Synergistic heterozygosity: Disease resulting from multiple partial defects in one or more metabolic pathways

Inborn errors of metabolism show considerable variation in the severity of symptoms. This is often ascribed to the differential effects of specific mu tations on gene/enzyme function; however, such genotype/phenotype correlati ons are usually imprecise. In addition, in some patients with clinical and biochemical findings consistent with a defect in a particular metabolic pat hway, it is ultimately impossible to arrive at a precise enzymatic diagnosi s. In this situation, we have increasingly been identifying concurrent part ial defects in more than one pathway, or at multiple steps in one pathway. In this study, we present the clinical, biochemical, and molecular findings from several patients showing multiple partial defects in energy metabolis m. These patients show clinical symptoms consistent with a defect in the af fected pathways even though they do not have a complete deficiency in any o ne enzyme. We hypothesize that such patients are exhibiting clinically sign ificant reductions in energy metabolism related to the compound effects of these partial defects, a phenomenon we term "synergistic heterozygosity." B ased on the frequencies of known disorders of energy metabolism, we propose that this may represent a previously unrecognized, relatively common mecha nism of disease of potentially great clinical relevance. (C) 2000 Academic Press.