Scientific Background
Muscular dystrophies are a clinically and genetically heterogeneous group of muscle diseases. They are classified according to the mode of inheritance: autosomal dominant (facioscapulohumerals), autosomal recessive (limb-girdle) and X-linked recessive (Duchenne/Becker muscular dystrophies).
Duchenne muscular dystrophy (DMD) has a prevalence of 1:3,500 (male newborns) and is the most common muscular disease in children. It manifests between 3 and 5 years of age with weakness of the pelvic and thigh muscles. Waddling gait, calf hypertrophy and a positive Gower’s sign are also common. The disease is progressive, so that most of those affected become wheelchair-bound at around 12 years of age. The respiratory and cardiac muscles are also affected. Life expectancy is significantly shortened to about 20-30 years. The milder Becker muscular dystrophy (BMD) occurs with a frequency of 1:20,000 (male newborns) and also affects the pelvic and thigh muscles. However, after manifestation between the ages of 6 and 12, disease progression is slower, so that the ability to walk can usually be maintained until the age of 60. Clinically, both DMD and BMD are associated with the progressive breakdown of muscle cells, which is accompanied by an increase in serum creatine kinase (CK) of up to 100 times the normal amount. The CK value can also be increased in carriers of DMD or BMD. In addition to serum CK, an electromyogram or histological examination of a muscle biopsy can also be used to make a diagnosis.
Pathogenic variants in the dystrophin (DMD) gene are the genetic cause of X-linked DMD and BMD muscular dystrophies. Dystrophin is a cytoskeleton protein localized to the sarcolemmal membrane of skeletal muscle fibers. In DMD patients, pathogenic changes lead to the synthesis of a shortened, inactive polypeptide that is prematurely degraded. This is caused by deletions or duplications that lead to a shift in the reading frame (out-of-frame) as well as translational stop variants due to nonsense variants, small deletions, insertions and splice variants. In BMD patients, the dystrophin biosynthesis is either reduced or a shortened or structurally altered protein with residual activity is produced. In-frame deletions and duplications that do not lead to a reading frame shift, as well as point mutations outside the functional N- and C-terminal domain, lead to a milder BMD phenotype. Approximately 30% of those affected fall ill due to a pathogenic de novo variant. About 70% of cases are familial in which the mother is the carrier of the disease. Overall, 65% of all pathogenic variants in DMD and 85% of those in BMD are deletions of single or multiple exons and 6-10% of all pathogenic variants in BMD and DMD are duplications. Both types of variants have proximal and distal hotspot regions. 25-30% of all DMD patients and 5-10% of all BMD patients have point mutations, splice variants or smaller insertions or deletions within the DMD gene that may be distributed throughout the gene.
References
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