# Understanding Duchenne muscular dystrophy-associated brain pathology

## TL;DR

Duchenne muscular dystrophy (DMD) causes muscle wasting and can also lead to brain-related issues like cognitive and behavioral problems, with research focusing on understanding and treating these neurological effects.

## Contribution

This review highlights brain pathology in DMD, behavioral traits in mouse models, and evaluates emerging genetic therapies for neurological symptoms.

## Key findings

- DMD is linked to behavioral and cognitive deficits in some individuals, including autism and ADHD traits.
- Mouse models show similar behavioral traits and brain changes, aiding research into DMD-related brain pathology.
- Exon skipping shows promise in preclinical studies for improving behavioral deficits, but challenges remain in translating these findings to humans.

## 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.

Summary: This Review discusses central nervous system involvement observed in a subset of individuals with Duchenne muscular dystrophy, highlighting behavioural alterations and brain pathology in humans and mice and evaluating potential therapeutic approaches.