title: Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II.
abstract: Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-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 alpha-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 alpha-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.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Monique M P
authors.initials: MM
authors.lastname: Hermans
authors.forename: Dik
authors.initials: D
authors.lastname: van Leenen
authors.forename: Marian A
authors.initials: MA
authors.lastname: Kroos
authors.forename: Clare E
authors.initials: CE
authors.lastname: Beesley
authors.forename: Ans T
authors.initials: AT
authors.lastname: Van Der Ploeg
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
authors.forename: Ron
authors.initials: R
authors.lastname: Wevers
authors.forename: Wim
authors.initials: W
authors.lastname: Kleijer
authors.forename: Helen
authors.initials: H
authors.lastname: Michelakakis
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Kirk
authors.forename: Janice
authors.initials: J
authors.lastname: Fletcher
authors.forename: Nils
authors.initials: N
authors.lastname: Bosshard
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Guy
authors.initials: G
authors.lastname: Besley
authors.forename: Arnold J J
authors.initials: AJ
authors.lastname: Reuser
mesh_terms: D000293:Adolescent; D000368:Aged; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D005087:Glucan 1,4-alpha-Glucosidase / Q000235:genetics* / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007223:Infant; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011110:Polymorphism, Genetic; D000520:alpha-Glucosidases
chemical_list: D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase