Differential diagnosis and follow-up of patients with urea cycle disorders
Urea cycle disorders are a group of inherited disorders of nitrogen detoxification that result from defects in any of the enzymes involved in the urea cycle.
Disruption of the urea cycle can result in the accumulation of ammonia, which is toxic to the nervous system.
Plasma amino acid analysis can be used to aid in the diagnosis of a urea cycle disorder as well as for follow-up of a known patient.
Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS)
Arginase Deficiency
Arginine
Argininemia
Argininosuccinic Acid
Argininosuccinic Acid Lyase Deficiency
Argininosuccinic Aciduria
Carbamoyl Phosphate Synthetase (CPS) Deficiency
Citrulline
Citrullinemia
CPS (Carbamoyl Phosphate Synthetase)
Glutamine
N-acetyl Glutamate Synthase (NAGS) Deficiency
NAGS (N-acetyl Glutamate Synthetase)
Ornithine
Ornithine Transcarbamylase (OTC) Deficiency
OTC (Ornithine Transcarbamylase)
UCD (Urea Cycle Disorder)
Urea Cycle Disorder (UCD)
Argininosuccinic Acid Synthetase Deficiency
Gyrate atrophy
Ornithine Aminotransferase (OAT) Deficiency
Plasma
1. Patient's age is required.
2. Include family history, clinical condition (asymptomatic or acute episode), diet, and drug therapy information.
Patient Preparation: Fasting (overnight preferred, 4 hours minimum). Infants should be drawn just before next feeding (2-3 hours without total parenteral nutrition if possible).
Collection Container/Tube:
Preferred: Green top (sodium heparin)
Acceptable: Lavender top (EDTA), plasma gel tube, or green top (lithium heparin)
Submission Container/Tube: Plastic vial
Specimen Volume: 0.5 mL
Collection Instructions:
1. Collect specimen and place on wet ice. Note: Thrombin-activated tubes should not be used for collection.
2. Centrifuge immediately or within 4 hours of collection if the specimen is kept at refrigerated temperature.
3. Being careful to ensure that no buffy coat is transferred, aliquot plasma into a plastic vial and freeze.
If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.
0.3 mL
Gross hemolysis | OK |
Gross lipemia | OK |
Gross icterus | OK |
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Plasma | Frozen | 14 days |
Differential diagnosis and follow-up of patients with urea cycle disorders
Urea cycle disorders are a group of inherited disorders of nitrogen detoxification that result from defects in any of the enzymes involved in the urea cycle.
Disruption of the urea cycle can result in the accumulation of ammonia, which is toxic to the nervous system.
Urea cycle disorders (UCD) are a group of inherited disorders of nitrogen detoxification that result when any of the enzymes in the urea cycle (carbamoylphosphate synthetase I [CPS I], ornithine transcarbamylase [OTC], argininosuccinic acid synthetase, argininosuccinic acid lyase, arginase, or the cofactor producer, N-acetyl glutamate synthetase [NAGS]), have deficient or reduced activity. The role of the urea cycle is to metabolize and clear waste nitrogen, and defects in any of the steps of the pathway can result in an accumulation of ammonia, which can be toxic to the nervous system. The urea cycle is also responsible for endogenous production of the amino acids citrulline, ornithine, and arginine. Infants with a complete urea cycle enzyme deficiency typically appear normal at birth but, as ammonia levels rise, present during the neonatal period with lethargy, seizures, hyper- or hypoventilation, and, ultimately, coma or death. Individuals with partial enzyme deficiency may present later in life, typically following an acute illness or other stressors. Symptoms may be less severe and may present with episodes of psychosis, lethargy, cyclical vomiting, and behavioral abnormalities. Patients with impaired ornithine metabolism due to ornithine aminotransferase deficiency may present with childhood-onset myopia progressing to vision loss in the 4th to 6th decades of life. Patients may or may not have accompanying hyperammonemia but display marked elevations in plasma ornithine.
All UCD are inherited autosomal recessively, with the exception of OTC deficiency, which is X-linked. UCD may be suspected in cases with elevated ammonia, normal anion gap, and a normal glucose. Plasma amino acids can be used to aid in the diagnosis of UCD and may aid in monitoring treatment effectiveness. Measurement of urinary orotic acid, enzyme activity (CPS I, OTC, or NAGS), and molecular genetic testing can help to distinguish the conditions and allows for diagnostic confirmation.
Acute treatment for UCD consists of dialysis and administration of nitrogen scavenger drugs to reduce ammonia concentration. Chronic management typically involves restriction of dietary protein with essential amino acid supplementation. More recently, orthotopic liver transplantation has been used with success in treating some patients.
GLUTAMINE
< or =23 months: 316-1020 nmol/mL
2-17 years: 329-976 nmol/mL
> or =18 years: 371-957 nmol/mL
ORNITHINE
< or =23 months: 20-130 nmol/mL
2-17 years: 22-97 nmol/mL
> or =18 years: 38-130 nmol/mL
CITRULLINE
< or =23 months: 9-38 nmol/mL
2-17 years: 11-45 nmol/mL
> or =18 years: 17-46 nmol/mL
ARGININE
< or =23 months: 29-134 nmol/mL
2-17 years: 31-132 nmol/mL
> or =18 years: 32-120 nmol/mL
ARGININOSUCCINIC ACID
<2 nmol/mL
Reference value applies to all ages.
The quantitative results of glutamine, ornithine, citrulline, arginine, and argininosuccinic acid with age-dependent reference values are reported without added interpretation. When applicable, reports of abnormal results may contain an interpretation based on available clinical interpretation.
Reference values are for fasting patients.
1. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Accessed October 5, 2022. https://ommbid.mhmedical.com/content.aspx?bookid=2709§ionid=225084071
2. Haberle J, Burlina A, Chakrapani A, et al: Suggested guidelines for diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019 Nov;42(6):1192-1230. doi: 10.1002/jimd.12100
3. Valle D, Simell O. The Hyperornithinemias. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Accessed October 5, 2022. https://ommbid.mhmedical.com/content.aspx?bookid=2709§ionid=225083672
4. Foshci FG, Morelli MC, Savini S, et al: Urea cycle disorders: A case report of a successful liver transplant and a literature review. World J Gastroenterol. 2015 Apr 7;21(13):4063-4068. doi: 10.3748/wjg.v21.i13.4063
5. Ah Mew N, Simpson KL, Gropman AL, et al: Urea cycle disorders overview. In: Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews[Internet]. University of Washington, Seattle; 2003. Updated June 22, 2017. Accessed October 5, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1217/
Quantitative analysis of amino acids is performed by liquid chromatography tandem mass spectrometry (LC-MS/MS) by labeling amino acids present in plasma, urine, and spinal fluid with aTRAQ Reagent 121. Samples are dried and reconstituted with aTRAQ Reagent 113-labeled Standard Mix. Amino acids are separated and detected by LC-MS/MS. The concentrations of amino acids are established by comparison of their ion intensity (121-labeled amino acids) to that of their respective internal standards (113-labeled amino acids).(Unpublished Mayo method)
Monday through Friday
This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.
82136
Test Id | Test Order Name | Order LOINC Value |
---|---|---|
AAUCD | Amino Acid, Urea Cycle Panel, P | 100368-0 |
Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
---|---|---|
32440 | Glutamine | 20643-3 |
32441 | Citrulline | 20640-9 |
32442 | Argininosuccinic Acid | 32227-1 |
32443 | Arginine | 20637-5 |
32444 | Ornithine | 20652-4 |
32445 | Interpretation (AAUCD) | 49247-0 |