PDH deficiency : genotype-phenotype.

Pyruvate dehydrogenease (PDH) deficiency is one of the most important inborn errors of metabolism causing congenital lactic acidosis. A wide spectrum of clinical presentations can accompany a PDH deficiency. In order to study the relationship between genotype and phenotype, we collected and analysed the clinical data of 39 patients with PDH deficiency in whom a mutation in the E1 alpha gene was found.
In females, mutations are clustered in exon 9, 10, 11, encoding the carboxy terminal end of the E1 alpha. This region is of regulatory importance to the PHD complex. Mostly a severe clinical presentation is encountered, consisting of severe mental retardation, microcephaly and early onset seizures. Prolonged survival is possible. Dilated ventricles, associated with cortical atrophy develop very frequently, except in those patients were the mutations are in less important functional sites. In boys mutations are more spread over the whole PDH-E1 alpha gene. Three clinical syndromes can occur. First there is a severe neonatal lactic acidosis associated with early death and correlating with very low residual enzymatic activities. In these patients mutations are found in important regulatory regions of the gene. Second there is group of boys who develop characteristics of Leigh's encephalomyopathy. Their residual activity is higher, and the mutations affect several exons. Finally a small group of boys develop symptoms later in life, despite very low residual enzymatic activities. They have a milder course of their illness with intermittent ataxia as main symptom. The mutations of these boys are situated at the very end of the carboxy terminal.