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Pyruvate dehydrogenase deficiency: Molecular basis for intrafamilial heterogeneity
Author(s) -
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 HansHenrik M.,
De Vivo Darryl C.
Publication year - 1994
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410360116
Subject(s) - pyruvate dehydrogenase complex , chemistry , biochemistry , enzyme
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.