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

Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome: Differential Diagnoses & Workup

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

Differential Diagnoses

Arginase Deficiency
Hepatorenal Syndrome
Argininosuccinate Lyase Deficiency
Hyperammonemia
Autoimmune Chronic Active Hepatitis
Malabsorption Syndromes
Citrullinemia
Malnutrition
Constitutional Growth Delay
N-Acetylglutamate Synthetase Deficiency
Failure to Thrive
Ornithine Transcarbamylase Deficiency
Fetal Alcohol Syndrome
Phenylketonuria
Fulminant Hepatic Failure
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)
Growth Failure
Pyruvate Carboxylase Deficiency
Hepatitis A
Pyruvate Dehydrogenase Complex Deficiency
Hepatitis B
Hepatitis C

Other Problems to Be Considered

Gyrate atrophy

Workup

Laboratory Studies

  • Amino acid studies reveal the following:
    • Plasma ornithine is increased at the time of presentation, which differentiates hyperornithinemia-hyperammonemia-homocitrullinemia (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-homocitrullinemia 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 [14 C]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 of14 C to tritium incorporated into cellular protein is measured.
    • The amount of14 C incorporated into fibroblasts from patients with hyperornithinemia-hyperammonemia-homocitrullinemia syndrome is typically only 15% of that incorporated into control fibroblasts.
    • This test has been extremely useful in the diagnosis of hyperornithinemia-hyperammonemia-homocitrullinemia 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.

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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