Lysine Intolerance in a Variant Form of Citrullinemia

Abstract

Summary MATERIALS AND METHODSAn oral loading of lysine (100 mg of lysine-HCL/kg) was performed in two patients, I&and 23-yr-old, with a variant form of citrullinemia.Serum citrulline levels were approximately 10 times higher than control level and lysine levels were within the normal range, in contrast to the classical form of the disease in which serum citrulline is approximately 100 times normal levels and hyperlysinemia is usually present.After lysine loading, lysine levels rose sharply and clearance was decreased. Blood ammonia rose approximately 2.5 times. Lysine, citrulline, and arginine were markedly elevated in urine, collected 90-210 min after the lysine loading. Baseline homocitrulline and homoarginine excretion was elevated and increased further after the load. SpeculationLysine tolerance was impaired in two patients with citrullinemia, although baseline lysine levels were normal. Lysine seemed to be catabolized along the alternate urea cycle: lysine-homocitrullinehomoarginine-urea. Hyperammpnemia was aggravated, suggesting competition between lysine and ammonia for a-ketoglutarate and inability to remove ammonia completely by these two alternate pathways.

Homocitrullinuria and homoargininuria in hyperargininaemia

“…Homocitrulline can be converted by argininosuccinate synthetase (EC 6.3.4.5) to homoargininosuccinate which is further metabolized to homoarginine (Strand- , 1971;Ratner, 1973). However, the appearance of homoargininuria in citrullinaemia due to argininosuccinate synthetase deficiency (Scott-Enmakpor et al, 1972;Matsuda et al, 1979) suggests that homoarginine is directly formed from lysine by transamidinating tysine via glycine transamidinase (EC 2.1.4.1) (Ryan et al, 1969). Inasmuch as arginine is used as a substrate in this metabolism and if homoarginine is metabolized to urea by arginase (Ryan et al, 1968;Paik et al, 1977), excess arginine and arginase deficiency may result in marked accumulation of homoarginine in hyperargininaemia.…”

Kinetic analysis of argininosuccinate synthetase in a variant form of citrullinaemia

“…As indicated, most cases of citrullinaemia in Japan are a variant form of the disease (Matsuda et al, 1979a;Saheki et al, 1981), in which a few cases had a qualitative ASA synthetase abnormality shown by altered kinetic properties (Matsuda et al, 1976;Saheki et al, 1981;Matsuda, 1979b), indicating a structure gene mutation. Most cases in Japan have a quantitative abnormality of ASA synthetase (Saheki et al, 1981).…”

“…Citrullinaemia (McKusick 21570) is a urea cycle disorder associated with deficient activity of argininosuccinate (ASA) synthetase (L-citrulline:L-aspartate ligase, EC6.3.4.5). At least three forms are found: a classical form whose onset occurs during infancy with periodic vomiting, seizures and mental retardation (McMurray et al, 1963); a rapid form which is fatal in the neonate (Van der Zee et at., 1971) with elevated serum citrulline levels appoximately 100 times the control level; and a variant form whose onset is in childhood or later, with seizures, stupor, usually but not always mental retardation, and a less elevated serum citrulline level, approximately 10-30 times the control level (Matsuda et al, 1976(Matsuda et al, , 1979a. In addition, even in patients with the same clinical form, genetic heterogeneities were identified by detailed biochemical studies (Kennaway et at., 1975;Saheki et al, 1981).…”