DEFICIENCY OF DIHYDROLIPOAMIDE DEHYDROGENASE DUE TO 2 MUTANT ALLELES (E340K AND G101DEL) - ANALYSIS OF A FAMILY AND PRENATAL TESTING

A male child with metabolic acidosis was diagnosed as having dihydroli poamide dehydrognase (E3) deficiency. E3 activity of the proband's cul tured fibroblasts and blood lymphocytes was 3-9% of normal, while in t he parent's lymphocytes it was about 60% of normal. The proband's pyru vate dehydrogenase complex (PDC) and the a-ketoglutarate dehydrogenase complex activities from cultured skin fibroblasts were 12% and 6% of normal, respectively. PDC activity in the parents cultured fibroblasts was 25-31% of normal. Western and Northern blot analyses showed simil ar quantities of E3 protein and mRNA in cultured fibroblasts from the proband and his parents, DNA sequencing of cloned full-length E3 cDNAs , from the proband and the parents, showed two mutations on different alleles of proband were inherited from the parents. One mutation is a three nucleotide (AGG) deletion, from the mother, resulting in deletio n of Gly101 in the FAD binding domain. The other mutation is a nucleot ide substitution (G to A), from the father, leading to substitution of Lys for Glu340 in the central domain. The same deletion mutation was found in E3 cDNA from a chorionic villus sample and cultured fibroblas ts obtained from the mother's subsequent offspring. This finding illus trates the possiblilty of successful prenatal diagnosis of E3 deficien cy utilizing mutations characterized prior to initiation of pregnancy. (C) 1997 Elsevier Science B.V.