Genetic heterogeneity in acid alpha-glucosidase deficiency.

Several clinical forms of acid alpha-glucosidase deficiency have been described. Our study was planned to identify differences at the molecular level in acid alpha-glucosidase deficiency. Of nine fibroblast strains derived from patients with the infantile form of the disease, eight were crossreacting material (CRM)-negative and one CRM-positive. This was demonstrated by both agar immunodiffusion and immunotitration. No difference in apparent enzymatic activity was observed between CRM-negative and CRM-positive infantile acid alpha-glucosidase deficiency fibroblasts. In two fibroblast strains with the adult form of acid alpha-glucosidase deficiency, rocket immunoelectrophoresis demonstrated a reduction in the amount of enzyme protein, which was directly proportional to the reduction in enzyme activity. In another fibroblast strain obtained from a patient with the adult form of the disease, the activity was within the range of the infantile form and no CRM could be identified. Fibroblasts with phenotype 2 of acid alpha-glucosidase, considered a normal variant, showed a reduction both in the amount of enzyme protein and in the ability of the enzyme to cleave glycogen. However, the catalytic activity for maltose was normal. The findings demonstrate extensive genetic heterogeneity in acid alpha-glucosidase deficiency. Molecular differences were identified both between the clinical forms of the disease and within the infantile and the adult forms of acid alpha-glucosidase deficiency. It remains unknown whether or not the enzyme deficiency in homozygotes for isozyme 2 of acid alpha-glucosidase will be sufficient to cause glycogen accumulation and lead to the development of muscular dystrophy-like disease later in life.