Research is increasingly uncovering the role of Duchenne muscular dystrophy (DMD) in cognition and behavior, but developing therapies that address both muscle and brain effects carries challenges, according to a review published recently in Disease Models and Mechanisms.
DMD is caused by pathogenic variants in the DMD gene, which prevent production of dystrophin, a protein essential for muscle integrity. While the disease is most recognized for its progressive muscle weakness and loss of ambulation, approximately one-third of individuals also experience cognitive or behavioral differences.
These include lower-than-average IQ, attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder and learning difficulties in reading, arithmetic and memory.
“These issues highlight the clinical need to develop therapeutics that can provide effective treatment of these conditions to ameliorate them,” the review’s authors noted.
Neuroimaging of people with DMD has revealed reduced total brain volume, gray matter loss in motor and cognitive areas, and disruptions in white matter microstructure, suggesting altered neurodevelopment.
The complexity of DMD’s impact on the brain is linked to the variable expression of dystrophin isoforms in different brain regions and developmental stages. Isoforms such as Dp140 and Dp71, which are abundant in the fetal brain, are thought to play roles in cognition and emotion.
In people with DMD, the absence of specific isoforms correlates with more severe motor and neurobehavioral outcomes. However, translating these findings into therapies remains challenging. Many disease-modifying treatments, including exon-skipping agents, gene transfer therapies and antisense oligonucleotides, are designed to target skeletal muscle, and their ability to cross the blood-brain barrier and restore dystrophin in the central nervous system remains limited.
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Standard pharmacologic therapy for DMD still centers on corticosteroids, which delay motor decline and reduce cardiopulmonary complications. Yet, steroids are also associated with behavioral changes, and recent neuroimaging studies suggest they may have effects on brain volume and white matter microstructure.
As genetic and imaging research deepens the understanding of brain involvement in DMD, experts see potential for future therapies to target both muscle and mind, a development that could further improve quality of life for individuals with this complex condition.
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