Understanding Duchenne muscular dystrophy-associated brain pathology

Disease Models & Mechanisms, vol. 18

Abstract

The most common neuromuscular disorder, Duchenne muscular dystrophy (DMD), is caused by mutations in the DMD gene, resulting in a lack of dystrophin. In addition to severe and progressive muscle wasting, a subset of individuals with DMD experience, to largely varying extents, behavioural and cognitive deficits, including a lower IQ, and neurological comorbidities, such as autism spectrum disorder, obsessive compulsive disorder and attention deficit hyperactivity disorder. Neuroimaging studies in individuals with DMD have identified widespread pathology, including structural, physiological and connective alterations. DMD mouse models exhibit a number of DMD-associated behavioural traits, including anxiety, social deficits and learning disabilities, and have been used to investigate DMD brain pathology. Although there are currently no therapies to treat DMD brain pathology, genetic approaches are being developed to restore dystrophin expression. In particular, the exon skipping approach shows promise in ameliorating certain DMD-associated behavioural deficits in preclinical settings. However, the therapeutic potential of postnatal restoration of dystrophin isoforms involved in neurodevelopment is unknown. Furthermore, challenges such as low dystrophin restoration efficacy and translatability from DMD mouse models to the clinic remain to be addressed.

Authors 3

1. Minou A. T. Verhaeg Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center 1 Department of Human Genetics , , 2333 ZC Leiden ,

2. Rosanne Govaarts Aachen Department of Radiology

   Leiden University Medical Center

   Affiliation as printed

   C.J. Gorter MRI Center 2 , Department of Radiology , , 2333 ZA Leiden ,

   Leiden University Medical Center 2 , Department of Radiology , , 2333 ZA Leiden ,

3. Maaike van Putten Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center 1 Department of Human Genetics , , 2333 ZC Leiden ,