Prenatal diagnosis in CDG1 families: beware of heterogeneity.

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1) is an autosomal recessive, metabolic disorder with severe psychomotor retardation and a high mortality rate in early childhood. Most patients have a deficiency of phosphomannomutase, due to mutations in PMM2, a gene located on chromosome 16p13. Over a period of 18 months we offered prenatal diagnosis to eight families. In six cases and prior to the identification of the gene, the diagnosis was based on linkage analysis and phosphomannomutase measurements. Subsequently direct mutation analysis has been used in two families. It is shown here that phosphomannomutase activities are strongly reduced in cultured amniocytes and trophoblasts of affected foetuses. We refrained from offering prenatal testing in two other families, because either the disease did not link to chromosome 16 and/or normal phosphomannomutase activities were measured in fibroblasts from the proband. This confirms earlier suggestions of heterogeneity for CDG1.