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

Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome: Treatment & Medication

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

Treatment

Medical Care

  • Ornithine supplementation reduces ammonia levels in some patients with hyperornithinemia-hyperammonemia-homocitrullinemia (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 benzoate and phenylacetate is an investigational new drug for use in urea-cycle disorders and, as such, has not been approved for use in hyperornithinemia-hyperammonemia-homocitrullinemia syndrome. 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-homocitrullinemia syndrome. However, additional studies are needed. Oral sodium benzoate could also be effective.
  • 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.

Consultations

  • 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.

Diet

  • 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.

Medication

Metabolic agents

These agents assist in excreting nitrogen and serve as an alternative to urea in reducing waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.


Sodium phenylacetate and sodium benzoate (Ammonul, Ucephan)

Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, or argininosuccinate lyase deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea-cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.

Adult

Loading: 55 mL (5.5 g)/m2 IV over 90-120 min via central line
Maintenance: 55 mL (5.5 g)/m2/d IV over 24 h via central line
Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration

Pediatric

Ucephan: 250 mg/kg/d PO in 3-6 equally divided doses, not to exceed 10 g/d each of sodium benzoate and sodium phenylacetate
Ammonul:
<20 kg:
Loading: 2.5 mL (250 mg)/kg IV over 90-120 min via central line
Maintenance: 2.5 mL (250 mg)/kg/d IV over 24 h via central line
Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration
>20 kg: Administer as in adults

Penicillin may decrease effects of sodium benzoate and sodium phenylacetate; probenecid may inhibit renal excretion of products of sodium benzoate and sodium phenylacetate; valproate may antagonize efficacy of sodium benzoate and sodium phenylacetate; corticosteroids may increase body protein metabolism, thereby increasing plasma ammonia levels; do not use concomitantly with PO sodium phenylbutyrate (Buphenyl) because of additive effects

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin-binding sites on albumin); because of its sodium content, exercise caution when giving the drug to patients with congestive heart failure, severe renal dysfunction, and sodium retention with edema; common side effects include nausea, vomiting, tinnitus, and visual disturbance; IV must be diluted with dextrose 10% and administered via central line; phenylacetate may cause neurotoxicity; typically administered with antiemetic to prevent common occurrence of nausea and vomiting; caution in severe congestive heart failure or severe renal insufficiency because the drug contains large amount of sodium (30.5 mg/mL in undiluted IV product)

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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