptoms compatible with ADHD. Cerebral isoforms were affected in more than half of the participants (52 %). Symptoms compatible with ASD and OCD, and Childhood Autism Rating Scale (CARS) scores were associated with genotype and impairment of cerebral isoforms of dystrophin.

Conclusions  The prevalence of symptoms compatible with ASD (and higher CARS scores) and OCD among patients with dystrophinopathies are related to the position of the causal variant in DMD and the consequent involvement of cerebral isoforms, indicating an important genotype-phenotype correlation. The diagnosis of a patient with a genotype that affects these isoforms indicates the need for neuropsychological assessment and multidisciplinary follow-up.

Keywords
Genotype-phenotype correlation; Dystrophin isoforms; Dystrophinopathies; Autism spectrum disorder; Attention-deficit/hyperactivity disorder; Obsessive-compulsive disorder