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