Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity.

[pyruvate dehydrogenase deficiency]

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 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 E 1 alpha and E 1 beta subunits of the complex . Northern blot analysis for the E 1 alpha subunit showed normal results . In the 2 sons , complementary DNA sequence analysis revealed a cytosine to thymine mutation in exon 4 , resulting in a change of arginine 127 to tryptophan in the E 1 alpha subunit . Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E 1 alpha gene revealed that the mother was a heterozygotes . Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS 255 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 .