AASS (alpha-aminoadipate delta-semialdehyde synthase) is a bifunctional enzyme. The reaction forms saccharopine as an intermediate and 2-aminoadipic semialdehyde as the final product. Familial hyperlysinemia includes two conditions: hyperlysinemia type I, which presents with pipecolic aciduria, and hyperlysinemia type II, which presents with saccharopinuria. Defects in one or both activities result in familial hyperlysinemia (PMID:23890588).
Hyperlysinemia is described as a disorder that results from reduced activity of LKR and/or of SDH (PMID:10775527).
Ghadimi et al. (1965) found hyperlysinemia in 2 unrelated mentally retarded patients, one of whom was the product of father-daughter incest. The level of lysine in the cerebrospinal fluid was also elevated. Blood levels rose abnormally with lysine ... Ghadimi et al. (1965) found hyperlysinemia in 2 unrelated mentally retarded patients, one of whom was the product of father-daughter incest. The level of lysine in the cerebrospinal fluid was also elevated. Blood levels rose abnormally with lysine loading. A block in the metabolism of lysine was postulated. The patients were aged 2 and 27 years. Impaired sexual development, lax ligaments and muscles, convulsions in early life, and perhaps mild anemia were features. Woody (1964) found elevated lysine in the blood and spinal fluid of a physically and mentally retarded girl with convulsions, muscular and ligamentous asthenia, and normocytic, normochromic anemia which responded to dietary restriction of lysine. Woody (1964) suggested that incorporation of lysine into protein was defective. An ostensibly normal cousin also had hyperlysinuria. The parents of the proband were related. Dancis et al. (1969) demonstrated reduced lysine:alpha-ketoglutarate reductase activity in skin fibroblasts from 3 affected sibs. Subluxation of the lenses developed in some of the patients (Woody, 1971; Smith et al., 1971). The hyperlysinemia in the cases studied by Dancis et al. (1969) was more marked than that in other reported cases such as that of Ghadimi et al. (1965), yet the latter cases were more severely retarded. Colombo et al. (1964) described episodic vomiting, rigidity, and coma in an infant, which was relieved by a low protein diet. During coma, ammonia was high in the blood and the amino acids lysine and arginine were also high. Defect in degradation of lysine was proposed. Lysine is a potent competitive inhibitor of arginase. As a result, urea synthesis and ammonia detoxication are interfered with. Colombo et al. (1967) demonstrated a defect in L-lysine:NAD-oxido-reductase activity in liver. This apparently is responsible for accumulation of lysine. Scriver (1987) concluded that the disorder described by Colombo et al. (1964) is the same as hyperlysinemia. Dancis et al. (1983) reviewed 10 cases of familial hyperlysinemia with lysine:alpha-ketoglutarate reductase deficiency, identified through newborn screening programs or family surveys. No adverse mental or physical effects could be attributed to the hyperlysinemic mother. Treatment with low protein diet was not found to be warranted. Dancis (1983) suspected that ectopia lentis is not a feature of lysine:alpha-ketoglutarate reductase deficiency. The patient of Woody (1971) may have had a second recessive disorder responsible for lax ligaments and ectopia lentis. In the view of Dancis (1983), the cases of Ghadimi et al. (1965), in which lax ligaments were also described, represent a different disease in which mental retardation is prominent and hyperlysinemia relatively slight. Further study of the patients reported by Woody (1964), inbred Louisiana Cajuns, revealed that 2 successive enzymes in the major pathway of lysine degradation are deficient, i.e., lysine ketoglutarate reductase (Dancis et al., 1969) and saccharopine dehydrogenase (Cox et al., 1975; Dancis et al., 1976), the first 2 steps in the mammalian lysine degradation pathway, suggesting the existence of a bifunctional enzyme encoded by a single locus. In hyperlysinemia, both enzymatic functions of AASS are defective; in saccharopinuria (268700), some of the first enzymatic function is retained (Cox, 1985; Cox et al., 1985).
In a patient with hyperlysinemia originally reported by Dancis et al. (1976), Sacksteder et al. (2000) found homozygosity for an out-of-frame 9-bp deletion in exon 15 of the AASS gene (605113.0001).