Limb-Girdle Muscular Dystrophy Type 2A

Abstract

LGMD2A is due to mutations in the gene encoding calpain-3 (CAPN3), a neutral protease. The disease is typically characterized by a selective and progressive involvement of proximal limb-girdle muscles. Two phenotypes have been identified based on the distribution of muscle weakness at onset: the pelvifemoral form of Leiden-Möbius, which is the most frequently observed, in which muscle weakness is first evident in the pelvic girdle and later evident in the shoulder girdle, and the scapulohumeral form of Erb, which is usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later evident in the pelvic girdle. Another early and transient feature in LGMD2A is eosinophilic myositis, which has been reported in patients presenting with increased CK levels. CK levels are always elevated since infancy (5–80 times the normal). The age at onset of muscle weakness ranges between 2 and 40 years (in average 15 years). The first clinical symptoms are usually difficulty in running, the tendency to walk on tiptoes, and scapular winging caused by weakness of scapular girdle muscles. Weakness and wasting of the hip adductors/extensors and the posterior thigh muscles (gluteus maximus, semimembranosus, biceps femoris) are evident on both clinical examination and muscle CT and MRI imaging scans. Joint contractures are typically seen and may be present early. As the disease progresses, waddling gait and difficulty in climbing stairs, lifting weights, and getting up from the floor or a chair are evident. Muscle involvement is mainly symmetrical and atrophic. Facial and neck muscles are usually spared. The disease is invariably progressive, and the loss of ambulation occurs about 10–30 years after the onset of symptoms (between 10 and 45 years of age). In the advanced stage of the disease, respiratory insufficiency may be present, while cardiomyopathy and mental retardation are uncommon.

Calpain-3 immunoblot analysis remains the gold standard to diagnose LGMD2A, even if in about 20–30% of LGMD2A patients the protein has a quantitative normal expression, due to mutations that are expected to affect the enzyme function. The diagnosis of LGMD2A needs to be confirmed by mutation identification. Some mutations recur in specific population as the consequence of a founder effect followed by genetic isolation. The null mutation c.550delA recurs frequently in Caucasian populations.