eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome: Follow-up

Author: Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Coauthor(s): Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Contributor Information and Disclosures

Updated: Oct 30, 2009

Follow-up

Further Outpatient Care

  • Annual ophthalmologic examinations and electroretinography are often recommended in patients with hyperornithinemia-hyperammonemia-homocitrullinemia (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.

Deterrence/Prevention

  • Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome may be diagnosed in first trimester by studying the incorporation of [14 C]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 [14 C]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.

Prognosis

  • Growth improves with treatment.
  • Pregnancy is possible. A woman with hyperornithinemia-hyperammonemia-homocitrullinemia 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)

Miscellaneous

Medicolegal Pitfalls

  • Failure to measure ammonia levels: Ammonia levels should be measured in any individual with mental status changes or coma with no obvious etiology.
  • Diagnosis failure: Early intervention can prevent damage to the CNS. Failure to consider this diagnosis in a child with one or more developmental delays may allow significant progression of CNS damage. CNS symptoms, especially seizure or choreoathetosis, along with unusual feeding patterns should suggest hyperornithinemia-hyperammonemia-homocitrullinemia syndrome. This disorder can be diagnosed with a standard workup for developmental delay that includes assessment of organic acid and serum amino acid levels in urine.
  • Failure to monitor progression: Progression of developmental delays, neurologic symptoms, or abnormal liver function should suggest either noncompliance with treatment or an alternate diagnosis. Formal periodic neurologic, cognitive, and ophthalmologic examinations should be performed.
 


More on Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome

Overview: Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Differential Diagnoses & Workup: Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Treatment & Medication: Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Follow-up: Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Multimedia: Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
References
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References

  1. 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. May 2009;30(5):741-8. [Medline].

  2. Camacho JA, Obie C, Biery B. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet. Jun 1999;22(2):151-8. [Medline].

  3. 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. Dec 2006;386(7-8):2013-7. [Medline].

  4. 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. Oct 2006;60(4):423-9. [Medline].

  5. 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. Aug 2003;79(4):257-71. [Medline].

  6. Kang SS, Wong PW, Zhou JM, et al. Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism. Jul 1988;37(7):611-3. [Medline].

  7. 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. Mar 15 2004;218(1-2):53-8. [Medline].

  8. Lemay JF, Lambert MA, Mitchell GA. Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients. J Pediatr. Nov 1992;121(5 Pt 1):725-30. [Medline].

  9. 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].

  10. Salvi S, Santorelli FM, Bertini E, et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology. Sep 11 2001;57(5):911-4. [Medline].

  11. Shih VE, Laframboise R, Mandell R. Neonatal form of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and prenatal diagnosis. Prenat Diagn. Sep 1992;12(9):717-23. [Medline].

  12. 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].

  13. Smith L, Lambert MA, Brochu P. Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy. J Pediatr Gastroenterol Nutr. Nov 1992;15(4):431-6. [Medline].

  14. Tuchman M, Knopman DS, Shih VE. Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Arch Neurol. Oct 1990;47(10):1134-7. [Medline].

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

  16. Zammarchi E, Ciani F, Pasquini E. Neonatal onset of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with favorable outcome. J Pediatr. Sep 1997;131(3):440-3. [Medline].

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Further Reading

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Keywords

HHH syndrome, hyperammonemia-hyperornithinemia-homocitrullinuria syndrome, hyperammonemia-hyperornithinemia-homocitrullinemia syndrome,  ornithine, urea cycle, nitrogen, growth delay, developmental delay, learning disability, speech delay, ataxia, urea cycle defect, urea-cycle defect, formula intolerance, choreoathetosis, hypotonia, spasticity, polyneuropathy, episodic confusion, gait disturbance, attention deficit hyperactivity disorder, ADHD, failure to thrive, chorioretinal atrophy, pyramidal syndrome, buccofaciolingual dyspraxia, dysdiadochokinesia

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Contributor Information and Disclosures

Author

Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and International Neuropsychological Society
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 Academy of Pediatrics and American Society of Human Genetics
Disclosure: Nothing to disclose.

Medical Editor

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
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, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting; Amicus  Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Leonard G Feld, MD, PhD, MMM, FAAP, Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center
Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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