Muscles 2026, 5(3), 60; https://doi.org/10.3390/muscles5030060 - 26 Aug 2026
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Primary dystrophin deficiency, caused by X-chromosome mutations within the DMD gene, encompasses a continuous clinical spectrum of neurological, muscular, and cardiac disorders known as dystrophinopathies that exhibit profound phenotypic variability driven by specific mutation profiles and epigenetic factors. This comprehensive review analyzes the
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Primary dystrophin deficiency, caused by X-chromosome mutations within the DMD gene, encompasses a continuous clinical spectrum of neurological, muscular, and cardiac disorders known as dystrophinopathies that exhibit profound phenotypic variability driven by specific mutation profiles and epigenetic factors. This comprehensive review analyzes the clinical and molecular characteristics of seven primary classifications: Duchenne muscular dystrophy (DMD), a severe childhood myopathy caused by a complete absence of the protein that leads to loss of ambulation and fatal cardiorespiratory failure in youth; Becker muscular dystrophy (BMD), a milder variant with partial protein deficiency that preserves walking capabilities into adulthood and prolongs life expectancy; pseudometabolic dystrophinopathic syndrome, featuring exercise intolerance, cramps, and recurrent rhabdomyolysis that mimics metabolic diseases; asymptomatic dystrophinopathy, representing the mild end of the spectrum identified incidentally through chronically elevated creatine kinase levels; brain dystrophin-related syndrome, where the disruption of distal isoforms like Dp140 and Dp71 results in neurodevelopmental and neuropsychiatric comorbidities such as ADHD, autism, and intellectual disability; X-linked dilated cardiomyopathy (XLDCM), a cardiac-selective condition causing severe heart failure and arrhythmias while sparing skeletal muscle function; and female dystrophin-related syndrome, distinguishing between familial carriers—who can manifest symptoms due to skewed X-chromosome inactivation—and rare sporadic females who develop an exceptional, severe, Duchenne-like phenotype due to cytogenetic accidents such as Turner syndrome or chromosomal translocations. Ultimately, advancements in molecular testing (NGS and WGS) have significantly optimized diagnostic precision, proving essential for implementing early cardioprotective care, accurate genetic counseling, and the development of future tissue-specific targeted gene therapies. The present study also discusses the psychosocial impact that the disease has on patients.
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