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Genetics of Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) Syndrome Treatment & Management

  • Author: Richard E Frye, MD, PhD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Oct 28, 2015
 

Medical Care

Ornithine supplementation reduces ammonia levels in some patients with hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. A suggested dose of 22-44 mg/kg per dose administered 3 times per day with protein ingestion may improve protein tolerance and growth. Other studies show that 6 g/d reduces ammonia levels. This treatment further increases ornithine levels, and the long-term effects of hyperornithinemia are not known. Citrulline supplementation has also been used.

Arginine supplementation (7.5 g/d) reduces ammonia levels in some patients; however, this treatment has caused deleterious effects in others and is generally not recommended.

Sodium benzoate and sodium phenylacetate may reduce ammonia levels by providing an alternative pathway. A combination of sodium benzoate and sodium phenylacetate (Ammonul) is an intravenous drug for use in urea-cycle disorders. Oral sodium phenylbutyrate, which has been approved by the US Food and Drug Administration (FDA) for urea-cycle defects, could be helpful in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. However, additional studies are needed. Oral sodium benzoate could also be effective.

Glycerol phenylbutyrate is a pre-prodrug that undergoes metabolism to form phenylacetate. Results of a phase 3 study comparing ammonia control in adults showed glycerol phenylbutyrate was noninferior to sodium phenylbutyrate.[9] In a separate study involving young children ages 2 months through 5 years, glycerol phenylbutyrate resulted in a more evenly distributed urinary output of PAGN over 24 hours and accounted for fewer symptoms from accumulation of phenylacetate.[10]

Hyperammonemic crisis might be managed with short-term protein restriction and intravenous fluids that contain large amounts of glucose, followed by slow reintroduction of small amounts of protein. Theoretically, intravenous arginine and intravenous sodium benzoate and sodium phenylacetate might be effective, but these medications have not been approved in the United States for use in this disorder, and intravenous arginine could be dangerous and ineffective. Supportive measures are indicated.

If the high blood ammonia levels are due to the reduction of N-acetylglutamate or to the reduction of carbamoyl-phosphate synthase-I activity, N-carbamylglutamate (carglumic acid) can be administered together with the conventional therapy.[11]

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Consultations

A comprehensive team approach is justified and should include a metabolic disease specialist, a clinical biochemical geneticist, a developmental pediatrician, a neurologist, and other development specialists. This team should assess all aspects of cognitive function and periodically monitor the patient for development surveillance.

A nutritionist with expertise in treating metabolic diseases should also be consulted.

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Diet

A low-protein diet (1.2 g/kg/d, depending on age) may prevent postprandial hyperammonemia and has permitted normal development in several patients when initiated early in life.

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Contributor Information and Disclosures
Author

Richard E Frye, MD, PhD Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences

Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, International Neuropsychological Society, American Academy of Pediatrics

Disclosure: Nothing to disclose.

Coauthor(s)

Paul J Benke, MD, PhD Director of Clinical Genetics, Joe DiMaggio Children's Hospital

Paul J Benke, MD, PhD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

References
  1. 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].

  2. 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].

  3. 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].

  4. 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].

  5. 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].

  6. 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].

  7. 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].

  8. 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].

  9. 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].

  10. 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].

  11. Daniotti M, la Marca G, Fiorini P, Filippi L. New developments in the treatment of hyperammonemia: emerging use of carglumic acid. Int J Gen Med. 2011 Jan 7. 4:21-8. [Medline]. [Full Text].

  12. 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].

  13. 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].

  14. 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].

  15. 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].

  16. 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].

  17. 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].

  18. 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].

  19. 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].

  20. 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].

  21. 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].

  22. 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].

  23. 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].

  24. Valle D, Simell O. The metabolic basis of inherited disease. Scriver CR, ed. The Hyperornithinemias. New York, NY: McGraw-Hill; 1995. 1147-85.

  25. 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].

 
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Important products and enzymes in ornithine metabolism (see text for pathway detail). Enzymes and transporters are highlighted in italics.
 
 
 
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