Adult and infantile glycogenosis type II in one family, explained by allelic diversity.

To define the cause of clinical heterogeneity in glycogenosis type II we have studied the inheritance and molecular nature of acid alpha-glucosidase deficiency in a rare family with severe infantile as well as mild late-onset variants of this disease. The (mutant) acid alpha-glucosidase alleles of crucial family members were segregated in human-mouse somatic cell hybrids to investigate their individual function. Two types of mutant alleles were identified. The first leads to complete deficiency of acid alpha-glucosidase. Homozygosity of this allele is demonstrated in three cases of severe infantile glycogenosis type II in the family under study. The second mutant allele is characterized by a reduced net production of catalytically active acid alpha-glucosidase, resulting in partial enzyme deficiency. The eldest patient in the family, with very mild clinical symptoms, is shown to be a compound heterozygote having both types of mutant alleles. These studies emphasize the effect of allelic diversity on the level of residual acid alpha-glucosidase activity and on the clinical course of glycogenosis type II.