Developmental delay and neuropsychiatric comorbidities associated with Duchenne and Becker muscular dystrophy

Abstract

Neurodevelopmental disorders have been recognized in Duchenne muscular dystrophy (DMD) for over 50 years. At that time, the prevalence of intellectual disability was reported to be sixfold higher in DMD compared with the general population. Although the full-scale intelligence quotient (IQ) scores in children with DMD follow a normal distribution, their mean IQ score is 80, which is one standard deviation below the mean of a normative population. Overall, learning disabilities are seen in 27% of boys and young men with DMD, with cognitive delays apparent in the first few years of life. Lower IQ does not correlate with the severity of muscle weakness nor does IQ decline with advancing age. Dystrophin protein has an essential membrane-stabilizing effect in skeletal muscles protecting the sarcolemma from contractioninduced damage. In addition to skeletal and cardiac muscle, dystrophin is also expressed in the central nervous system and has been localized to areas critical for learning and higher cognitive functioning, including neurons within the cerebral cortex and hippocampus. The dystrophin gene can undergo splicing at various sites, giving rise to shorter isoforms that are expressed in several tissues. Compared with full-length dystrophin, which has a molecular weight of 427 kd, the smaller isoforms range from 71 to 260 kd. The 71-kd isoform (Dp71) is expressed in nonskeletal muscle tissues, including brain, retina, kidney, liver, and lung. Dp116 is expressed in adult peripheral nerves; Dp140 is expressed in brain, retina, and kidneys; and Dp260 is expressed predominantly in retinal cells. The location of mutations within the DMD gene can have an effect on the specific isoforms, thereby modifying the phenotype. Boys and young men with DMD with mutations between exons 31 to 79 and 46 to 79 show lower average full-scale IQ scores compared with those having more proximal mutations. Mutations distal to exon 45 have been postulated to alter Dp140 expression, an isoform that is present in the fetal brain. The Dp140 isoform is regulated by a promoter within exon 44, with the transcript of Dp140 beginning at exon 51. This was corroborated by other studies that reported mutations affecting Dp140 and Dp260 isoforms to be associated with a higher likelihood of learning disability (60% of patients), autism spectrum disorder (77%), and anxiety (94%). Neuropsychiatric disorders also show higher prevalence in boys and young men with DMD, with increased overall rates of attention-deficit hyperactivity disorder (ADHD) (32% of patients), anxiety (27%), and autism spectrum disorder (15%). Mutations in exons 45 to 55, affecting the Dp140 isoform expression, have a higher likelihood of ADHD that is unrelated to corticosteroid regimen. Although mutations at this location were associated with an increased risk of neuropsychiatric symptoms, this relationship was not absolute. Patients with identical mutations do not always demonstrate the same cognitive or behavioral phenotype, indicating that other genetic modifiers appear to contribute to their development. DMD exists at the more severe end of the phenotype spectrum with earlier-onset symptoms, more rapid disease progression, and earlier loss of ambulation compared with Becker muscular dystrophy (BMD). The likelihood of developing one vs the other depends largely upon whether a gene deletion or duplication affects the reading frame. Mutations affecting the reading frame result in rapid degeneration of dystrophin pre-mRNA with no functional dystrophin produced, giving rise to a DMD phenotype. Mutations that do not disrupt the reading frame can result in the production of partial-length dystrophin and a milder phenotype consistent with BMD. Less is known about the neurodevelopmental and neuropsychiatric symptoms of boys and young men with the BMD phenotype, which may be due to its lower prevalence, later age of onset, and even greater phenotypic variability than that seen in DMD. Boys and young men with BMD have been reported to have a higher risk of learning difficulties (despite normal intelligence) as well as a greater risk of ADHD compared with the general population. Similar to DMD, the absence of Dp140 expression has also been postulated to be the basis of cognitive impairment in BMD patients. In this issue of the Journal, Lambert et al report the frequency of neurodevelopmental delays and neuropsychiatric comorbidities in patients with BMD and evaluate whether a relationship can be established with the location of mutation position along the dystrophin gene. They report on a cohort of 70 boys and young men with BMD (age range, 1 to 36.7 years) with data that had been collected retrospectively over 17 years. Consistent with an earlier study, neurodevelopmental abnormalities were common among their patients. Based on parental report or self-report, with or without formal diagnosis, 77% of patients exhibited at least one neurodevelopmental symptom, including language or speech delays (36%), attention deficit disorder (inattention and hyperactive features, 36%), and/or autistic features (11%). Anxiety and/or obsessive–compulsive Received: 26 November 2019 Revised: 1 December 2019 Accepted: 3 December 2019