Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II

Glycogen storage disease type II (GSDII) is a recessively inherited disorder due to the deficiency of acid a-glucosidase (GAA) that results in impaired glycogen degradation and its accumulation in the lysosomes.We report here the complete molecular analysis of the GAA gene performed on 40 Italian patients with late onset GSDII. Twelve novel alleles have been identified: missense mutations were functionally characterized by enzyme activity and protein processing in a human GAA-deficient cell line while splicing mutations were studied by RT-PCR and in silico analysis. A complex allele was also identified carrying three different alterations in cis. The c.-32-13T4G was the most frequent mutation, present as compound heterozygote in 85% of the patients (allele frequency 42.3%), as described in other late onset GSDII Caucasian populations. Interestingly, the c.-32-13T4G was associated with the c.2237G4A (p.W746X) in nine of the 40 patients. Genotype phenotype correlations are discussed with particular emphasis on the subgroup carrying the c.-32- 13T4G/c.2237G4A genotype.