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PubMed1979

Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on terminology.

Enzyme assays of skin fibroblasts from five children with familial hyperlysinemia from unrelated families are added to the previous report of three children from two unrelated families. In all instances there was a deficiency in lysine-ketoglutarate reductase, saccharopine dehydrogenase, and saccharopine oxidoreductase activities. To complete the studies on the enzymes associated with familial hyperlysinemia, saccharopine oxidoreductase was partially purified from human liver and characterized. The activity did not separate from that of lysine-ketoglutarate reductase or saccharopine dehydrogenase. A simple screening test for familial hyperlysinemia is described based on the evolution of 14CO2 from lysine-14C by skin fibroblasts. The test differentiated, without overlap, seven patients with familial hyperlysinemia from control subjects. The relation of the two genetic entities involving lysine degradation, familial hyperlysinemia and saccharopinuria, is discussed. It is suggested that familial hyperlysinemia, type I, be applied to patients with major defects in lysine-ketoglutarate reductase and saccharopine dehydrogenase, and that familial hyperlysinemia, type II, to be used to designate patients in whom significant amounts of lysine-ketoglutarate reductase are retained. The nomenclature would be consistent with that of an analogous disease, orotic aciduria.

Amino Acid Metabolism, Inborn Errors↗

PubMed2000

Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia.

The first two steps in the mammalian lysine-degradation pathway are catalyzed by lysine-ketoglutarate reductase and saccharopine dehydrogenase, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Defects in one or both of these activities result in familial hyperlysinemia, an autosomal recessive condition characterized by hyperlysinemia, lysinuria, and variable saccharopinuria. In yeast, lysine-ketoglutarate reductase and saccharopine dehydrogenase are encoded by the LYS1 and LYS9 genes, respectively, and we searched the available sequence databases for their human homologues. We identified a single cDNA that encoded an apparently bifunctional protein, with the N-terminal half similar to that of yeast LYS1 and with the C-terminal half similar to that of yeast LYS9. This bifunctional protein has previously been referred to as "alpha-aminoadipic semialdehyde synthase," and we have tentatively designated this gene "AASS." The AASS cDNA contains an open reading frame of 2,781 bp predicted to encode a 927-amino-acid-long protein. The gene has been sequenced and contains 24 exons scattered over 68 kb and maps to chromosome 7q31.3. Northern blot analysis revealed the presence of several transcripts in all tissues examined, with the highest expression occurring in the liver. We sequenced the genomic DNA from a single patient with hyperlysinemia (JJa). The patient is the product of a consanguineous mating and is homozygous for an out-of-frame 9-bp deletion in exon 15, which results in a premature stop codon at position 534 of the protein. On the basis of these and other results, we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia.

Amino Acid Sequence↗

PubMed1984

Familial hyperlysinemias. Purification and characterization of the bifunctional aminoadipic semialdehyde synthase with lysine-ketoglutarate reductase and saccharopine dehydrogenase activities.

Familial hyperlysinemias are autosomal recessive disorders in the oxidative degradation of lysine. Hyperlysinemia type I is associated with a combined deficiency in lysine-ketoglutarate reductase and saccharopine dehydrogenase activities, the first two sequential steps in the lysine degradative pathway. In familial hyperlysinemia type II, only saccharopine dehydrogenase activity is deficient. We report here that these reductase and dehydrogenase activities occur on a single protein based on the following findings. (i) The activity ratio of reductase/dehydrogenase remained constant (close to unity) throughout a 500-fold purification of both enzyme activities from mitochondrial extracts of baboon and bovine livers. The activity profiles of the reductase and the dehydrogenase superimpose on each other as the enzyme was eluted from DEAE-cellulose and Sephacryl S-300 columns. (ii) Activity-staining of the native polyacrylamide gel showed that both activities migrated the same distance toward the anode. (iii) The highly purified enzyme with the reductase and dehydrogenase activities showed a single polypeptide band of Mr = 115,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The native enzyme from baboon and bovine livers has an apparent Mr of 468,000 (Stokes radius = 69.5 A) as determined by gel filtration, which suggests a tetrameric structure of identical subunits. The presence in mammalian tissues of a single protein catalyzing both the reductase and dehydrogenase reactions explains the combined enzyme deficiency observed in hyperlysinemia type I. We propose that the bifunctional enzyme be called aminoadipic semialdehyde synthase.

Amino Acid Metabolism, Inborn Errors↗

PubMed1983

The prognosis of hyperlysinemia: an interim report.

Ten patients with familial hyperlysinemia with lysine-ketoglutarate reductase deficiency, identified through newborn screening programs or family surveys, were selected for review. Ages ranged from 2 to 24 years when last examined. A low-protein diet had been administered to two patients, which reduced the plasma lysine levels from 20 mg per dl or more to about 12 mg per dl. The rest were untreated. Mental development was judged normal or above average in nine. Mildly subnormal performance in three was considered appropriate to family and social background. No adverse mental or physical effects could be attributed to the hyperlysinemia. A normal child has been born to a mother with hyperlysinemia, indicating that the fetus may develop normally despite exposure to high lysine levels.

Adolescent↗

PubMed1981

Hyperlysinemia without clinical findings.

A three-year-old asymptomatic boy with hyperlysinemia is presented. The patient's plasma lysine levels have been constantly high (685-1370 mumol/l) and excessive urinary excretion of ornithine, arginine and cystine have been noted. There was no detectable activity of lysine-ketoglutarate reductase nor saccharopine dehydrogenase in skin fibroblast culture. Review of the reported cases and this patient with serious biochemical defect but without symptoms indicate clinical heterogeneity in hereditary hyperlysinemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed1976

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, less than 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.

Adolescent↗

PubMed1976

Clinical and biochemical studies on periodic hyperammonemia with hyperlysinemia and homocitrullinuria.

An 18-year-old mentally and physically retarded boy, suffering from episodes of anorexia, vomiting, coma and convulsion which have been severer with advance in age, had periodic hyperammonemia, hyperlysinemia and homocitrullinuria. Blood cell arginase activity of the patient on normal diet was markedly reduced after an oral load of L-lysine. The oral loading tests of L-lysine revealed hyperammonemia, hyperlysinemia, hyperargininemia, hypercitrullinemia and homocitrullinuria. Etiology of metabolic error of our patient was discussed in reference to lysine-urea cycle.

Adolescent↗

PubMed1991

[Hyperlysinemia and hyperammonemia].

A quite important increase of plasma lysine was often reported in different cases of hyperammonemia. This retrospective study of patients with different types of hyperammonemia shows that hyperlysinemia is not automatically associated to hyperammonemia (lysinemia is expressed as the percent of total aminoacidemia). Hyperlysinemia was observed with neonatal propionic and methylmalonic acidurias. Reye's syndrome and to a less extent with ornithine transcarbamylase deficiency.

Ammonia↗

PubMed1979

Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria.

A 7-year-old boy with speech delay, hyperactive behavior, and minor neurologic abnormalities had been found in the past to have "intermittent cystinuria." A more detailed investigation revealed hyperlysinemia and hyperlysinuria, with lesser increases in urinary excretion of arginine and cystine. The plasma and urine abnormalities increased on a diet of 3 gm of protein/kg body weight/day. Saccharopine, a normal metabolite of lysine not found in the body fluids of normal people, was present in plasma, cerebrospinal fluid, and urine of the patient. Lysine-ketoglutarate reductase and saccharopine dehydrogenase activities were not detectable in extracts of cultured skin fibroblasts. Re-examination of the urine of previously studied cases of this double enzyme deficiency suggests that saccharopinuria of variable degree is the rule and not the exception.

Cells, Cultured↗

PubMed1969

Familial hyperlysinemia with lysine-ketoglutarate reductase insufficiency.

Fibroblasts grown in tissue culture from the skin of normal subjects have lysine-ketoglutarate reductase activity (lysine: alpha-ketoglutarate: triphosphopyridine nucleotide (TPNH) oxidoreductase (epsilon-N-[L-glutaryl-2]-L-lysine forming)). The activity of the enzyme is considerably reduced in the skin fibroblasts grown from three siblings with hyperlysinemia. The high concentrations of lysine in the blood of these patients, the previous demonstration in the intact subject of a reduction in the ability to degrade lysine, and the present demonstration of diminished lysine-ketoglutarate reductase activity, accurately define the metabolic defect and establish the saccharopine (epsilon-N-[L-glutaryl-2]-L-lysine) pathway as the major degradative pathway for lysine in the human.

Alcohol Oxidoreductases↗

PubMed1976

Propionic acidemia and hyperlysinemia in a case with ornithine transcarbamylase (OTC) deficiency.

A female infant with episodic hyperammonemia due to a disorder of the urea cycle and who had hyperlysinemia and an unusual elevation of short chain fatty acids, mainly propionate, is described. Both occurred apparently only during attacks of hyperammonemia. Propionic acidemia was ruled out by enzyme studies. OTC deficiency was diagnosed on the basis of: 1) decreased enzyme activity in leukocytes;2) hyperammonemia in response to protein intakes in excess of 2.0 g/kg/day; 3) orotic aciduria in the patient and her asymptomatic mother; 4) suggestive evidence of x-linked dominant inheritance; and 5) exclusion of citrullinemia, argininosuccinic aciduria, argininemia, and disorders of lysine metabolism that are associated with hyperammonemia. Homocitrullinuria, presence of epsilon-N-acetyl-l-lysine in urine, and absence of saccharopine indicate deficiency of the saccharopine pathway of lysine degradation. However, alpha-ketoglutarate reductase was normal in fibroblasts. Since these metabolites were observed only in conjunction with hyperammonemia but not after a lysine load, we suggest that there was competition between ammonia and lysine for alpha-ketoglutarate. The link between disorders of the urea cycle and short chain fatty acid metabolism remains unexplained..

Acid-Base Imbalance↗

PubMed1964