Scandinavian CDG-Ia patients: genotype/phenotype correlation and geographic origin of founder mutations

Congenital disorders of glycosylation type Ia, (previous name carbohydrate- deficient glycoprotein syndrome type Ia; CDG-Ia) is an inherited disorder o f the glycosylation of certain glycoproteins. The defect is caused by mutat ions in the phosphomannomutase 2 (PMM2) gene located in chromosome region 1 6p13. The purpose of this study was twofold: (1) to investigate the possibl e correlation between certain genotypes and the phenotype of the patients a nd their PMM activity, and (2) to study further the founder origin of the S candinavian mutations. Sixty-four CDG-Ia patients were studied. Regardless of mutation combination, the patients showed the basic neurological symptom s associated with CDG-Ia. However, patients carrying the mutation 548T-->C had less severe disease, e.g., no pericardial effusions, malnutrition, or c linical coagulation disturbances. Liver dysfunction and peripheral neuropat hy were milder. In contrast, patients carrying mutation 691G-->A showed a h igh incidence of severe malnutrition and hepatopathy, and they had the high est mortality including affected siblings. Heterozygotes for the two most c ommon mutations (422G-->A and 357C-->A) displayed a phenotype of variable s everity sometimes leading to early death. PMM activity showed no correlatio n with either genotype or phenotype but was reduced in most patients. There was a pronounced geographic clustering for some of the Scandinavian mutati ons. For example, 548T-->C was almost exclusively found in patients stemmin g from southeastern parts of Sweden, whereas 26G-->A was found to cluster i n a region in the most southern parts of Sweden, suggesting that these muta tions originated in these two regions separately as founder mutations. The most frequent mutation (422G-->A) did not show a specific geographic focus. The widespread 422G-->A mutation is probably an older mutation, although h aplotype data from intragenic polymorphisms indicate that this mutation als o arose only once. The detailed information of the origin of mutations and their respective associated phenotypic pattern should enable improvements t o be made regarding tools for genetic counseling and for prenatal diagnoses in CDG-Ia families.