Stem cell researchers identify possible mechanism of neurocognitive problems in Duchenne muscular dystrophy

Research at KU Leuven suggests a cause for the neurodevelopmental disturbances experienced by a third of patients with Duchenne muscular dystrophy. The discovery suggests possible underlying mechanisms of these problems, which appear targetable by therapeutic interventions in a cellular model. 

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder in which the muscles, including the heart and respiratory muscles, progressively become weaker. The disease is caused by deficiency of dystrophin, a protein responsible for the muscle cell membrane stability. Symptoms begin in early childhood, usually between the ages of three and five. There is no cure, but corticosteroid treatment slows down the progression of the disorder, and patients now commonly live into their thirties.

In addition to the muscular problems, around 30% of patients with DMD experience neurodevelopmental and neuropsychological problems. There is a higher incidence of specific learning problems, behavioural problems, autism spectrum disorder, and attention-deficit hyperactivity disorder. Dystrophin is also present in the brain, but its role in the central nervous system is poorly understood. 

"In muscle, dystrophin stabilises the mechanics of contraction, but obviously the brain does not contract. So, we wanted to see what effect a lack of dystrophin was having on brain cells," says Dr Samie Patel, who recently completed his PhD in the KU Leuven Stem Cell Institute. 

The stem cell techniques developed by the Institute provided an ideal platform for investigating this question. Starting with pluripotent stem cells from patients with DMD, it is possible to grow tissues in the lab that resemble those in the patient’s brain and can be closely examined for structural changes or functional defects. 

The first step was to look at cortical neurons, but these turned out to function normally. So Dr Patel focussed on ’astrocytes’, cells supporting the neurons in the brain. When these astrocytes were grown from DMD patient stem cells (lacking dystrophin), they had abnormal internal structures and a range of functional defects. Their negative influence on normal neurons was also striking, resulting in drastic changes in their growth and behaviour. 

One particular defect appears to be behind this effect of astrocytes on cortical neurons. Normal astrocytes are responsible for controlling levels of glutamate, a molecule involved in the transmission of signals between neurons. But the DMD astrocytes perform this task poorly. In the brain, this would result in high levels of glutamate and an over-stimulation of the neurons.

This hypothesis was tested in two ways. First, there is a drug that can override one particular genetic defect that results in DMD. When this was applied to astrocytes from a DMD patient with the mutation in question, dystrophin production resumed and glutamate handling returned to normal. The negative effect on neurons also disappeared. Second, the negative effect on neurons was also prevented by chemicals that block the action of glutamate. 

These findings, published in the medical journal Translational Psychiatry, are important as they advance the understanding of mechanisms leading to neurodevelopmental problems in DMD. "In the laboratory, the mechanism seems amenable to corrective interventions, but whether or not this could lead to new treatment options for patients is currently unknown," says Dr Patel.

Click here to read the study "Dystrophin deficiency leads to dysfunctional glutamate clearance in iPSC derived astrocytes" (DOI: 10.1038/s41398-019-0535-1) in Translational Psychiatry.  Press review copies are available from the authors.


  • Biomedical Sciences Group
  • Faculty of Medicine
  • Department of Development and Regeneration
  • University Hospitals Leuven

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