Abstract
BackgroundA significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms.Methods and ResultsSixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented.SignificanceThese data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.
Highlights
Duchenne muscular dystrophy (DMD) is a clinically heterogeneous disorder of at least 4 clinical subphenotypes characterised by differences in the severity of muscle and brain dysfunction (Online Mendelian Inheritance in Man (OMIM) 310200) [1]
Results for 62 male DMD subjects are provided in Table 1, including data relating to the identified mutation, the exons affected by the mutation, the location of a predicted premature termination codon, the isoform(s) affected as inferred from mutation location, and results of the neuropsychological assessments
The descriptive IQ results for the Sydney Children’s Hospital (SCH) study group are representative of previously published studies of cognitive deficits in DMD, with the mean Full Scale Intelligence Quotients (FSIQ), verbal intelligence quotients (VIQ) and performance intelligence quotients (PIQ) scores being found to be approximately one standard deviation (15 IQ points) below the normative mean of 100, with a VIQ-PIQ deficit of approximately 7 IQ points
Summary
Duchenne muscular dystrophy (DMD) is a clinically heterogeneous disorder of at least 4 clinical subphenotypes characterised by differences in the severity of muscle and brain dysfunction (Online Mendelian Inheritance in Man (OMIM) 310200) [1]. Several studies have compared performance intelligence quotients (PIQ). Most studies are in agreement that VIQ is more affected than PIQ and that the difference of their means is about 5–8 points [7,8,9,10], other authors have maintained that the deficits are global in nature [11,12]. A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms
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