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Sections Genetics of Hyperammonemia
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Workup

Laboratory Studies

Plasma ammonia level

Obtain this measurement when clinical signs and symptoms are suggestive of hyperammonemia. Especially in the newborn, symptoms and signs suggestive of sepsis must always be accompanied by a plasma ammonia measurement, since the distinction between the two entities cannot be made by any clinical means and the presence of one does not preclude the other, in any case.

No other laboratory test can substitute for this measurement, nor does any other test indicate the need for it.

Only clinical suspicion indicates need.

Liver function studies (ie, serum transaminases, prothrombin time [PT]/activated partial thromboplastin time [aPTT]), alkaline phosphatase levels, bilirubin levels)

Severe liver disease can cause hyperammonemia; therefore, evaluating the function of the liver is always appropriate as a first approximation to etiology.

Plasma amino acid level quantitation

Certain primary genetic causes can be suspected based on specific increases in amino acid levels, such as increased citrulline or argininosuccinic acid levels.

By contrast, severe liver disease tends to cause a generalized increase in plasma amino acid levels.

Urinary organic acid profile

Disorders that involve metabolic intermediates of amino acid catabolism can cause mild-to-moderate inhibition of the urea cycle, resulting in hyperammonemia as a secondary phenomenon.

This test can help to identify increases in levels of such intermediates as propionic acid, methylmalonic acid, isovaleric acid, or other organic acids and aid in diagnosis.

Urine amino acid levels

These are helpful in confirming argininosuccinic aciduria; lysinuric protein intolerance; or hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome.

Blood lactate levels

This is useful in ruling out mitochondrial diseases, in some of which an elevated blood ammonia level may be found.

Blood gas levels

Patients with urea cycle disorders may have alkalosis due to stimulation of the respiratory drive by ammonia.

Patients with urea cycle disorders are rarely acidotic. Severe refractory acidosis suggests organic acid disorder or mitochondrial disorder.

BUN level

This is often very low (< 3 mg of urea/100 mL) in persons with urea cycle disorders.

N-carbamoyl-L-glutamic acid

In infants with confirmed hyperammonemia, oral loading with N -carbamoyl-L-glutamic acid has been advocated as both diagnostic and therapeutic for patients with N -acetylglutamate (NAG) synthetase deficiency.

Imaging Studies

Some authors advocate baseline MRI studies in patients with confirmed genetic causes of hyperammonemia; this is because some suggestive data indicate an elevated risk for stroke in these patients.

Treatment & Management

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Kasahara M, Sakamoto S, Horikawa R, et al. Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transplant. Feb/2014. 18:6-15. [QxMD MEDLINE Link].
Perito ER, Rhee S, Roberts JP, et al. Pediatric liver transplantion for urea cycle disorders and organic acidemias: United Network for Organ Sharing data for 2002-2012. Liver Transpl. Jan/2014. 20:89-99. [QxMD MEDLINE Link].
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Media Gallery

Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (4); the reaction is mediated by argininosuccinate (ASA) synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.

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Author

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, The Scientific Research Honor Society, Society for Pediatric Research, Southern Society for Pediatric Research

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, FAAP, FACMG Professor (Clinical), Department of Pediatrics, University of Wisconsin School of Medicine and Public Health; Editor-in-Chief, Genetics in Medicine; Chief Medical Officer, PreventionGenetics

Robert D Steiner, MD, FAAP, FACMG 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: PreventionGenetics, ACMG, Acer Therapeutics, Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, CTX Alliance, Aeglea, Eton, Leadiant<br/>Serve(d) as a speaker or a member of a speakers bureau for: France Foundation, Medscape<br/>Received research grant from: Alexion<br/>Received income in an amount equal to or greater than $250 from: Marshfield Clinic, France Foundation, Medscape, PreventionGenetics, ACMG, Acer Therapeutics; Raptor, Retrophin/Travere, Censa; Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, Aeglea, Leadiant<br/>Travel Support for: CTX Alliance.

Sections Genetics of Hyperammonemia
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Medication
Follow-up
References

Genetics of Hyperammonemia Workup

Laboratory Studies

Imaging Studies

References

Tables

Contributor Information and Disclosures

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