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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Medical Genetics

Diagnosing ASA: Understanding Lab Reports and Biomarkers

At a Glance

Argininosuccinic aciduria (ASA) is definitively diagnosed by finding high levels of argininosuccinic acid in the blood and urine. Doctors will also check for elevated citrulline, monitor ammonia levels, and use ASL gene sequencing to confirm the specific mutations causing the disorder.

Confirming a diagnosis of Argininosuccinic Aciduria (ASA) involves looking for specific “chemical signatures” in the blood and urine. Because ASA is a metabolic disorder, the most reliable information comes from measuring the substances that the body is failing to process correctly [1][2].

The Definitive Marker: Argininosuccinic Acid

In medicine, a definitive (or pathognomonic) sign is something that is so highly specific it proves a person has a particular disease. For ASA, that marker is argininosuccinic acid [3][4].

In a healthy urea cycle, the ASL enzyme quickly converts argininosuccinic acid into arginine. When the enzyme is missing, this acid builds up to high levels in the blood (plasma) and “spills over” into the urine [3][5]. Seeing this specific acid in lab results is the definitive hallmark of ASA.

Understanding Citrulline: Proximal vs. Distal

Doctors often use citrulline levels to figure out exactly where the urea cycle is broken. The urea cycle is like an assembly line; some defects happen early in the line (proximal), and some happen later (distal) [6][7].

  • Proximal Defects: If the “blockage” happens at the very beginning of the cycle, citrulline levels will be very low or even zero [8][9].
  • Distal Defects (ASA): ASA is a “distal” defect. Because the cycle gets stuck after citrulline has already been produced, individuals with ASA will have elevated citrulline levels in their blood [10][11].

Newborn Screening (NBS) and Its Limitations

Most babies are screened for ASA shortly after birth using a “heel prick” blood test. This test uses a technology called tandem mass spectrometry (LC-MS/MS) to look for high levels of citrulline [11][12].

However, newborn screening is not perfect:

  • Milder Cases Can Be Missed: If a child has a “hypomorphic” mutation (meaning their enzyme works just a little bit), their citrulline levels might be low enough to fall within the “normal” range during the first days of life [13].
  • Late-Onset Overlap: Screening protocols are often optimized to find the most severe, life-threatening cases. This means some children with late-onset ASA may have a “normal” screening result but still develop symptoms later in childhood or adulthood [13][14].

Confirming the Diagnosis

If labs show high argininosuccinic acid and elevated citrulline, doctors will use genetic testing to confirm the diagnosis. This involves sequencing the ASL gene to identify the two specific mutations (one from each parent) that caused the enzyme deficiency [1][15].

Diagnostic Checklist for Patients and Families

When discussing labs with your metabolic team, ensure the following tests have been completed and reviewed:

  • [ ] Plasma Amino Acid (PAA) Profile: To check for elevated citrulline and the presence of argininosuccinic acid in the blood [11].
  • [ ] Urine Amino Acid (UAA) Test: To definitively confirm the presence of argininosuccinic acid spilling over into the urine [3].
  • [ ] Ammonia Level: To check for immediate toxic buildup (a medical emergency if very high) [16].
  • [ ] Common Liver Enzymes (ALT/AST): To see if the liver is under stress or showing early signs of inflammation [17][3].
  • [ ] ASL Gene Sequencing: To identify the specific genetic mutations causing the disorder [1].

Common questions in this guide

What is the definitive lab test for diagnosing ASA?
The most reliable marker for argininosuccinic aciduria is finding argininosuccinic acid in the blood and urine. Because a healthy body processes this acid quickly, its presence definitively proves the ASL enzyme is missing or not functioning correctly.
Why are citrulline levels elevated in argininosuccinic aciduria?
ASA is considered a distal urea cycle defect, meaning the cycle gets blocked after citrulline is already made. As a result of this specific blockage, citrulline builds up and shows as elevated on plasma amino acid profiles.
Can a newborn screening test miss an ASA diagnosis?
Yes, newborn screening can miss milder or late-onset cases of ASA. If a child's enzyme works even a little bit, their citrulline levels might look normal during the first few days of life, which can delay the diagnosis until symptoms appear.
How do doctors officially confirm an argininosuccinic aciduria diagnosis?
If blood and urine tests show high argininosuccinic acid and elevated citrulline, doctors will order genetic testing. This involves sequencing the ASL gene to identify the two specific genetic mutations inherited from the parents.
Why do doctors check liver enzymes when diagnosing ASA?
Doctors check liver enzymes like ALT and AST to see if the liver is under stress or showing early signs of inflammation. Because the urea cycle primarily takes place in the liver, monitoring these enzymes helps doctors assess your liver health.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Can you show me the lab results and point out the specific levels of argininosuccinic acid and citrulline?
  2. 2.Since the diagnosis was missed by the newborn screening, what does that tell us about the likely severity or 'onset' type of the condition?
  3. 3.What was the ammonia level at its highest, and what is the target 'normal' range we should aim for?
  4. 4.Has the genetic testing confirmed mutations in both copies of the ASL gene?
  5. 5.Are we seeing any elevations in liver enzymes (ALT/AST) that we should be concerned about?
  6. 6.How often will we need to repeat the plasma amino acid (PAA) profile?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (17)
  1. 1

    [Genetic diagnosis of a Chinese pedigree affected with neonatal argininosuccinic aciduria].

    Li W, Li H

    Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2019; (36(9)):926-929 doi:10.3760/cma.j.issn.1003-9406.2019.09.018.

    PMID: 31515792
  2. 2

    Clinical, biochemical and genetic characteristics of patients with argininosuccinate lyase deficiency from a single center cohort in China.

    Zhang K, Lu D, Liang L, et al.

    Orphanet journal of rare diseases 2025; (20(1)):509 doi:10.1186/s13023-025-04026-2.

    PMID: 41068918
  3. 3

    Low prevalence of argininosuccinate lyase deficiency among inherited urea cycle disorders in Korea.

    Kim D, Ko JM, Kim YM, et al.

    Journal of human genetics 2018; (63(8)):911-917 doi:10.1038/s10038-018-0467-2.

    PMID: 29773863
  4. 4

    NGS in argininosuccinic aciduria detects a mutation (D145G) which drives alternative splicing of ASL: a case report study.

    Wen W, Yin D, Huang F, et al.

    BMC medical genetics 2016; (17()):9 doi:10.1186/s12881-016-0273-7.

    PMID: 26843370
  5. 5

    Free Radical Scavengers Prevent Argininosuccinic Acid-Induced Oxidative Stress in the Brain of Developing Rats: a New Adjuvant Therapy for Argininosuccinate Lyase Deficiency?

    Seminotti B, da Silva JC, Ribeiro RT, et al.

    Molecular neurobiology 2020; (57(2)):1233-1244 doi:10.1007/s12035-019-01825-0.

    PMID: 31707633
  6. 6

    Ex vivo precision-cut liver slices model disease phenotype and monitor therapeutic response for liver monogenic diseases.

    Perocheau D, Gurung S, Touramanidou L, et al.

    F1000Research 2023; (12()):1580 doi:10.12688/f1000research.142014.2.

    PMID: 38618017
  7. 7

    Inborn Errors of Metabolism with Hyperammonemia: Urea Cycle Defects and Related Disorders.

    Summar ML, Mew NA

    Pediatric clinics of North America 2018; (65(2)):231-246 doi:10.1016/j.pcl.2017.11.004.

    PMID: 29502911
  8. 8

    Citrulline for urea cycle disorders in Japan.

    Tanaka K, Nakamura K, Matsumoto S, et al.

    Pediatrics international : official journal of the Japan Pediatric Society 2017; (59(4)):422-426 doi:10.1111/ped.13163.

    PMID: 27613354
  9. 9

    The role of orotic acid measurement in routine newborn screening for urea cycle disorders.

    Staretz-Chacham O, Daas S, Ulanovsky I, et al.

    Journal of inherited metabolic disease 2021; (44(3)):606-617 doi:10.1002/jimd.12331.

    PMID: 33190319
  10. 10

    Determination of amino acid profile for argininosuccinic aciduria disorder using High-Performance Liquid Chromatography with fluorescence detection.

    Salmanizadeh H, Sahi N

    Acta biochimica Polonica 2020; (67(3)):347-351 doi:10.18388/abp.2020_5164.

    PMID: 32931185
  11. 11

    Rapid quantification of underivatized alloisoleucine and argininosuccinate using mixed-mode chromatography with tandem mass spectrometry.

    Griffin C, Ammous Z, Vance GH, et al.

    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2019; (1128()):121786 doi:10.1016/j.jchromb.2019.121786.

    PMID: 31518899
  12. 12

    Unraveling the Cyclization of l-Argininosuccinic Acid in Biological Samples: A Study via Mass Spectrometry and NMR Spectroscopy.

    Mamani-Huanca M, Gradillas A, López-Gonzálvez Á, Barbas C

    Analytical chemistry 2020; (92(19)):12891-12899 doi:10.1021/acs.analchem.0c01420.

    PMID: 32822159
  13. 13

    Argininosuccinic Acid Lyase Deficiency Missed by Newborn Screen.

    Ganetzky RD, Bedoukian E, Deardorff MA, Ficicioglu C

    JIMD reports 2017; (34()):43-47 doi:10.1007/8904_2016_2.

    PMID: 27515243
  14. 14

    Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects.

    Baruteau J, Diez-Fernandez C, Lerner S, et al.

    Journal of inherited metabolic disease 2019; (42(6)):1147-1161 doi:10.1002/jimd.12047.

    PMID: 30723942
  15. 15

    Late-onset argininosuccinic aciduria associated with hyperammonemia triggered by influenza infection in an adolescent: A case report.

    Osawa Y, Wada A, Ohtsu Y, et al.

    Molecular genetics and metabolism reports 2020; (24()):100605 doi:10.1016/j.ymgmr.2020.100605.

    PMID: 32435591
  16. 16

    Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan.

    Kido J, Matsumoto S, Häberle J, et al.

    Journal of inherited metabolic disease 2021; (44(4)):826-837 doi:10.1002/jimd.12384.

    PMID: 33840128
  17. 17

    Prevalence of fibrosis in hepatic explants and biopsies from individuals with urea cycle disorders.

    Ali S, Nisar A, Zhang A, et al.

    Molecular genetics and metabolism 2025; (145(4)):109175 doi:10.1016/j.ymgme.2025.109175.

    PMID: 40540899

This page explains lab tests and biomarkers for Argininosuccinic Aciduria (ASA) for educational purposes. Always consult your metabolic team or geneticist to interpret your specific newborn screening or lab results.

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