ATP synthesis in lipoamide dehydrogenase deficiency.

Lipoamide dehydrogenase deficiency is an inborn error of several metabolic pathways, including pyruvate metabolism, Krebs cycle, and branched-chain amino acid degradation. The clinical course is variable, ranging from infantile neurodegenerative disease to recurrent episodes of liver failure or myoglobinuria starting later in life. In contrast, residual enzymatic activity in muscle tissue spans over a narrow range. Despite the recent elucidation of the underlying molecular pathology in most patients, relationships between the genotype and the biochemical and clinical phenotype remain unclear. In order to find a suitable assay for the prediction of clinical outcome and assessment of treatment, we have evaluated enzymatic activities and energetic states in fibroblasts from lipoamide dehydrogenase-deficient patients representing three different phenotypes and genotypes. Direct relationships between clinical parameters such as age of onset and disease severity and biochemical characteristics, including lipoamide dehydrogenase activity, pyruvate dehydrogenase complex activity, and ATP production ratio in fibroblasts, were identified. Clinical parameters were not reflected by lactate/pyruvate ratio. ATP production rate was in direct relationship with the severity of the neurological involvement; the patient with reduced ATP synthesis to 30% of the control mean had a severe neurodegenerative disease, whereas ATP synthesis values above 45% were associated with a more favorable course. Incubation of the patients' fibroblasts with dichloroacetate coupled with thiamin resulted in slight but significant improvement of the cell energetic state. Copyright 2000 Academic Press.