Molecular analysis of the AGL gene: Identification of 25 novel mutations and evidence of genetic heterogeneity in patients with Glycogen Storage Disease Type III

Purpose: Glycogen Storage Disease Type III (limit dextrinosis; Cori or Forbes disease) is an autosomal recessive disorder of glycogen metabolism caused by deficient activity of glycogen debranching enzyme in liver and muscle (Glycogen Storage Disease Type IIIa) or liver only (Glycogen Storage Disease Type IIIb). These two clinically distinct phenotypes are caused by mutations in the same gene (amylo-1,6-glucosidase or AGL). Although most patients with Glycogen Storage Disease Type III have private mutations, common mutations have been identified in some populations, and two specific mutations in exon 3, c.18_19delGA (p.Gln6HisfsX20) and c.16C>T (p.Gln6X), are associated with the Glycogen Storage Disease Type IIIb phenotype. Methods: To further examine the heterogeneity found in Glycogen Storage Disease Type III patients, we have sequenced the AGL gene in 34 patients with a clinically and/or biochemically confirmed diagnosis of Glycogen Storage Disease Type III. Results: We have identified 38 different mutations (25 novel and 13 previously reported) and have compiled a list of all mutations previously reported in the literature. Discussion: We conclude that Glycogen Storage Disease Type III is a highly heterogeneous disorder usually requiring full gene sequencing to identify both pathogenic mutations. The finding of at least one of the two exon 3 mutations in all of the Glycogen Storage Disease Type IIIb patients tested allows for diagnosis of this subtype without the need for a muscle biopsy.