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Biomarkers Identified in Inborn Errors for Lysine, Arginine, and Ornithine

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Biomarkers Identified in Inborn Errors for Lysine, Arginine, and Ornithine The Journal of Nutrition 6th Amino Acid Assessment Workshop Biomarkers Identified in Inborn Errors for Lysine, Arginine, and Ornithine1,2 Jean-Marie Saudubray* and Daniel Rabier Departments of Pediatrics and Biochemistry, Centre Hospitalier Universitaire Necker Enfants-Malades, Universite´ Rene´ Descartes, Paris 75015, France Downloaded from https://academic.oup.com/jn/article-abstract/137/6/1669S/4664947 by guest on 23 May 2019 Abstract Inborn errors of lysine, arginine, and ornithine metabolism are very rare: only a few patients affected with these disorders have been carefully investigated, and very few reports on long-term outcome are available. These rare data make it difficult to define safety limits of these amino acids and useful biomarkers from these disorders. Only 4 disorders give rise to an important increase of the plasma amino acid concentration proximal to the metabolic block: lysine in 2-aminoadipic semialdehyde synthase deficiency, arginine in arginase deficiency, ornithine in ornithine amino transferase deficiency, and hyperammonemia hyperornithinemia homocitrullinuria syndrome. There is an obvious discrepancy between the important physiological role of these amino acids in cell metabolism and nutrition and the clinical consequences that are actually observed in these disorders. J. Nutr. 137: 1669S–1672S, 2007. Inborn errors of lysine, arginine, and ornithine metabolism are very urea cycle disorders, pyruvate carboxylase deficiency, and or- rare; only a few patients affected with these disorders have been ganic acid disorders. carefully investigated, and very few reports on long-term outcome are available. This paucity of data makes it difficult to define safety Inborn errors with hyperlysinemia limits of these amino acids and useful biomarkers from these Hyperlysinemia/saccharopinuria syndrome. The hyper- disorders. Figure 1 shows the simplified metabolic pathways of lysinemia/saccharopinuria syndrome is caused by a deficiency dibasic amino acids and urea cycle withina cell and identifiesthe 14 of the bifunctional protein 2 aminoadipic semialdehyde syn- metabolic blocks known so far to disturb lysine, arginine, orni- thase, the first enzyme of the main route of lysine degradation thine, and citrulline plasma levels. Among them, only 4 give rise to catalizing conversion of lysine to 2-aminoadipic semialdehyde an important increase of the plasma amino acid concentration (1). In these disorders (hyperlysinemia type I: lysine-2oxoglutarate proximal to the metabolic block: lysine in 2-aminoadipic semial- reductase defect, and type II: saccharopine dehydrogenase dehyde synthase deficiency, arginine in arginase deficiency, and defect), plasma lysine is accumulated proximal to the enzymatic ornithine in ornithine amino transferase deficiency and hyperam- block and can reach up to 1700 mmol/L in plasma (n ¼ 110–250) monemia-hyperornithinemia-homocitrullinuria syndrome (Table and up to 270 mmol/L in CSF (n ¼ 28) without any significant 1). In addition, many of these disorders disturb citrulline plasma variation of other dibasic amino acids (arginine and ornithine). levels. They can be classified into 3 major categories: 1) the urea A slight ‘‘cystinuria’’ pattern, homocitrullinuria, and e-acetyllysine cycle defects, 2) the cytoplasmic or mitochondrial carriers, and 3) are present in the former, and in addition to these findings, a the so-called ‘‘satellite’’ enzymes (Table 2). significant plasma, urine, cerebrospinal fluid (CSF)3 saccharo- pine accumulation is present in the latter. Inborn errors of lysine metabolism About half of the patients described with these disorders were Inborn errors of lysine catabolism are rare, but hyperlysinemia is detected incidentally and are healthy, raising the question that a concomitant of many inborn errors of metabolism, including hyperlysinuria/saccharopinuria could be a rare ‘‘nondisease’’ despite the fact that the other half of the patients were found 1 Published in a supplement to The Journal of Nutrition. Presented at the because of motor – mental retardation, seizures, muscular hypo- conference ‘‘The Sixth Workshop on the Assessment of Adequate and Safe tonia, and spasticity. There are no data on the long-term out- Intake of Dietary Amino Acids’’ held November 6–7, 2006 in Budapest. The conference was sponsored by the International Council on Amino Acid Science come of a low-lysine diet in these patients. Accordingly, no safe (ICAAS). The organizing committee for the workshop was David H. Baker, limits of lysine concentration can be defined. Dennis M. Bier, Luc A. Cynober, Yuzo Hayashi, Motoni Kadowaki, Sidney M. In the recently described 2-aminoadipic semialdehyde de- Morris, Jr., and Andrew G. Renwick. The Guest Editors for the supplement were hydrogenase defect responsible for pyridoxine-responsive epi- David H. Baker, Dennis M. Bier, Luc A. Cynober, Motoni Kadowaki, Sidney M. lepsy, there is no hyperlysinemia but a significant elevation of Morris, Jr., and Andrew G. Renwick. Disclosures: all Editors and members of the organizing committee received travel support from ICAAS to attend the pipecolic acid, a-aminoadipic semialdehyde, and D-1-piperideine workshop and an honorarium for organizing the meeting. 6-carboxylate (P6C). The latter compound undergoes a Knoevenagel 2 Author disclosures: J.-M. Saudubray, expenses to attend the meeting provided by ICAAS; and D. Rabier, no conflicts of interest. * To whom correspondence should be addressed. E-mail: elisabeth.saudubray@ 3 Abbreviations used: CSF, cerebrospinal fluid; LPI, lysinuric protein intolerance; nck.aphp.fr. N, normal; NO, nitric oxide. 0022-3166/07 $8.00 ª 2007 American Society for Nutrition. 1669S Downloaded from https://academic.oup.com/jn/article-abstract/137/6/1669S/4664947 by guest on 23 May 2019 FIGURE 1 Simplified metabolic pathways of dibasic amino acids and urea cycle. Corresponding enzymes: 1, acetylglutamate synthase; 2, carbamoylphosphate synthetase i; 3, ornithine carbamoyltransferase; 4, argininosuccinate synthetase (citrullinemia type I); 5, citrin (citrullinemia type II); 6, argininosuccinate lyase; 7, arginase; 8, mitochondrial ornithine carrier (ORNT1), hyperammonemia-hyperornithinemia-homocitrullinuria syndrome; 9, dibasic amino acids transporter (LPI); 10, ornithine aminotransferase; 11, D1-pyrroline-5-carboxylate synthase; 12, a-aminoadipic semialdehyde synthase (reductase); 13, a-aminoadipic semialdehyde synthase (dehydrogenase); 14, pyruvate carboxylase. condensation with pyridoxal phosphate at physiological tem- ornithine (15 mmol/L), and arginine (15 mmol/L) because of perature and pH. Pharmacological doses of pyridoxine can poor intestinal absorption and urinary loss of these amino acids, rescue this disorder (2). There is no hyperlysinemia in glutaryl- particularly lysine (4). Deficiencies of arginine and ornithine, CoA dehydrogenase deficiency (glutaric aciduria type I), another intermediates of the urea cycle, lead to hyperammonemia and distal disorder of lysine catabolism. protein intolerance, and insufficient supply of lysine probably Hyperlysinemia secondary to defective bioavailability plays a major role in the growth retardation and skeletal and of 2-oxoglutarate. Another mechanism responsible for hyper- immunological manifestations of LPI. lysinemia is the defective bioavailability of 2-oxoglutarate, a molecule required in the mitochondria compartment to stochio- Inborn errors of arginine metabolism metrically catabolize lysine to saccharopine through lysine Hyperargininemia. In arginase deficiency (5), arginine is ele- ketoglutarate reductase (3). Such situations are actually ob- vated up to 700–800 mmol/L . This is the only defect in the urea served in the urea cycle disorders, where plasma lysine can reach cycle that presents with severe progressive neurological involve- up to 1400 mmol/L in neonatal forms of OTC and is positively ment (hypertonicity, loss of motor and mental skills, spastic para- correlated to plasma glutamine and alanine, and in pyruvate plegia of the lower extremities, seizures, ataxia, athetosis, and carboxylase deficiency, where lysine can reach up to 800 mmol/L, dysarthria) in the absence of hyperammonemic decompensation. concomitant with a low concentration of sum of glutamate plus The dietetic treatment aims to keep arginine plasma levels below glutamine. These observations indicate that plasma lysine con- 150 mmol/L. Interestingly the neurological manifestations have centrations may partly reflect the 2-oxoglutarate concentration been prevented and even partly reversed by orthotopic liver in mitochondria. transplantation that fully normalized arginine plasma levels in 2 patients (6). Inborn errors with hypolysinemia. In 2-oxoglutarate dehy- drogenase defect, there is a huge accumulation of 2-ketoglutarate Inborn errors with hypoargininemia. Arginine is low (20–50 with a low plasma lysine (46 6 28 mmol/L compared with 183 6 mmol/L) in all metabolic blocks of urea cycle distal to arginase. 39 for control 1-y-old) (3). In lysinuric protein intolerance (LPI), Accordingly, arginine is given as a supplement in all these there is a defective basolateral dibasic amino acid transporter, re- disorders to maintain plasma levels between 50 and 150 mmol/L. sulting in low plasma concentrations of lysine (50–70 mmol/L), Plasma arginine is low in LPI (see above and Table 1). 1670S Supplement TABLE 1 Inborn errors of dibasic amino acids metabolism (lysine, ornithine, arginine)1 Disease/enzyme Lys Orn Arg Cit NH3 Clinical signs Lysine With Hyperlysinemia – Hyperlysinemia Type I Up to 1700 (270
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