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Genetics of Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) Syndrome Follow-up

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

Further Outpatient Care

Annual ophthalmologic examinations and electroretinography are often recommended in patients with hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.

Growth and developmental milestones need to be closely monitored.

Follow-up should be approached with a comprehensive development team.

A dietary log helps to track total daily protein ingestion.

Ammonia, liver transaminases, and ornithine levels should be periodically monitored, especially after changing or starting diet or supplement therapy.

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Deterrence/Prevention

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome may be diagnosed in first trimester by studying the incorporation of [14C]ornithine into proteins of chorionic villi cells. Although this is theoretically possible, it has never been reported in the literature.

Amniocytes demonstrate decreased incorporation of [14C]ornithine, but amniotic fluid amino acid levels are normal.

Because neonatal ornithine levels may be normal, especially if the patient is asymptomatic, these levels cannot be used to screen neonates for this disorder.

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Prognosis

Growth improves with treatment.

Pregnancy is possible. A woman with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome gave birth to a healthy baby on a diet that consisted of 1 g/kg of protein per day.

Some patients do not respond to diet therapy.

One case of rapidly progressive deterioration after formula feeding, leading to neonatal death, has been reported.

Older patients may develop progressive disease, but patients who have had good neurologic and cognitive function into adulthood have been reported. Abnormalities in the central and peripheral nervous systems in older patients can be detected using electrophysiologic tests (see Other Tests). The following manifestations can also occur:

  • Irritability, opposition, and aggressiveness, suggesting a conduct disorder
  • Lower IQ score (ie, in the mildly mentally retarded range)
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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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