Familial hyperlysinemia with lysine-ketoglutarate reductase insufficiency

Enzyme Studies in a Patient with Saccharopinuria: A Defect of Lysine Metabolism

“…Lysine-oxoglutarate reductase activity has been previously demonstrated in cultured skin fibroblasts [5]. The present investigation of the enzyme activity in skin fibroblasts from mitocllondrial preparations from healthy individuals showed an activity 5 times greater than that of the whole cell homogenate, which suggested that lysine-oxoglutarate reductase is also a mitochondrial enzyme.…”

“…T h e results obtained from the skin fibroblasts both of the normal subjects and our patient with saccharopinuria (Table 11) shows that the rate of saccharopine synthesis in the patient is considerably reduced compared with the normal control subjects. I n three patients reported [5] with hyperlysinemia due to lysine-oxoglutarate reductase deficiency, saccharopine synthesis was approximately 10% of that in the patient with saccharopinuria and 3.5% of that in normal control subjects. However, lysine load tests in our patient with saccharopinuria [3] did not suggest a primary defect in the first step of lysine degradation, inasmuch as an appreciable increase in saccharopine synthesis occurred.…”

“…I t has been demonstrated that saccllaropine is lormed by L-lysine in the presence of a-oxoglutarate by isolated rat liver mitochondria [15] and an enzyme, lysine-oxoglutarate reductase which catalyzes the formation of saccharopine from lysine with a-oxoglutarate has been partially purified from human liver [16]. Several patients with hyperlysinemia have been described i n the literature [l, 12, 281 and in three of these patients it has been sllown [5] that tlie hyperlysinemia results from a deficiency of lysine-oxoglutarate reductase.…”

Lysine degradation through the saccharopine pathway in mammals: involvement of both bifunctional and monofunctional lysine-degrading enzymes in mouse

“…We focused mainly on liver and kidney but a number of aspects regarding the function of LOR and SDH in other tissues should be explored hereafter, mainly those concerning their involvement in genetic disorders such as familial hyperlysinaemias. Two types of familial hyperlysinaemia have been described so far : type I is associated with a combined deficiency of the two enzyme activities, LOR and SDH, whereas in familial hyperlysinaemia type II only the dehydrogenase activity is impaired [6,24,25]. A deficiency in the bifunctional LOR\SDH mRNA levels might explain, for example, why there is a combined deficiency in type I disease ; a mutation in only the SDH domain might explain the type II disease.…”

“…This opens the question of whether the degradation of lysine has any functional significance during brain development and puts a new focus on the nutritional requirements for lysine in gestation and infancy. Fourthly, LOR and\or SDH deficiencies seem to be involved in a human autosomic genetic disorder known as familial hyperlysinaemia, which is characterized by serious defects in the functioning of the nervous system [10,24,25].…”