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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.



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.



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)
Contributor Information and Disclosures

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.


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.

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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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