Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity

• Published in: Annals of neurology Vol. 36; no. 1; p. 83
• Main Authors: Fujii, T, Van Coster, R N, Old, S E, Medori, R, Winter, S, Gubits, R M, Matthews, P M, Brown, R M, Brown, G K, Dahl, H H
• Format: Journal Article
• Language: English
• Published: United States 01.07.1994
• Subjects: Base Sequence; Dosage Compensation, Genetic; Family; Female; Heterozygote; Humans; Infant; Male; Molecular Sequence Data; Mutation; Pedigree; Polymerase Chain Reaction; Pyruvate Dehydrogenase Complex Deficiency Disease - genetics
• ISSN: 0364-5134
• DOI: 10.1002/ana.410360116

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 E1 alpha and E1 beta subunits of the complex. Northern blot analysis for the E1 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 E1 alpha subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1 alpha gene revealed that the mother was a heterozygotes. 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.