Alternative titles; symbols
ORPHA: 2203; DO: 9274;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q31.32 | Hyperlysinemia | 238700 | Autosomal recessive | 3 | AASS | 605113 |
A number sign (#) is used with this entry because hyperlysinemia type I is caused by homozygous or compound heterozygous mutation in the alpha-aminoadipic semialdehyde synthase gene (AASS; 605113) on chromosome 7q31.
Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant (summary by Tondo et al., 2013; Houten et al., 2013).
The AASS gene encodes a bifunctional enzyme: lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type I, both enzymatic functions of AASS are defective; in hyperlysinemia type II, also known as saccharopinuria (268700), some of the first enzymatic function is retained (Cox, 1985; Cox et al., 1986).
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.
Cederbaum et al. (1979) reported a 7-year-old boy with mild developmental delay, hyperactivity, and speech delay who was found to have increased serum and urinary lysine and saccharopine. Saccharopine was also present in cerebrospinal fluid. Initial studies suggested cystinuria, but further analysis indicated that the amino acid was saccharopine. Patient fibroblasts showed undetectable activities of both lysine ketoglutarate reductase and saccharopine dehydrogenase. Reexamination of the urine of previously studied cases of this double enzyme deficiency (Dancis et al., 1976) suggested that saccharopinuria of variable degree is the rule and not the exception in patients with 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. In addition, a child with no clinical manifestations of hyperlysinemia was born to an affected mother.
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.
Tondo et al. (2013) reported 2 unrelated children with hyperlysinemia type I. Both presented in infancy with seizures and were found to have increased lysine in serum, urine, and cerebrospinal fluids. Pipecolic acid was also increased in serum and urine, whereas ornithine was decreased. The patients had mild cognitive impairment, with poor speech, hyperactivity, and poor attention span. One patient had optic nerve hypoplasia and fine motor deficits. Brain MRI showed no abnormalities, and neither patient had dysmorphic features. A lysine-restricted diet yielded mild improvement in symptoms and laboratory abnormalities, but was difficult to follow and did not reverse cognitive impairment.
Houten et al. (2013) directly sequenced the AASS gene in a sample of 8 patients with hyperlysinemia who were identified retrospectively from a cohort of patient samples sent for metabolic screening due to a variety of distinct neurologic abnormalities. Biallelic mutations or deletions involving the AASS gene were identified in all samples (see, e.g., 605113.0006 and 605113.0007). Patient fibroblasts showed no detectable lysine alpha-ketoglutarate dehydrogenase or saccharopine dehydrogenase activity, and immunoblot analysis detected AASS at decreased levels in only 1 patient; the others had no detectable AASS protein. Patients had been referred for a variety of reasons, including delayed psychomotor development, failure to thrive, spastic tetraparesis or diplegia, seizures, hypotonia, and hyperactivity. Some patients had dysmorphic features. There was no definitive common phenotype among the referred patients except for increased serum lysine. Houten et al. (2013) concluded that the hyperlysinemia in these individuals resulted from mutations in the AASS gene; however, given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality.
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).
In 2 unrelated patients with type I hyperlysinemia and mild cognitive deficits, Tondo et al. (2013) identified compound heterozygous mutations in the AASS gene (605113.0002-605113.0005). All mutations affected splicing or resulted in truncated proteins, consistent with a loss of function.
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.
Carson, N. A. J., Scally, B. G., Neill, D. W., Carre, I. J. Saccharopinuria: a new inborn error of lysine metabolism. Nature 218: 679 only, 1968. [PubMed: 5690339] [Full Text: https://doi.org/10.1038/218679a0]
Cederbaum, S. D., Shaw, K. N. F., Dancis, J., Hutzler, J., Blaskovics, J. C. Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria. J. Pediat. 95: 234-238, 1979. [PubMed: 571908] [Full Text: https://doi.org/10.1016/s0022-3476(79)80657-5]
Colombo, J. P., Burgi, W., Richterich, R., Rossi, E. Congenital lysine intolerance with periodic ammonia intoxication: a defect in L-lysine degradation. Metabolism 16: 910-925, 1967.
Colombo, J. P., Richterich, R., Donath, A., Spahr, A., Rossi, E. Congenital lysine intolerance with periodic ammonia intoxication. Lancet 283: 1014-1015, 1964. Note: Originally Volume I. [PubMed: 14129804] [Full Text: https://doi.org/10.1016/s0140-6736(64)91924-5]
Colombo, J. P., Vassella, F., Humbel, R., Burgi, W. Lysine intolerance with periodic ammonia intoxication. Am. J. Dis. Child. 113: 138-141, 1967. [PubMed: 6015890] [Full Text: https://doi.org/10.1001/archpedi.1967.02090160188030]
Cox, R. P., Hutzler, J., Woody, N. C., Dancis, J. Multiple enzyme deficiency in familial hyperlysinemia. (Abstract) Am. J. Hum. Genet. 27: 29A only, 1975.
Cox, R. P., Markovitz, P. J., Chuang, D. T. Familial hyperlysinemias--multiple enzyme deficiencies associated with the bifunctional aminoadipic semialdehyde synthase. Trans. Am. Clin. Climatol. Assoc. 97: 69-81, 1986. [PubMed: 3939388]
Cox, R. P. Personal Communication. Cleveland, Ohio 10/22/1985.
Dancis, J., Hutzler, J., Ampola, M. G., Shih, V. E., van Gelderen, H. H., Kirby, L. T., Woody, N. C. The prognosis of hyperlysinemia: an interim report. Am. J. Hum. Genet. 35: 438-442, 1983. [PubMed: 6407303]
Dancis, J., Hutzler, J., Cox, R. P., Woody, N. C. Familial hyperlysinemia with lysine-ketoglutarate reductase insufficiency. J. Clin. Invest. 48: 1447-1452, 1969. [PubMed: 5796356] [Full Text: https://doi.org/10.1172/JCI106110]
Dancis, J., Hutzler, J., Cox, R. P. Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on terminology. Am. J. Hum. Genet. 31: 290-299, 1979. [PubMed: 463877]
Dancis, J., Hutzler, J., Woody, N. C., Cox, R. P. Multiple enzyme defects in familial hyperlysinemia. Pediat. Res. 10: 686-691, 1976. [PubMed: 934735] [Full Text: https://doi.org/10.1203/00006450-197607000-00011]
Dancis, J. Personal Communication. New York, N. Y. 6/15/1983.
Ghadimi, H., Binnington, V. I., Pecora, P. Hyperlysinemia associated with mental retardation. New Eng. J. Med. 273: 723-729, 1965. [PubMed: 5825685] [Full Text: https://doi.org/10.1056/NEJM196509302731401]
Ghadimi, H. The hyperlysinemias. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): Metabolic Basis of Inherited Disease. (4th ed.) New York: McGraw-Hill (pub.) 1978. Pp. 387-396.
Houten, S. M., te Brinke, H., Denis, S., Ruiter, J. P. N., Knegt, A. C., de Klerk, J. B. C., Augoustides-Savvopoulou, P., Haberle, J., Baumgartner, M. R., Coskun, T., Zschocke, J., Sass, J. O., Poll-The, B. T., Wanders, R. J. A., Duran, M. Genetic basis of hyperlysinemia. Orphanet J. Rare Dis. 8: 57, 2013. Note: Electronic Article. [PubMed: 23570448] [Full Text: https://doi.org/10.1186/1750-1172-8-57]
Markovitz, P. J., Chuang, D. T., Cox, R. P. Familial hyperlysinemias: purification and characterization of the bifunctional aminoadipic semialdehyde synthase with lysine-ketoglutarate reductase and saccharopine dehydrogenase activities. J. Biol. Chem. 259: 11643-11646, 1984. [PubMed: 6434529]
Sacksteder, K. A., Biery, B. J., Morrell, J. C., Goodman, B. K., Geisbrecht, B. V., Cox, R. P., Gould, S. J., Geraghty, M. T. Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia. Am. J. Hum. Genet. 66: 1736-1743, 2000. [PubMed: 10775527] [Full Text: https://doi.org/10.1086/302919]
Scriver, C. R. Personal Communication. Montreal, Quebec, Canada 7/28/1987.
Smith, T. H., Holland, M. G., Woody, N. C. Ocular manifestations of familial hyperlysinemia? Trans. Am. Acad. Ophthal. Otolaryng. 75: 355-360, 1971. [PubMed: 5557172]
Tondo, M., Calpena, E., Arriola, G., Sanz, P., Martorell, L., Ormazabal, A., Castejon, E., Palacin, M., Ugarte, M., Espinos, C., Perez, B., Perez-Duenas, B., Perez-Cerda, C., Artuch, R. Clinical, biochemical, molecular and therapeutic aspects of 2 new cases of 2-aminoadipic semialdehyde synthase deficiency. Molec. Genet. Metab. 110: 231-236, 2013. [PubMed: 23890588] [Full Text: https://doi.org/10.1016/j.ymgme.2013.06.021]
Woody, N. C., Hutzler, J., Dancis, J. Further studies of hyperlysinemia. Am. J. Dis. Child. 112: 577-580, 1960.
Woody, N. C., Pupene, M. B. Derivation of pipecolic acid from L-lysine by familial hyperlysinemics. Pediat. Res. 5: 511-513, 1971.
Woody, N. C., Pupene, M. B. Excretion of hypusine by children and by patients with familial hyperlysinemia. Pediat. Res. 7: 994-995, 1973. [PubMed: 4753051] [Full Text: https://doi.org/10.1203/00006450-197312000-00008]
Woody, N. C. Hyperlysinemia. Am. J. Dis. Child. 108: 543-553, 1964. [PubMed: 14209691] [Full Text: https://doi.org/10.1001/archpedi.1964.02090010545015]
Woody, N. C. Personal Communication. New Orleans, La. 1971.