NEURODEVELOPMENTAL ABNORMALITIES AND LACTIC-ACIDOSIS IN A GIRL WITH A20-BP DELETION IN THE X-LINKED PYRUVATE-DEHYDROGENASE E1-ALPHA SUBUNIT GENE

We describe a girl with developmental abnormalities of the CNS and a l actic acidosis whose cultured fibroblasts showed a profound deficiency of pyruvate dehydrogenase complex (PDHC) activity (patient = 0.14 nmo l/mg protein per minute, controls = 0.7 to 1.1 nmol/mg protein per min ute). Immunocytochemistry demonstrated the fibroblast culture to be mo saic, with 14% of cells expressing the PDHC E1alpha subunit protein in normal amounts and the remaining 86% having no detectable immunoreact ive activity. Direct sequencing of cDNA for the X-linked PDHC E1alpha subunit established that the patient was heterozygous for a 20-bp dele tion beginning in the codon for Ser300 of the derived amino acid seque nce. The pattern of methylation at the DXS255 locus suggested predomin ant expression of the X chromosome carrying the mutant allele in the f ibroblast culture. There was a good correlation between the residual P DHC activity, the proportion of cells with immunoreactive E1alpha prot ein, and the X chromosome inactivation ratio, demonstrating the import ance of X-inactivation for expression of this X-linked neurometabolic disease in females.