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

Updated: Jan 07, 2019
  • Author: Richard E Frye, MD, PhD; Chief Editor: Maria Descartes, MD  more...
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Workup

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.

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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.

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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

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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.

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