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Familial Hyperlysinemia

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Familial Hyperlysinemia Familial hyperlysinemia is an inborn error of metabolism v. Dominant and recessive forms of inherited sub- caused by a defect in the bifunctional protein α-aminoadipic luxation of the lens semialdehyde synthase. DIAGNOSTIC INVESTIGATIONS GENETICS/BASIC DEFECTS 1. Plasma amino acid quantitative analysis: hyperlysinemia 1. Inheritance: autosomal recessive 2. Urinary amino acid quantitative analysis: hyperlysinuria 2. A heterogeneous group of at least three disorders 3. Urinary organic acid analysis: variable saccharopinuria a. Caused by mutations in the gene encoding α-aminoad- 4. Cultured skin fibroblasts: absent lysine-ketoglutarate ipic semialdehyde synthase (AASS), the bifunctional reductase and saccharopine dehydrogenase activities protein that contains both lysine-ketoglutarate reduc- 5. Molecular genetic study: homozygous deletion in AASS tase (LKR) and saccharopine dehydrogenase (SDH) gene activity 6. EEG for seizures b. Deficiency in lysine-ketoglutarate reductase (LKR) and/or saccharopine dehydrogenase (SDH) activities GENETIC COUNSELING leads to a clinical phenotype characterized by hyper- 1. Recurrence risk lysinemia, lysinuria and variable saccharopinuria a. Patient’s sib: 25% c. Deficiency in saccharopine oxidoreductase activity, b. Patient’s offspring: not increased unless the spouse is along with deficient LKR and SDH activities, is also a carrier in which case 50% of the offspring will be observed in children with familial hyperlysinemia. affected 2. Prenatal diagnosis has not been reported CLINICAL FEATURES 3. Management a. Dietary control with reduction in lysine intake 1. Mental retardation of varying degree b. Other supportive therapies 2. Other neurolomuscular manifestations a. Poor muscle tone (hypotonia) b. Muscle weakness REFERENCES c. Clumsy hand movements Armstrong MD, Robinow M: A case of hyperlysinemia: biochemical and clin- d. Cross adductor reflexes ical observations. Pediatrics 39:546–554, 1967. e. Ankles clonus Carson NAJ, Scally BG, Neill DW, et al.: Saccharopinuria: a new inborn error f. High arched feet of lysine metabolism. Nature 218:679, 1968. Cederbaum SD, Shaw KN, Dancis J, et al.: Hyperlysinemia with saccharopinuria g. Awkward gait due to combined lysine-ketoglutarate reductase and saccharopine dehy- h. Hyperactive deep tendon reflexes drogenase deficiencies presenting as cystinuria. J Pediatr 95:234–238, i. Seizures 1979. j. Progressive spastic paraparesis/diplegia Cox RP: Errors in lysine metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 3. Developmental delay, especially speech delay 8th ed. New York: McGraw-Hill, 2001, Chapter 86, Pp 1965–1970. 4. Hyperactive behavior Dancis J, Hutzler J, Cox RP, et al.: Familial hyperlysinemia with lysine- 5. Ligamentous laxity ketoglutarate reductase insufficiency. J Clin Invest 48:1447–1452, 1969. 6. Ocular manifestations Dancis J, Hutzler J, Woody NC, et al.: Multiple enzyme defects in familial a. Bilateral subluxated lenses (ectopia lentis) hyperlysinemia. Pediatr Res 10:686–691, 1976. Dancis J, Hutzler J, Cox RP: Familial hyperlysinemia: enzyme studies, diag- b. Lateral rectus muscle paresis nostic methods, comments on terminology. Am J Hum Genet 31: 290– c. Bilateral spherophakia 299, 1979. 7. Hyperlysinemia alone may not be associated with a clini- Dancis J, Hutzler J, Ampola MG, et al.: The prognosis of hyperlysinemia: an cal phenotype interim report. Am J Hum Genet 35:438–442, 1983. 8. Differential diagnosis Ghadimi H, Binnington VI, Pecora P: Hyperlysinemia associated with retardation. N Engl J Med 273:723–729, 1965. a. Hyperlysinemia: periodic hyperlysinemia with Ghadimi H, Zischka R, Binnington VI: Further studies on hyperlysinemia asso- ammonia intoxication ciated with retardation. Am J Dis Child 113:146–151, 1967. b. Ectopia lentis Markovitz PJ, Chuang DT, Cox RP: Familial hyperlysinemias: purification and i. Marfan syndrome characterization of the bifunctional aminoadipic semialdehyde synthase with lysine-ketoglutarate reductase and saccharopine dehydrogenase ii. Homocystinuria activities. J Biol Chem 259:11643–11646, 1984. iii. Marchesani syndrome Özalp I, Hasanoˇglu A, Tunçbilek E, et al.: Hyperlysinemia without clinical iv. Ehlers-Danlos syndromes findings. Acta Paediatr Scand 70:951–953, 1981. 386 FAMILIAL HYPERLYSINEMIA 387 Sacksteder KA, Biery BJ, Morrell JC, et al.: Identification of the alpha- Woody NC, Ong EB: Paths of lysine degradation in patients with hyperlysine- aminoadipic semialdehyde synthase gene, which is defective in familial mia. Pediatrics 40:986–992, 1967. hyperlysinemia. Am J Hum Genet 66:1736–1743, 2000. Woody NC, Pupene MB: Excretion of pipecolic acid by infants and by patients Simell O, Visakarpi JK, Donner M: Saccharopinuria. Arch Dis Child 47:52, with hyperlysinemia. Pediatr Res 4:89–95, 1970. 1972. Woody NC, Pupene MB: Excretion of hypusine by children and by patients Smith TH, Holland MG, Woody NC: Ocular manifestations of familial hyper- with familial hyperlysinemia. Pediatr Res 7:994–995, 1973. lysinemia. Trans Am Acad Ophthalmol Otolaryngol 75:355–360, 1971. Woody NC, Hutzler J, Dancis J: Further studies of hyperlysinemia. Am J Dis Van Gelderen HH, Teijema HL: Hyperlysinemia: harmless inborn error of Child 112:577–580, 1966. metabolism? Arch Dis Child 48:892, 1973. Yiannikas C, Cordato D: Familial hyperlysinemia in a patient presenting with Woody NC: Hyperlysinemia. Am J Dis Child 108:543, 1964. progressive spastic paraparesis. Neurology 47:846, 1996. 388 FAMILIAL HYPERLYSINEMIA Fig. 1. A 27-year-old female with hyperlysinemia showing global delay, spasticity, rigidity, and multiple joint contractures. She was diagnosed to have hyperlysinemia since about 1 1/2 years of age with markedly elevated serum lysine of 1,618 μM (45–144). As a neonate, she had frequent emesis and noted to be stiff and irritable with pro- gressive developmental delay. She began to walk with a ramp and rails until approximately four years of age when she started to develop increased spasticity and significant scissoring, necessitating adductor release. On the recent plasma amino acid analysis, lysine was markedly elevated at 1252 μM (41–225)..
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