Prenatal diagnosis of succinic semialdehyde dehydrogenase deficiency: Increased accuracy employing DNA, enzyme, and metabolite analyses

Inherited succinic semialdehyde dehydrogenase (SSADH; EC1.2.1.24; McKusick 271980) deficiency is a defect of GABA degradation which leads to accumulat ion of 3-hydroxybutyric acid (gamma -hydroxybutyric acid; GHB) in physiolog ic fluids of patients. Prenatal diagnosis (PND) was performed in three at-r isk pregnancies employing combinations of: (1) reverse-transcription-polyme rase chain reaction (RT-PCR) and genomic DNA amplification followed by sequ encing using isolated leukocytes or cultured human lymphoblasts; (2) GHB qu antitation in amniotic fluid; or (3) SSADH enzyme assay in chorionic villus (CV) and/or amniocytes, In two pregnancies, all analyses were concordant f or prediction of disease status in the fetus. In the third case, enzyme act ivity in CV (deficient) and metabolite analysis in amniotic fluid (normal) were discordant. For clarification, mutation analysis was undertaken in CV, confirming heterozygosity for the mutation previously identified in the pr oband, We hypothesize that delayed transit time for shipment of CV between Greece and the United States (8 days) led to enhanced degradation of hetero zygous SSADH enzyme activity. Our data demonstrate the importance of combin ed metabolite, enzyme, and DNA analysis for increased accuracy in the PND o f SSADH-deficiency. (C) 2001 Academic Press.