Argininosuccinic aciduria

Report of two new cases and demonstration of intermittent elevation of blood ammonia
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      In the process of a routine survey of mentally retarded children, two brothers were found to have argininosuccinic aciduria. The older brother, now age seventeen years, excretes up to 9 gm. of argininosuccinic acid per day. The younger brother, age five years, excretes approximately 2 gm. per day. Both patients have had brief generalized seizures, and the older brother has been ataxic intermittently. Both patients have intelligence quotients of between 30 and 40. No abnormality of hair has been found. The parents are first cousins once removed.
      The concentration of argininosuccinic acid in spinal fluid in both patients was between 8 and 10 mg. per 100 ml., that in the blood 2.5 mg. per 100 ml. Intermittent elevation of blood ammonia up to 400 μg. per 100 ml. has been demonstrated in the older patient. Plasma citrulline levels are elevated in both patients, and are higher than those in their spinal fluid. The patients' red blood cells have no demonstrable argininosuccinase activity. Argininosuccinic acid is not demonstrable in the parents' urine, but argininosuccinase activity in their red blood cells is less than normal.
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        • Allan J.D.
        • Cusworth D.C.
        • Dent C.E.
        • Wilson V.K.
        A disease, probably hereditary, characterized by severe mental deficiency and a constant gross abnormality of amino acid metabolism.
        Lancet. 1958; 1: 182
        • Westall R.G.
        Argininosuccinic aciduria.
        in: 2nd ed. Proceedings of the Fourth International Congress on Biochemistry. V.168. 1958 (Vienna)
        • Westall R.G.
        Argininosuccinic aciduria. Identification and reactions of the abnormal metabolite in a newly described form of mental disease, with some preliminary metabolic studies.
        Biochem. J. 1960; 77: 135
        • Krebs H.A.
        Urea Synthesis.
        in: 2nd ed. The Enzymes. vol. 2. Academic Press, Inc, New York1951: 866
        • Ratner S.
        • Petrack B.
        • Rochovansky O.
        Biosynthesis of urea. V. Isolation and properties of argininosuccinic acid.
        J. Biol. Chem. 1953; 204: 95
        • Levin H.M.
        • Mackay M.
        • Oberholzer V.G.
        Argininosuccinic aciduria. An inborn error of amino acid metabolism.
        Arch. Dis. Childhood. 1961; 36: 622
        • Carson N.A.J.
        • Neill D.W.
        Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland.
        Arch. Dis. Childhood. 1962; 37: 505
        • Armstrong M.D.
        • Yates K.N.
        • Stemmerman M.G.
        An occurrence of argininosuccinic aciduria.
        Pediatrics. 1964; 33: 280
        • Coryell M.E.
        • Hall W.K.
        • Thevaos T.G.
        • Welter D.A.
        • Gatz A.J.
        • Horton B.F.
        • Sisson B.D.
        • Looper Jr., J.W.
        • Farrow R.T.
        A familial study of a human enzyme defect, argininosuccinic aciduria.
        Biochem. & Biophys. Res. Commun. 1964; 14: 307
        • Schreier K.
        • Leuchte G.
        Deutsch. Med. Wchnschr. 1965; 90: 864
        • Russell A.
        • Levin B.
        • Oberholzer V.G.
        • Sinclair L.
        Hyperammonemia. A new instance of an inborn enzymatic defect of the biosynthesis of urea.
        Lancet. 1962; 2: 699
        • Freeman J.M.
        • Nicholson J.F.
        • Masland W.S.
        • Rowland L.P.
        • Carter S.
        Ammonia intoxication due to congenital defect in urea synthesis.
        J. Pediat. 1964; 65: 1039
        • McMurray W.C.
        • Rathbun J.C.
        • Mohyuddin F.
        • Koegler S.J.
        Pediatrics. 1963; 32: 347
        • Tomlinson S.
        • Westall R.G.
        Argininosuccinic aciduria, argininosuccinase and arginase in human blood cells.
        Clin. Sc. 1964; 26: 261
        • Smith I.
        2nd ed. Chromatographic and Electrophoretic Techniques. vol. 2. Heinemann, London1960
        • Hamilton P.B.
        Ion exchange chromatography of amino acids.
        Anal. Chem. 1963; 35: 2055
        • Efron M.S.
        Quantitative estimation of amino acids in physiological fluids using a Technicon Amino Acid Analyzer.
        in: Proceedings of the Technicon Symposium on Automation in Analytical Chemistry, September 8, 1965 Mediad, Inc, New York1966: 637
        • McDermott Jr., W.V.
        • Adams R.D.
        Episodic stupor associated with an Eck fistula in the human with particular reference to the metabolism of ammonia.
        J. Clin. Invest. 1954; 33: 1
        • Conway E.J.
        Apparatus for the microdetermination of certain volatile substances. IV. The blood ammonia, with observations on normal human blood.
        Biochem. J. 1935; 29: 2755
        • Carver M.J.
        • Paska R.
        Ion-exchange chromatography of urinary amino acids.
        Clin. chim. acta. 1961; 6: 721
        • Soupart P.
        Urinary excretion of free amino acids in normal adult men and women.
        Clin. chim. acta. 1959; 4: 265
      1. Ratner, S. To be published.

        • Knauff H.G.
        • Seybold D.
        • Kanters A.
        Freie Plasmaaminosäuren und Blutammoniak nach oralen Proteinzufuhr. Untersuchungen bei Gesunden und bei Patienten mit Lebercirrhose.
        Klin. Wchnschr. 1965; 43: 382
        • Conn H.O.
        Ammonia tolerance in liver disease.
        J. Lab. & Clin. Med. 1960; 55: 855
        • McDermott Jr., W.V.
        • Huston C.J.W.
        The oral ammonium tolerance test as aid in the investigation of suspected esophagogastric varices.
        Ann. Surg. 1963; 158: 820
        • White L.P.
        • Phear E.A.
        • Summerskill W.H.J.
        • Sherlock S.
        Ammonium tolerance in liver disease. Observations based on catheterization of the hepatic veins.
        J. Clin. Invest. 1955; 34: 158
        • Traeger H.S.
        • Gabuzda Jr., G.J.
        • Ballou A.N.
        • Davidson C.S.
        Blood “ammonia” concentration in liver disease, and liver coma.
        Metabolism. 1954; 3: 99
        • Adams R.D.
        • Foley J.M.
        The neurological disorder associated with liver disease.
        in: 2nd ed. Metabolic and Toxic Diseases of the Nervous System. vol. 32. Williams & Wilkins Co, Baltimore1953: 198
        • Sherlock S.
        • Summerskill W.H.J.
        • White L.P.
        • Phear E.A.
        Portal-systemic encephalopathy. Neurological complications of liver disease.
        Lancet. 1954; 2: 453
        • Bickford R.G.
        • Butt H.R.
        Hepatic coma: the electroencephalographic pattern.
        J. Clin. Invest. 1955; 34: 790
        • Stahl J.
        • Rohmer F.
        • Bockel R.
        • Kurtz D.
        • Imler M.
        Études électroencéphalographiques au cours de l'hyperammoniémie provoquée par ingestion de sels ammoniacaux et par ingestion protidique chez des cirrhotiques.
        Presse Méd. 1959; 67: 1928
        • McDermott Jr., W.V.
        • Adams R.D.
        • Riddell A.G.
        Ammonia levels in blood and cerebrospinal fluid.
        in: 2nd ed. Proc. Soc. Exper. Biol. & Med.88. 1955: 380
        • Moore E.W.
        • Strohmeyer G.W.
        • Chalmers T.C.
        Distribution of ammonia across the blood—cerebrospinal fluid barrier in patients with hepatic failure.
        Am. J. Med. 1963; 35: 350
        • Perry T.L.
        • Jones R.T.
        The amino acid content of human cerebrospinal fluid in normal individuals and in mental defectives.
        J. Clin. Invest. 1961; 40: 1363
        • Macbeth W.A.A.G.
        • Kass E.H.
        • McDermott Jr., W.V.
        Treatment of hepatic encephalopathy by alteration of intestinal flora with lactobacillus acidophilus.
        Lancet. 1965; 1: 399
        • Silen W.
        • Harper H.A.
        • Mawdsley D.L.
        • Weirich W.L.
        Effect of antibacterial agents on ammonia production within the intestine.
        in: 2nd ed. Proc. Soc. Exper. Biol. & Med.88. 1955: 138
        • Meister A.
        Biochemistry of the Amino Acids.
        in: 2nd ed. Academic Press Inc, New York/London1965: 697
        • Meister A.
        Biochemistry of the Amino Acids.
        in: 2nd ed. Academic Press Inc, New York/London1965: 288
        • Ratner S.
        • Anslow W.B.
        • Petrack B.
        Biosynthesis of urea. VI. Enzymatic cleavage of argininosuccinic acid to arginine and fumaric acid.
        J. Biol. Chem. 1953; 204: 115
        • Bollman J.L.
        • Mann F.C.
        • Magath T.B.
        Studies on the physiology of the liver. VIII. Effect of total removal of the liver on the formation of urea.
        Am. J. Physiol. 1924; 69: 371
        • Kennan A.L.
        • Cohen P.P.
        Ammonia detoxication in liver from humans.
        in: 6th ed. Proc. Soc. Exper. Biol. & Med.106. 1961: 170
        • Pearl D.C.
        • McDermott Jr., W.V.
        A vulnerable and rate-limiting step in urea synthesis in patients with hyperammoniaemia.
        in: 6th ed. Proc. Soc. Exper. Biol. & Med.97. 1958: 440
        • Ratner S.
        • Petrack B.
        The mechanism of arginine synthesis from citrulline in kidney.
        J. Biol. Chem. 1953; 200: 175
        • Ratner S.
        • Morell H.
        • Carvalho E.
        Enzymes of arginine metabolism in brain.
        Arch. Biochem. & Biophys. 1960; 91: 280
        • Tomlinson S.
        • Westall R.G.
        Argininosuccinase activity in brain tissue.
        Nature. 1960; 188: 235
        • Walker J.B.
        Role for pancreas in biosynthesis of creatine.
        in: 6th ed. Proc. Soc. Exper. Biol. & Med.98. 1958: 7
        • Sporn M.B.
        • Dingman W.
        • Defalco A.
        • Davies R.K.
        The synthesis of urea in the living rat brain.
        J. Neurochem. 1959; 5: 62
        • Dent C.E.
        Argininosuccinic aciduria. A new form of mental deficiency due to metabolic causes.
        in: 6th ed. Proc. Royal Soc. Med.52. 1959: 885
        • Bessman S.P.
        • Bessman A.N.
        The cerebral and peripheral uptake of ammonia in liver disease with an hypothesis for the mechanism of hepatic coma.
        J. Clin. Invest. 1955; 34: 622
        • Gabuzda G.J.
        Hepatic coma: clinical considerations, pathogenesis and management.
        Adv. Int. Med. 1962; vol. 11
        • Starer F.
        • Couch R.
        Cerebral atrophy in hyperammonaemia.
        Clin. Radiol. 1963; 14: 353
        • Victor M.
        • Adams R.D.
        • Cole M.
        The acquired (non-Wilsonian) type of chronic hepatocerebral degeneration.
        Medicine. 1965; 44: 345
        • Rothman S.
        Physiology and Biochemistry of the Skin.
        in: University of Chicago Press, Chicago1954: 352
        • Pisano J.J.
        • Mitoma C.
        • Udenfriend S.
        Biosynthesis of 7 guanidinobutyric acid from γ aminobutyric acid and arginine.
        Nature. 1960; 180: 1125
        • Irreverre F.
        • Evans R.L.
        • Hayden A.R.
        • Silber R.
        Occurrence of γ guanidinobutyric acid.
        Nature. 1957; 180: 704
      2. An ammonia detoxicant, arginine glutamate (Modumate).
        J. A. M. A. 1964; 187: 359
        • McDermott Jr., W.V.
        • Victor M.
        • Point W.W.
        Exclusion of the colon in the treatment of hepatic encephalopathy.
        New England J. Med. 1962; 267: 850