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Genetics of Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) Syndrome Workup

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

Laboratory Studies

Amino acid studies reveal the following:

  • Plasma ornithine is increased at the time of presentation, which differentiates hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome from other urea-cycle disorders. Ornithine levels may range from 200-1000 µmol/L, slightly lower than in patients with gyrate atrophy. The plasma ornithine level may be lowered by protein restriction or even normalized by extreme protein restriction. Neonatal ornithine levels may be normal.
  • Postprandial homocitrullinuria biochemically differentiates this disorder from gyrate atrophy.
  • Homocitrulline levels are elevated in the urine. A recently described liquid chromatography tandem mass spectrometric method may be more accurate than older coelution methods.
  • Free ornithine levels are elevated in the urine, although they can widely vary. Ornithine metabolite levels and other gamma-glutamyl amino acid metabolite levels may be elevated in urine.
  • Glutamine and alanine levels are often elevated at the time of presentation, and glutamine levels may paradoxically increase with protein restriction.

Orotic acid levels in the urine are elevated despite normal serum ammonia values.

Ammonia levels at the time of diagnosis have ranged from 60-216 μ g/dL.

Postprandial hyperammonemia differentiates this disorder from gyrate atrophy.

Random levels are within the reference range if treatment is successful.

Even with treatment, plasma ammonia levels may increase after protein ingestion.

High-protein diets result in chronic hyperammonemia.

Increased levels of liver transaminases and alkaline phosphatase with normal levels of gamma-glutamyl transpeptidase and bilirubin are common.

Increased lactic acid levels and an elevated lactate-to-pyruvate ratio have been reported.

Lactate and Krebs cycle intermediates can be found in the urine.

Coagulation factors VII and X should be measured and may be deficient.

Cultured skin fibroblasts from patients with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome or ornithine aminotransferase deficiency incorporate only one sixth the amount of labeled tracer ornithine into protein as control fibroblasts.

In this test, cells are incubated with [14C]ornithine and leucine labeled with tritium. The labeled leucine provides a measure of general protein synthesis.

In fibroblasts, ornithine is not used in the urea cycle but is processed in the mitochondrial matrix to form glutamate, which is subsequently incorporated into proteins.

The ratio of 14C to tritium incorporated into cellular protein is measured.

The amount of 14C incorporated into fibroblasts from patients with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is typically only 15% of that incorporated into control fibroblasts.

This test has been extremely useful in the diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.


Imaging Studies

MRI may reveal increased signal in cortical white matter, subcortical or cortical atrophy, or basal ganglia calcifications; conversely, the findings may be normal.

Liver-spleen scan may reveal increased uptake with mild diffuse liver involvement.


Other Tests

Electrophysiologic studies may reveal abnormalities in older patients. Findings may include the following:

  • Electroencephalogram that reveals diffuse slowing of background activity
  • Nerve-conduction velocity and short-latency somatosensory–evoked potential results compatible with mild sensorimotor peripheral neuropathy
  • Visual-evoked potential results revealing prolonged cortical conduction time and shape and amplitude anomalies

Histologic Findings

Liver biopsy reveals distended vacuolated periportal hepatocytes filled with intracytoplasmic and intranuclear glycogen.

Nuclei are small and contain dense chromatin.

The rough endoplasmic reticulum is decreased. The smooth endoplasmic reticulum is highly developed, giving it a stacked appearance.

Mitochondria in hepatocytes, myocytes, leukocytes, and fibroblasts may be large and bizarre in shape and size, with segmented ridges, lamellar crystal-like inclusions, and innumerable closely packed and parallel cristae.

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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