Multiple enzyme defects in familial hyperlysinemia

Lysine-ketoglutarate reductase (EC. 1.5.1.8) deficiency in skin fibroblasts has been previously reported in patients with familial hyperlysinemia, providing an adequate explanation for the biochemical derangements noted clinically. In the present study, analysis of liver obtained at autopsy from a patient with familial hyperlysinemia confirmed the lysine-ketoglutarate reductase deficiency but, unexpectedly, also revealed an absence of saccharopine dehydrogenase (EC. 1.5.1.9) and saccharopine oxidoreductase activity. Skin fibroblasts from two siblings with the disease and a third patient from an unrelated family were also deficient in all three enzymes (lysine-ketoglutarate reductase, average 9%; saccharopine dehydrogenase, average 4%; saccharopine oxidoreductase, <10% of normal). The possibility that saccharopine dehydrogenase is a substrate-inducible enzyme was investigated by maintaining normal skin fibroblasts in a medium with minimal lysine concentration, and exposing hyperlysinemic fibroblasts to elevated saccharopine concentrations. There was no significant modification in saccharopine dehydrogenase activity. Multiple enzyme defects have now been recognized in three genetic diseases, maple syrup urine disease, orotic aciduria, and hyperlysinemia, presumably arising from single mutations. It is not unlikely that additional examples will emerge as investigators increase their efforts in this direction. The simultaneous loss of enzymes may provide insights into mechanisms of control and/or the evolutionary development of enzymes.