Brain dystrophinopathies and cognitive impairment: Pathogenesis, diagnosis, and therapies

The dystrophin protein plays a critical role not only in muscles but also in the central nervous system. The absence of and mutations in the Duchenne muscular dystrophy gene (the dystrophin gene) (DMD), which encodes the dystrophin protein, lead to progressive muscle degeneration. In addition, these deficiencies result in impaired brain functions with varying clinical outcomes. Several studies have shown that patients with DMD have an IQ one standard deviation lower than that of the general population. Although the neurological and cognitive manifestations of the absence of or mutations in the dystrophin gene have been known for more than two decades, the therapeutic approach has remained primarily focused on neuromuscular manifestations. In this review, we summarize the studies exploring the associations between DMD mutations or absence and cognitive impairment. First, we review the mouse models available to study various dystrophin gene mutations. Then, we provide an overview of the localization of different dystrophin isoforms in the brain. Further, we summarize the diagnostic tools for assessing cognitive impairment in patients with DMD and modern therapies that could be used to ameliorate these cognitive impairments. This review describes recent advances in our understanding of the role of dystrophin in the brain, exploring its involvement in synaptic plasticity, neurotransmission, and brain morphology. Understanding the brain-related consequences of dystrophin deficiency is critical for elucidating the neuropathogenesis of muscular dystrophies and designing targeted therapies aimed at improving both muscle and cognitive function in DMD patients. We conclude that a holistic approach is needed in diagnosing cognitive impairment in DMD patients. We also highlight the importance of modern therapies in addressing this unmet need.