MOLECULAR EPIDEMIOLOGY OF GLYCOGEN-STORAG E-DISEASE TYPE 1A IN ITALIAN CAUSISTICS - APPLICATION TO NONINVASIVE DIAGNOSIS AND PREVENTION

Diagnosis of glycogen storage disease type 1a (GSD type 1a) currently is established by demonstrating the lack of glucose-6-phosphatase (G6P -ase) in patient's biopsied liver specimen. Recent cloning of the G6P- ase cDNA and identification of mutations in the GBP-ase gene that caus e GSD type la allow for a non invasive diagnosis. A diagnostic method based on mutation analyses need a rapide screening method for-detectin g the majority of these mutations and the prevalent mutations in diffe rent ethnic/racial group. In the present report we have examined the G 6P-ase gene of 43 italian patients with GSD type 1a, 36 of them with e nzimatically confirmed diagnosis and 7 with clinical diagnosis. Using SSCP analysis we detected four mutations in 72.1% of mutated alleles. R83C (44.1%) and Q347X (23.2%) are the must prevalent mutations. The R 295C rate mutation was identified in two compound heterozygotes. The m utation S298P is a new mutation, confirmed by direct sequencing, ident ified in a homozygous patient born to related parents. Of the 43 patie nts analyzed, 7 contained no identifiable mutant alleles, 10 contained only one mutant allele and 26 contained two mutant alleles (17 homozy gotes and 9 compound heterozygotes). Our results demonstrate that two mutations, R83C and Q347X, are the major cause of GSD type In in Italy and moreover; that the patients of Sicilian origin have mostly R83C m utation (10/11 known alleles). A DNA based diagnosis can be used as an initial screening for italian patients clinically suspected of have G SD type 1a, overall, if they come from Sicily. The knowledge of the ge notype may be applicable to carrier detection and prenatal diagnosis.