TY - JOUR
T1 - Synergistic heterozygosity
T2 - Disease resulting from multiple partial defects in one or more metabolic pathways
AU - Vockley, Jerry
AU - Rinaldo, Piero
AU - Bennett, Michael J.
AU - Matern, Dietrich
AU - Vladutiu, Georgirene D.
N1 - Funding Information:
We gratefully acknowledge the many physicians who referred patients and samples for evaluation. This work was supported in parts by PHS Grants RO1-DK45482 and RO1-DK54936 to J.V., and a grant to G.D.V. from the Muscular Dystrophy Association.
PY - 2000
Y1 - 2000
N2 - Inborn errors of metabolism show considerable variation in the severity of symptoms. This is often ascribed to the differential effects of specific mutations on gene/enzyme function; however, such genotype/phenotype correlations are usually imprecise. In addition, in some patients with clinical and biochemical findings consistent with a defect in a particular metabolic pathway, it is ultimately impossible to arrive at a precise enzymatic diagnosis. In this situation, we have increasingly been identifying concurrent partial 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 metabolism. These patients show clinical symptoms consistent with a defect in the affected pathways even though they do not have a complete deficiency in any one enzyme. We hypothesize that such patients are exhibiting clinically significant reductions in energy metabolism related to the compound effects of these partial defects, a phenomenon we term 'synergistic heterozygosity.' Based on the frequencies of known disorders of energy metabolism, we propose that this may represent a previously unrecognized, relatively common mechanism of disease of potentially great clinical relevance. (C) 2000 Academic Press.
AB - Inborn errors of metabolism show considerable variation in the severity of symptoms. This is often ascribed to the differential effects of specific mutations on gene/enzyme function; however, such genotype/phenotype correlations are usually imprecise. In addition, in some patients with clinical and biochemical findings consistent with a defect in a particular metabolic pathway, it is ultimately impossible to arrive at a precise enzymatic diagnosis. In this situation, we have increasingly been identifying concurrent partial 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 metabolism. These patients show clinical symptoms consistent with a defect in the affected pathways even though they do not have a complete deficiency in any one enzyme. We hypothesize that such patients are exhibiting clinically significant reductions in energy metabolism related to the compound effects of these partial defects, a phenomenon we term 'synergistic heterozygosity.' Based on the frequencies of known disorders of energy metabolism, we propose that this may represent a previously unrecognized, relatively common mechanism of disease of potentially great clinical relevance. (C) 2000 Academic Press.
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U2 - 10.1006/mgme.2000.3066
DO - 10.1006/mgme.2000.3066
M3 - Article
C2 - 11001791
AN - SCOPUS:0033803952
SN - 1096-7192
VL - 71
SP - 10
EP - 18
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 1-2
ER -