Genetics of Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) Syndrome Treatment & Management

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

Ornithine supplementation reduces ammonia levels in some patients with hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. A suggested dose of 22-44 mg/kg per dose administered 3 times per day with protein ingestion may improve protein tolerance and growth. Other studies show that 6 g/d reduces ammonia levels. This treatment further increases ornithine levels, and the long-term effects of hyperornithinemia are not known. Citrulline supplementation has also been used.

Arginine supplementation (7.5 g/d) reduces ammonia levels in some patients; however, this treatment has caused deleterious effects in others and is generally not recommended.

Sodium benzoate and sodium phenylacetate may reduce ammonia levels by providing an alternative pathway. A combination of sodium benzoate and sodium phenylacetate (Ammonul) is an intravenous drug for use in urea-cycle disorders. Oral sodium phenylbutyrate, which has been approved by the US Food and Drug Administration (FDA) for urea-cycle defects, could be helpful in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. However, additional studies are needed. Oral sodium benzoate could also be effective.

Glycerol phenylbutyrate is a pre-prodrug that undergoes metabolism to form phenylacetate. Results of a phase 3 study comparing ammonia control in adults showed glycerol phenylbutyrate was noninferior to sodium phenylbutyrate. [9] In a separate study involving young children ages 2 months through 5 years, glycerol phenylbutyrate resulted in a more evenly distributed urinary output of PAGN over 24 hours and accounted for fewer symptoms from accumulation of phenylacetate. [10]

Hyperammonemic crisis might be managed with short-term protein restriction and intravenous fluids that contain large amounts of glucose, followed by slow reintroduction of small amounts of protein. Theoretically, intravenous arginine and intravenous sodium benzoate and sodium phenylacetate might be effective, but these medications have not been approved in the United States for use in this disorder, and intravenous arginine could be dangerous and ineffective. Supportive measures are indicated.

If the high blood ammonia levels are due to the reduction of N-acetylglutamate or to the reduction of carbamoyl-phosphate synthase-I activity, N-carbamylglutamate (carglumic acid) can be administered together with the conventional therapy. [11]



A comprehensive team approach is justified and should include a metabolic disease specialist, a clinical biochemical geneticist, a developmental pediatrician, a neurologist, and other development specialists. This team should assess all aspects of cognitive function and periodically monitor the patient for development surveillance.

A nutritionist with expertise in treating metabolic diseases should also be consulted.



A low-protein diet (1.2 g/kg/d, depending on age) may prevent postprandial hyperammonemia and has permitted normal development in several patients when initiated early in life.



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.


Long-Term Monitoring

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.