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- Title
Pyruvate dehydrogenase deficiency: Molecular basis for intrafamilial heterogeneity.
- Authors
Fujii, Tatsuya; Van Coster, Rudy N.; Old, Susan E.; Medori, Rosella; Winter, Susan; Gubits, Ruth M.; Matthews, Paul M.; Brown, Ruth M.; Brown, Garry K.; Dahl, Hans-Henrik M.; De Vivo, Darryl C.
- Abstract
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.
- Publication
Annals of Neurology, 1994, Vol 36, Issue 1, p83
- ISSN
0364-5134
- Publication type
Article
- DOI
10.1002/ana.410360116