Twenty-two novel mutations in the lysosomal ?-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II

TLDR

Glycogen storage disease type II (Pompe disease) is an autosomal recessive disorder that causes progressive muscle weakness due to acid α‑glucosidase deficiency and presents with a spectrum of clinical phenotypes. The authors examined 29 GSDII patients, identified 55 pathogenic GAA mutations, expressed missense and other mutations in COS cells, and investigated a novel splice‑site mutation by real‑time PCR. They found 34 distinct mutations, 22 of which were novel, and demonstrated that the clinical phenotype is largely determined by the mutation type, establishing a genotype‑phenotype correlation that can aid in predicting disease course. Hum Mutat 23:47–56, 2004; © 2003 Wiley‑Liss, Inc.

Abstract

Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid α-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid α-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid α-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype–phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease. Hum Mutat 23:47–56, 2004. © 2003 Wiley-Liss, Inc.