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 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.
Fujii
T
T
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY.
Van Coster
R N
RN
Old
S E
SE
Medori
R
R
Winter
S
S
Gubits
R M
RM
Matthews
P M
PM
Brown
R M
RM
Brown
G K
GK
Dahl
H H
HH
D001483:Base Sequence; D004303:Dosage Compensation, Genetic; D005190:Family; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000235:genetics*