Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations

Abstract

ABBREVIATIONS 3Di-svDevelopmental, Diagnostic and Dimensional Interview -short version ASD Autistic spectrum disorder CBCL Child Behavior Checklist DMD Duchenne muscular dystrophy SCDC Social Communication Disorder Checklist AIM Duchenne muscular dystrophy (DMD) is associated with neuropsychiatric disorders. The aim of the study was to characterize the DMD neuropsychiatric profile fully and to explore underlying genotype/phenotype associations.METHOD One hundred and thirty males with DMD (mean age 9y 10mo, range 5-17y) in four European centres were included and completed IQ assessment and a neurodevelopmentalscreening questionnaire. Of these, 87 underwent comprehensive neuropsychiatric assessment using structured diagnostic interview and parent-reported questionnaires. RESULTSThe overall mean score on the neurodevelopmental questionnaire was significantly abnormal compared with the general population of children (p<0.001). On average, intelligence was below the population mean, with intellectual disability observed in 34 males (26%). Autistic spectrum disorder was identified in 18 (21%), hyperactivity in 21 (24%), and inattention in 38 (44%). Clinical levels of internalizing and externalizing problems were observed in 21 (24%) and 13 (15%) respectively. Over a third of males scored more than two measures of emotional, behavioural, or neurodevelopmental problems. Males with mutations at the 3 0 end of the DMD gene affecting all protein isoforms had higher rates of intellectual disability and clusters of symptoms.INTERPRETATION Males with DMD are at very high risk of neuropsychiatric disturbance, and this risk appears to increase with mutations at the 3 0 end of the gene. Patterns of symptom clusters suggest a DMD neuropsychiatric syndrome, which may require prompt evaluation and early intervention.Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder affecting one in 5000 live male births, which causes progressive muscle weakness leading to loss of ambulation in the mid-adolescent years. Affected males generally present in the first few years of life with motor symptoms and enlarged calves. However, neurodevelopmental disorders are increasingly recognized features and can be the initial presenting symptoms. 1,2 DMD occurs as a result of mutations in the dystrophin gene. The large dystrophin gene contains 79 exons plus seven promoters. These tightly regulated internal promoters generate a range of different protein isoforms, with diverse expression in tissues. Mutations in the 5 0 end of the gene (i.e. mutations from exons 1-31) only affect the three longest isoforms, Dp427M, Dp427C, and Dp427P, which are expressed in skeletal and cardiac muscles, in the neurons in the cortex, and in cerebellar Purkinje cells respectively. However, mutations progressively further along the gene affect increasingly more isoforms. Mutations between exons 31 and 44, in addition to disrupting expression of the long isoforms, will also disrupt Dp260 (expressed mostly in the retina); mutations between exons 4...

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

“…Moreover, patients lacking Dp140 isoforms performed worse on all neuropsychological tests (general cognitive abilities, verbal memory, attention and executive functions) compared to those with preserved Dp140 25 . The relationship between the isoforms that are affected and the cognitive profile is further supported by the higher incidence of neurodevelopmental disorders in patients missing Dp140 compared to patients missing only Dp427 5,26 . This group distinction was already detectable below the age of four, as assessed with developmental quotients 8 .…”

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

“…Fourteen of the patients had deletion mutations between exons 45 and 48, which put them at risk of being deficient in the Dp140 isoform localized to the central nervous system. This has been associated with changes in CBF and cognitive deficits [5,27]. The design was a randomized double-blind, placebo-controlled, crossover study of two 4-week treatments with either placebo (lactose monohydrate oral in gelatin capsules, 3 times daily) or sildenafil 20 mg [Revatio in gelatin capsules (Pfizer, New York, NY, USA), p.o., 3 times daily], with the treatments separated by a washout period of 2 weeks.…”

“…In addition to muscle symptoms, some patients also suffer from cognitive impairment [1][2][3][4][5].…”

“…The occurrence of cognitive impairment in patients with DMD and BMD suggests a role for dystrophin in brain function [4,5,[16][17][18]. Neurons, glia, and the microvasculature of the brain have a DGC-like complex, corresponding to the muscle DGC, that also anchors nNOS [19]; nevertheless, the role of dystrophin in the brain is not well established.…”

Muskelsykdommer med debut i barnealder

“…Også respirasjonsmuskler rammes, og etter hvert får mange tegn på kardiomyopati. Hos omtrent en tredel finnes en ikke-progredierende mental retardasjon, og forekomsten av nevropsykiatriske lidelser er noe økt (6,7).…”