5Metabolic errors in lysine degradation

Abstract

Summary Two types of permanent hereditary hyperlysinaemia have been describedGroup I due to lysine-α-ketoglutarate reductase deficiency (10 patients) and Group Il due to deficiency of saccharopine dehydrogenase (2 patients). Both types are extremely rare. The common clinical finding in both groups was mental retardation and short stature. A patient has been described with periodic hyperlysinaemia associated with ammonia intoxication when the patient was receiving a normal intake of protein. Symptoms were prevented by giving a low protein intake. Liver enzymes of the urea cycle and ammonia detoxication were found to be normal although red cell arginase was inhibited and this was thought to be due to competitive inhibition by the high levels of lysine. Lysine-α-ketoglutarate reductase activity was found to be only 25 per cent of normal accounting for the high lysine levels. No satisfactory explanation is known for the series of events leading to the ammonia intoxication in this patient. Pipecolic acid is derived from lysine and in man appears to be a metaboliteof a minor pathway of lysine degradation. This concept has been supported by the discovery of a child with a degenerative neurological disease and hepatomegaly in whom markedly elevated levels of plasma pipecolic acid were found. Lysine loading studies revealed no impairment of lysine metabolism. Experimental work has shown that lysine is the sole source of hydroxy-lysine in collagen and its formation is vital to the normal cross linking process in this tissue. It is normally excreted together with hydroxy-proline in the bound form and only traces of free hydroxylysine are present. Six patients with hydroxylysinuria have been reported by four differentgroups of workers. Two hypotheses are put forward to account for its presence. First, that it is due to a transport defect in hydroxylysine and second, there is a defect in the enzymatic degradation of hydroxylysine possibly at the level of hydroxylysine kinase. Neither have so far been proved, but the latter concept has considerable biochemical data to recommend it. A second metabolic defect with no over-excretion of hydroxylysine hasbeen described. Here, the defect is due to a deficiency of enzymatic hydroxylation of lysine in the collagen fibre, resulting clinically in a connective tissue disorder. In the patients with hydroxylysinuria the main presenting symptoms were mental retardation and convulsions.