Diagnostic difficulties of pyruvate dehydrogenase deficiency, our experience with 22 Spanish patients.

PDH complex deficiency is one of the most common causes of primary lactic acidosis. Its diagnosis is complicated because of heterogeneity of the clinical presentation, the variability of the pattern of metabolites in plasma and urine, and the finding of high residual activities, especially for PDH E1 alpha deficiency in some heterozygous females. In addition, methods for measurement of PDH activity have pitfalls due to the complexity of this enzyme. We have mixed ideas from different authors to obtain a radiometric method for determination of PDH and E1 activities in fibroblasts and tissues. With this method we have detected 22 patients with low PDH activities. In four of them a mutation in the coding region of the E1 alpha gene has been found: 242 del 3 bp exon 7 in a girl with lactic academia, microcephaly and corpus callosum agenesia, H113D exon 4 in a girl with cerebral lactic academia, hypotonia and spastic tetraparesia, and in two boys affected by Leigh syndrome R263G exon 8 and Y369Q exon 11 have been found respectively. In the latter patient, codon 369 (TAC) is changed to CAA; this finding of two changes in the same codon is a rather exceptional observation. Two other patients were suspected of E3 deficiency because of the urine organic acid profile, but lipoamide dehydrogenase activity was normal. Three more girls presented multiple mitochondrial enzyme deficiencies and in one of them these deficiencies were likely attributable to decreased amount of hsp60. 13 other patients presented clinical features suggesting PDH deficiency and the activities of the complex and the E1 component were decreased or low-normal, but no mutation was demonstrated in the E1 alpha gene.