Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles (E340K and G101del) Analysis of a family and prenatal testing

AbstractA male child with metabolic acidosis was diagnosed as having dihydrolipoamide dehydrognase (E3) deficiency. E3 activity of the proband's cultured fibroblasts and blood lymphocytes was 3–9% of normal, while in the parent's lymphocytes it was about 60% of normal. The proband's pyruvate dehydrogenase complex (PDC) and the α-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 similar 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 deletion of Gly101 in the FAD binding domain. The other mutation is a nucleotide 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 fibroblasts obtained from the mother's subsequent offspring. This finding illustrates the possiblilty of successful prenatal diagnosis of E3 deficiency utilizing mutations characterized prior to initiation of pregnancy