Genetics of Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) Syndrome Medication
- Author: Richard E Frye, MD, PhD; Chief Editor: Maria Descartes, MD more...
Sodium benzoate and sodium phenylacetate may reduce ammonia levels by providing an alternative pathway.
Urea Cycle Disorder Treatment Agents
These agents assist in excreting nitrogen and serve as an alternative to urea in reducing waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.
Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, or argininosuccinate lyase deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea-cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.
Glycerol phenylbutyrate is a nitrogen-binding agent for chronic management of adult and pediatric patients aged 2 years or older with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for treatment of hyperammonemia.
Zanatta A, Viegas CM, Tonin AM, Busanello EN, Grings M, Moura AP, et al. Disturbance of redox homeostasis by ornithine and homocitrulline in rat cerebellum: a possible mechanism of cerebellar dysfunction in HHH syndrome. Life Sci. 2013 Aug 6. 93 (4):161-8. [Medline].
Viegas CM, Tonin AM, Zanatta A, Seminotti B, Busanello EN, Fernandes CG, et al. Impairment of brain redox homeostasis caused by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in vivo. Metab Brain Dis. 2012 Dec. 27 (4):521-30. [Medline].
Amaral AU, Leipnitz G, Fernandes CG, Seminotti B, Zanatta A, Viegas CM, et al. Evidence that the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome induce oxidative stress in brain of young rats. Int J Dev Neurosci. 2009 Nov. 27 (7):635-41. [Medline].
Viegas CM, Zanatta A, Knebel LA, Schuck PF, Tonin AM, Ferreira Gda C, et al. Experimental evidence that ornithine and homocitrulline disrupt energy metabolism in brain of young rats. Brain Res. 2009 Sep 29. 1291:102-12. [Medline].
Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci. 2008 Jan 15. 264 (1-2):187-94. [Medline].
Mhanni AA, Chan A, Collison M, Seifert B, Lehotay DC, Sokoro A, et al. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) presenting with acute fulminant hepatic failure. J Pediatr Gastroenterol Nutr. 2008 Mar. 46 (3):312-5. [Medline].
Tessa A, Fiermonte G, Dionisi-Vici C, et al. Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Hum Mutat. 2009 May. 30(5):741-8. [Medline].
Camacho JA, Obie C, Biery B. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet. 1999 Jun. 22(2):151-8. [Medline].
Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2012 Sep 7. [Medline]. [Full Text].
Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, et al. Ammonia Control in Children Ages 2 Months through 5 Years with Urea Cycle Disorders: Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate. J Pediatr. 2013 Jan 13. [Medline].
Al-Dirbashi OY, Al-Hassnan ZN, Rashed MS. Determination of homocitrulline in urine of patients with HHH syndrome by liquid chromatography tandem mass spectrometry. Anal Bioanal Chem. 2006 Dec. 386(7-8):2013-7. [Medline].
Camacho JA, Mardach R, Rioseco-Camacho N, et al. Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediatr Res. 2006 Oct. 60(4):423-9. [Medline].
Camacho JA, Rioseco-Camacho N, Andrade D, et al. Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder. Mol Genet Metab. 2003 Aug. 79(4):257-71. [Medline].
Kang SS, Wong PW, Zhou JM, et al. Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism. 1988 Jul. 37(7):611-3. [Medline].
Korman SH, Kanazawa N, Abu-Libdeh B, et al. Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family. J Neurol Sci. 2004 Mar 15. 218(1-2):53-8. [Medline].
Lemay JF, Lambert MA, Mitchell GA. Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients. J Pediatr. 1992 Nov. 121(5 Pt 1):725-30. [Medline].
Nakajima M, Ishii S, Mito T. Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Brain Dev. 1988. 10(3):181-5. [Medline].
Salvi S, Santorelli FM, Bertini E, et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology. 2001 Sep 11. 57(5):911-4. [Medline].
Shih VE, Laframboise R, Mandell R. Neonatal form of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and prenatal diagnosis. Prenat Diagn. 1992 Sep. 12(9):717-23. [Medline].
Shimizu H, Maekawa K, Eto Y. Abnormal urinary excretion of polyamines in HHH syndrome (hyperornithinemia associated with hyperammonemia and homocitrullinuria). Brain Dev. 1990. 12(5):533-5. [Medline].
Smith L, Lambert MA, Brochu P. Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy. J Pediatr Gastroenterol Nutr. 1992 Nov. 15(4):431-6. [Medline].
Tuchman M, Knopman DS, Shih VE. Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Arch Neurol. 1990 Oct. 47(10):1134-7. [Medline].
Valle D, Simell O. The metabolic basis of inherited disease. Scriver CR, ed. The Hyperornithinemias. New York, NY: McGraw-Hill; 1995. 1147-85.
Zammarchi E, Ciani F, Pasquini E. Neonatal onset of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with favorable outcome. J Pediatr. 1997 Sep. 131(3):440-3. [Medline].