Summary

Glycogen storage disease type 2 (GSD II) is a lysosomal storage disease which particularly affects the skeletal and respiratory muscles with varying degrees of gravity and which, in the infantile form, is associated with hypertrophic cardiomyopathy. Incidence is estimated at about 1/57,000 for the adult form and 1/138,000 for the infantile form. The infantile form of Pompe disease starts before the age of 3 months with major hypotonia, sucking and swallowing difficulties, hypertrophic cardiomyopathy and progressive hepatomegaly. The adult form results in progressive limb-girdle myopathy beginning with the lower limbs, and affects the respiratory system, which can be the first sign of the disease. A large spectrum of intermediate forms exists between these two extremes. The disease is caused by a deficiency in alpha-1,4-glucosidase acid, which hydrolyzes glycogen into glucose, leading to intra-lysosomal glycogen overload. The deficiency is ubiquitous but it is only expressed by certain organs (mainly the heart and/or skeletal muscle). The gene (GAA) is localized to chromosome 17q25. Clinical heterogeneity has resulted in the identification of numerous mutations, although some are more frequent than others. Transmission is autosomal recessive. Biological diagnosis is based on evidence of enzyme deficiency (lymphocytes in dry blood spots, fibroblasts or fresh chorionic villus sampling). In the infantile form, differential diagnoses are principally Werdnig-Hoffman disease (see this term), and metabolic or idiopathic hypertrophic cardiomyopathy. When disease onset is later it is reminiscent of Danon disease (see this term). For the adult form, differential diagnoses include other causes of myopathy. Carrier testing is possible when both mutations have been identified in the patient. Prenatal diagnosis is possible by measuring enzyme activity in a fresh choronic villus sample, and by evaluating identified mutations in the fetal cells of the patient. In very rare cases, prenatal diagnosis is complicated by pseudodeficiencies. In addition to symptomatic treatment, enzyme substitution therapy is available: in March 2006 alglucosidase alfa obtained European marketing authorization as an orphan drug for the treatment of patients with Pompe disease. The benefits of recombinant enzyme substitution therapy have not yet been established for later onset forms of the disease. In the absence of treatment, patients with the infantile form of the disease are at risk of death in the first two years of life as a result of cardio-respiratory failure. For patients with the later onset form, disease progression in the absence of treatment necessitates the use of a wheelchair and/or respiratory assistance.

Expert reviewer(s)

• Dr Roseline FROISSART
• Dr Irène MAIRE