Muscular Dystrophy Duchenne/Becker [G71.0]
Dr. rer. nat. Karin Mayer, Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh
Muscular dystrophies are a clinically and genetically heterogeneous group of muscle diseases. They are classified according to their inheritance pattern into autosomal dominant (facioscapulohumeral), autosomal recessive (limb-girdle) and X chromosomal recessive (Duchenne/Becker) muscular dystrophies.
With a prevalence of 1 in 3,500 (male newborns), the Duchenne muscular dystrophy (DMD) is the most frequent muscle disease in children. It manifests between the 3rd to 5th year of life and is characterized by weakness in the pelvic and thigh muscles. Moreover, waddling gait, calf hypertrophy as well as positive gower’s sign (climbing up on oneself) are characteristic. The course of the disease is progressive; most patients use a wheelchair approximately from the age of 12. Furthermore, respiratory and heart muscles are affected. With approx. 20-30 years, life expectancy is severely shortened. The milder form, Becker muscular dystrophy (BMD), has a frequency of 1 in 20,000 (male newborns) and also affects the pelvic and thigh muscles. However, after manifestation between the 6th and 12th year of life, the course of the disease is considerably more favorable; most patients are able to walk until approximately the 60th year of life. A clinical sign of both DMD and BMD is progressive degradation of muscle cells which is accompanied by elevation of the serum creatine kinase (CK) activity, which may be up to 100 times the normal level. The CK level may also be elevated in female conductors of DMD or BMD. Apart from serum CK, electromyography or histological examination of a muscle biopsy may aid in establishing a diagnosis.
The X chromosomal Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the dystrophin (DMD) gene. Dystrophin is a protein of the cytoskeleton and is located at the sarcolemmal membrane of the skeletal muscle fibers. In DMD patients, mutations cause synthesis of a shortened, inactive polypeptide which is degraded early. The cause is deletions or duplications which lead to a reading frame shift (out-of-frame) as well as translational stop mutations resulting from nonsense mutations, small deletions, insertions and splice mutations. In BMD patients, the dystrophin biosynthesis is either severely reduced or a shortened or structurally changed protein is produced with residual activity. In frame deletions and duplications which cause no reading frame shift, as well as point mutations outside of the functional N- and C-terminal domain lead to a milder BMD phenotype. About 30% of all affected patients develop the disease due to a new mutation. Approximately 70% of all cases are familial cases in which the disease was passed on by the mother. About 65% of all mutations in DMD and 85% of all mutations in BMD are deletions of single or multiple exons. 6-10% of all mutations in BMD and DMD are duplications. There are proximal and distal hotspot regions for both mutation types. 25-30% of all DMD patients and 5-10% of all BMD patients have point mutations, splice mutations or small insertions or deletions within the DMD gene which may be located anywhere in the gene.