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 .

Diseases
Validation

Diseases presenting "skin fibroblasts" symptom

child syndrome

cowden syndrome

cystinuria

dentinogenesis imperfecta

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

gm1 gangliosidosis

homocystinuria without methylmalonic aciduria

krabbe disease

malignant atrophic papulosis

monosomy 21

neonatal adrenoleukodystrophy

pyruvate dehydrogenase deficiency

werner syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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