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Prenatal diagnosis in CDG1 families: beware of heterogeneity
G Matthijs1, E Schollen, J J Cassiman
1Center for Human Genetics, University of Leuven, Belgium.
Insights
Prenatal diagnosis for Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1) is feasible using phosphomannomutase activity assays and genetic analysis. These methods help identify affected fetuses, aiding family planning and confirming CDG1 heterogeneity.
Area of Science:
- Clinical Genetics
- Metabolic Disorders
- Prenatal Diagnosis
Background:
- Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1) is a severe autosomal recessive metabolic disorder.
- It is characterized by psychomotor retardation and high early childhood mortality.
- Most CDG1 cases result from phosphomannomutase deficiency due to PMM2 gene mutations on chromosome 16p13.
Purpose of the Study:
- To evaluate the utility of prenatal diagnostic methods for CDG1.
- To assess phosphomannomutase activity in fetal tissues for diagnostic purposes.
- To investigate potential genetic heterogeneity within CDG1.
Main Methods:
- Prenatal diagnosis offered to eight families over 18 months.
- Methods included linkage analysis, phosphomannomutase activity measurements in cultured amniocytes and trophoblasts, and direct mutation analysis.
- Fibroblast analysis was used to assess phosphomannomutase activity in probands.
Main Results:
- Prenatal diagnosis was successfully performed in six families.
- Phosphomannomutase activities were significantly reduced in amniocytes and trophoblasts from affected fetuses.
- Two families were excluded from testing due to lack of linkage to chromosome 16 or normal phosphomannomutase activity in probands.
Conclusions:
- Prenatal diagnosis for CDG1 is achievable through phosphomannomutase activity assays and genetic analysis.
- Reduced phosphomannomutase activity in fetal cells is a reliable indicator of CDG1.
- The findings support the existence of genetic heterogeneity for CDG1.
Abstract:
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.