Duchenne Muscular Dystrophy: The Brain Is Affected Too

Researchers, physicians, families and affected patients view Duchenne muscular dystrophy (DMD) as a neuromuscular condition. Children are diagnosed during the first years of life because they have difficulty walking and moving in other ways. Later on, older children and teens with Duchenne develop respiratory and cardiac problems that researchers have described. But Duchene also has effects on the brain and, as a consequence, on cognition and behavior.

Earlier this month, lead author Cyrille Vaillend, director of the Paris-Saclay Institute of Neuroscience at the Université Paris-Saclay in Paris, and his colleagues published a review of the recent research and insights of the brain-related comorbidities in the journal Nature Communications.

Here are five takeaways from their review:

Specific forms of dystrophin are found in the brain

The DMD gene is the largest gene in the human genome, and it produces different forms — or isoforms — of the protein dystrophin. DMD is caused by deficient dystrophin. Researchers have begun to figure out that certain isoforms are more common or active in the brain than elsewhere in the body. For example, research suggests that the Dp427 isoforms affect gamma-aminobutyric acid type A receptors and that Dp71 plays a role in the functioning of astrocytes. Mouse models suggest a role for Dp140 in cognitive dysfunction.

Brain involvement is primary consequence of dystrophin deficiencies

Patients with other severe neuromuscular conditions, such as spinal muscular atrophy and muscular dystrophies caused by dystrophin that is found only in the muscle do not have the same brain-related comorbidities as children and teens with DMD. That difference, along with research that has linked different genotypes to different isoforms and phenotypes “strongly supports the view that CNS [central nervous system involvement] in DMD is a primary consequence of brain dystrophin deficiency, not a second phenomenon,” the researchers wrote.

IQ tests suggest a role for certain dystrophin isoforms

Vaillend and his colleagues reference a 2022 meta-analysis published in the journal Brain Sciences that found the IQ of the individuals with DMD in the studies was one standard deviation lower below the normal average. They also point to other research that found that the prevalence of low IQ was higher among individuals whose DMD involved Dp140 and Dp71.

Brain imaging studies also suggest a role for certain dystrophin isoforms

Brain MRIs don’t show structural abnormalities in the brains of people with DMD, but total brain and gray matter volumes are smaller than they are in people without DMD, according to Vaillend and his colleagues. Measurements of the white matter also show some differences. Studies looking at dystrophin isoforms have shown that children lacking both Dp427 and Dp140 had more obvious gray matter differences and lower cerebral blood flow compared with those with only Dp427 involvement.

DMD may affect the brains of female carriers

Because DMD is an X-linked disorder, women with the mutated gene do not typically experience symptoms. But Vaillend and his colleagues cite a study published in 2020 in the journal Muscle & Nerve that showed that carrier mothers had cognitive deficits in several areas, such as working memory, visuospatial skills and executive function. “This suggests that there may be a degree of brain involvement in carrier mothers of children with DMD, an aspect that requires further investigation,” they wrote

Psychopharmacologic treatments for people with DMD are understudied

Vaillend and his colleagues point to a 2022 review of all the studies of psychopharmacologic treatments for mental disorders affecting people with neuromuscular disorders published between 2000 and 2021. The researchers who conducted that review identified only five studies: two case reports, two case series and an observational study without a control group. The observational study of 10 boys with DMD suggested a benefit from methylphenidate — sold under Ritalin, Concerta and other brand names — as a treatment for attention deficit/hyperactivity disorder. Other studies have suggested the same, although because of DMD’s cardiac complications, there has been some wariness about prescribing stimulants for people with the condition.