Pyruvate dehydrogenase deficiency: Molecular basis for intrafamilial heterogeneity



Two half-brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages of 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1α and E1β subunits of the complex. Northern blot analysis for the E1α subunit showed normal results. In the 2 sons, complementary DNA sequence analysis reveled a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1α subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1α gene revealed that the mother was a heterozygote. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X-inactivation patterns in different organs of female heterozygotes.