Objectives: The aim of this study was to investigate executive skills in children with dystrophinopathy and to examine the association between executive functions and dystrophin gene mutation position. Methods: Fifty boys with dystrophinopathy (mean age, 11 years 0 months; ages range, 5 to 17 years) completed measures of intellectual functioning (IF), working memory and executive functioning [including Digit Span (working memory) and measures from the NIH Toolbox (selective attention/inhibitory control, set shifting, working memory, and processing speed)]. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Mutation positions were categorized into three groups (upstream exon 30, 31–62, and downstream exon 63). Paired-samples t tests compared performance on executive measures to IF, and a one-way (three-group) multivariate analysis of covariance compared cognitive performance with mutation location controlling for motor functioning. Results: Mean performance on all executive measures was significantly lower than IF. Parents were also more likely to rate their child with dystrophinopathy as having clinically significant executive difficulties on the Shift, Emotional Control, and Behavior Regulation indices of the BRIEF. Mutation analyses resulted in small groups limiting power to detect subtle differences. Those with a downstream mutation position had significantly poorer performance on IF and Total Digit Span, but not on other measures of executive function including behavior. Conclusions: Individuals with dystrophinopathy have executive skill deficits, but they are not generally associated with more distal mutations. (JINS, 2019, 25, 146–155)

Objectives: To examine academic performance in dystrophinopathy as a function of dystrophin gene mutation position as well as intellectual function, executive skills, socioeconomic status (SES), behavior, and physical ability. Methods: In a cross-sectional study, boys with dystrophinopathy (ages 5–17; n=50) completed tests of academics (Woodcock-Johnson-III: spelling, reading, calculation and total scores), executive functioning (selective attention/inhibitory control, set shifting, working memory, and processing speed), single word comprehension and nonverbal reasoning. Motor skills were assessed and parents provided demographic information and child behavioral assessments. Dystrophin gene mutation positions were dichotomized into groups (upstream versus downstream of exon 43, location of isoforms previously linked to intellectual impairment). Genetic mutation groups were compared on measures of academic achievement, and multiple regression analyses examined unique and joint contributions of executive skills, intelligence quotient (IQ), SES, motor abilities, behavior, and mutation positions to academic outcomes. Results: Academic performance was slightly, yet significantly, lower than IQ and varied as a function of dystrophin gene position, wherein boys possessing the downstream mutation exhibited greater impairment than boys with the upstream mutation. Digit span forward (indexing verbal span), but no other measure of executive function, contributed significant variance to total academic achievement, spelling and calculation. Conclusions: Weak academic performance is associated with dystrophinopathy and is more common in downstream mutations. A specific deficit in verbal span may underlie inefficiencies observed in children with dystrophinopathy and may drive deficits impacting academic abilities. (JINS, 2018, 24, 928–938)

Cardiomyopathy develops in >90% of Duchenne muscular dystrophy (DMD) patients by the second decade of life. We assessed the associations between DMD gene mutations, as well as Latent transforming growth factor-beta-binding protein 4 (LTBP4) haplotypes, and age at onset of myocardial dysfunction in DMD. DMD patients with baseline normal left ventricular systolic function and genotyping between 2004 and 2013 were included. Patients were grouped in multiple ways: specific DMD mutation domains, true loss-of-function mutations (group A) versus possible residual gene expression (group B), and LTBP4 haplotype. Age at onset of myocardial dysfunction was the first echocardiogram with an ejection fraction <55% and/or shortening fraction <28%. Of 101 DMD patients, 40 developed cardiomyopathy. There was no difference in age at onset of myocardial dysfunction among DMD genotype mutation domains (13.7±4.8 versus 14.3±1.0 versus 14.3±2.9 versus 13.8±2.5, p=0.97), groups A and B (14.4±2.8 versus 12.1±4.4, p=0.09), or LTBP4 haplotypes (14.5±3.2 versus 13.1±3.2 versus 11.0±2.8, p=0.18). DMD gene mutations involving the hinge 3 region, actin-binding domain, and exons 45–49, as well as the LTBP4 IAAM haplotype, were not associated with age of left ventricular dysfunction onset in DMD.

The goal of the current investigation was to examine adaptive behavior and cognitive skills in young children with Duchenne muscular dystrophy (DMD), a genetic disorder that causes progressive muscular weakness and concomitant cognitive deficits. Previous studies have documented specific language deficits in older children with DMD, but there are limited data on younger children. Twenty children with DMD who were between 3 and 6 years old and 20 unaffected family control children were recruited. Parents completed questionnaires relating to development and adaptive functioning, while children completed neuropsychological testing. Results of paired t tests indicate that children with DMD are rated as delayed relative to familial controls on measures of adaptive functioning, as assessed by the Vineland Adaptive Behavior Scales. Furthermore, children with DMD exhibit impairments on multiple measures of cognition, including measures of receptive language, expressive language, visuo-spatial skills, fine-motor skills, attention, and memory skills. Across all domains examined, the young children with DMD performed more poorly than their familial controls. These deficits appear to be more generalized than those reported in older children with this disorder. Dystrophin, a missing protein product, is hypothesized to be responsible for these cognitive and behavioral impairments. (JINS, 2008, 14, 853–861.)

Patients with Duchenne muscular dystrophy (DMD), an X-linked lethal muscle-wasting disease, have abnormal expression of the protein dystrophin within their muscle fibres. In the mdx mouse model of this condition, both germline and neonatal somatic gene transfers of dystrophin cDNAs have demonstrated the potential of gene therapy in treating DMD. However, in many DMD patients, there appears to be no dystrophin expression when muscle biopsies are immunostained or western blots are performed. This raises the possibility that the expression of dystrophin following gene transfer might trigger a destructive immune response against this ‘neoantigen’. Immune responses can also be generated against the gene transfer vector used to transfect the dystrophic muscle, and the combined immune response could further damage the already inflamed muscle. These problems are now beginning to be investigated in immunocompetent mdx mice. Although much work remains to be done, there are promising indications that these immune responses might not prove as much of a concern as originally envisaged.

The distribution of nitric oxide synthase at the neuromuscular junction (NMJ) of normal, denervated and mdx mice was studied using a specific antibody against the neuronal isoform of nitric oxide synthase (nNOS). Fluorescence confocal microscopy demonstrated that nNOS immunoreactivity was localised mainly in the sarcolemma and presynaptic region covering acetylcholine receptor branches. The expression of presynaptic nNOS was greatly reduced in dystrophin-deficient muscles. In normal denervated muscles, nNOS was still present in the presynaptic region and there were no qualitative changes in the expression of this protein. These results suggest that the presynaptic distribution of nNOS is associated with terminal Schwann cells. The relationship between nNOS and the presynaptic components of the neuromuscular junction may open new perspectives for improving our understanding of the pathogenesis of dystrophic muscles.

Forty-one boys diagnosed with Duchenne muscular dystrophy (DMD) were each compared to an unaffected sibling on a battery of neuropsychological tests. Verbal, visuospatial, attention/memory, abstract thinking, and academic achievement skills were tested. Results indicated the boys with DMD performed similarly to their siblings on the majority of measures, indicating intact verbal, visuospatial, long-term memory, and abstract skills. However, the DMD group did significantly more poorly than their siblings on specific measures of story recall, digit span, and auditory comprehension, as well as in all areas of academic achievement (reading, writing, and math). This profile indicates that verbal working memory skills are selectively impaired in DMD, and that that likely contributes to limited academic achievement. The association between the known impact of the genetic mutation on the development of the central nervous system and boys' cognitive profile is discussed. (JINS, 2001, 7, 45–54.)