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PubMed This is a summary of 14 peer-reviewed journal articles Updated
Medical Genetics

Diagnosis and Understanding Your Labs

At a Glance

When CPS1 deficiency is suspected, doctors look for high ammonia, low citrulline, high glutamine, and low or normal urine orotic acid. Genetic testing of CPS1 and related genes is preferred for confirmation, but emergency treatment should not wait for results.

Diagnosing CPS1 deficiency is a step-by-step process that often begins in the delivery room or the emergency department. Because high ammonia is toxic to the brain, doctors must act quickly to identify the cause and start treatment. Diagnosis involves a combination of newborn screening, specialized blood and urine chemistry, and definitive genetic testing [1][2].

The Role of Newborn Screening (NBS)

In some regions, CPS1 deficiency may be flagged by newborn screening, where a small heel-prick of blood is taken shortly after birth [3].

  • Low Citrulline: The primary marker the lab looks for is a very low level of citrulline, an amino acid produced by the urea cycle [4][5].
  • Limitations and False Positives: While NBS is a useful tool, it is not a diagnosis. A “low citrulline” result can sometimes be a false positive, often seen in premature babies, infants with digestive issues, or those who haven’t fed adequately [5][3].
  • False Negatives: Conversely, a normal newborn screen does not universally exclude CPS1 deficiency, nor is the disorder screened for in every jurisdiction. An abnormal or normal screen never overrides clinical symptoms or an elevated ammonia result [5].

Essential Lab Markers

If a child has high ammonia (hyperammonemia), doctors will order a “urea cycle profile.” These results form a supportive pattern, but should never be interpreted independently of the clinical picture:

Lab Test What it Measures Typical CPS1 Result
Ammonia Toxic waste in the blood High [6]
Citrulline A urea cycle byproduct Low or Undetectable [6]
Glutamine Ammonia storage molecule High [7]
Orotic Acid A urine-based chemical Low or Normal [8]

The presence of high ammonia and low citrulline suggests a “block” in the proximal (early) part of the urea cycle. However, the level of orotic acid in the urine is a helpful clue that can distinguish CPS1 from its more common “cousin,” OTC deficiency. In OTC deficiency, orotic acid is usually very high; in CPS1 deficiency, it is low or absent [6][8].

Why Genetic Testing is Preferred

While blood tests can point toward CPS1 deficiency, they cannot definitively distinguish it from a nearly identical condition called NAGS deficiency [9][10]. This distinction is critical because NAGS deficiency has a specific, highly effective treatment (carglumic acid) [11].

Molecular genetic testing is the preferred confirmatory test. This involves:

  • Multigene Panels: Testing the CPS1, NAGS, and OTC genes simultaneously to find the specific mutation [9][12].
  • Copy-Number Analysis: Looking for larger “missing pieces” of the gene that standard sequencing might miss [9].
  • RNA Sequencing: In some complex cases where standard DNA tests are unclear, doctors may use RNA analysis to see how the gene is actually functioning [9].

While genetics is the best confirmatory tool, testing can sometimes be negative, incomplete, or yield a “variant of uncertain significance.” In these cases, diagnosis may require biochemical, functional, or segregation (parental) evidence [13]. In all cases, emergency biochemical treatment must not be delayed while waiting for genetic results [14].

Common questions in this guide

Can a newborn screening test diagnose CPS1 deficiency?
No. The screen may flag CPS1 deficiency when citrulline is very low, but low citrulline can occur for other reasons and may be a false positive. A normal screen also does not rule out CPS1 deficiency, so symptoms and ammonia results still matter.
What blood and urine results are common in CPS1 deficiency?
Doctors often see high ammonia, low or undetectable citrulline, high glutamine, and low or normal urine orotic acid. This pattern suggests a problem early in the body’s ammonia-removal pathway, but results must be interpreted with the clinical picture.
Why is urine orotic acid measured when CPS1 deficiency is suspected?
Urine orotic acid helps distinguish CPS1 deficiency from OTC deficiency, another urea cycle disorder with a similar lab pattern. It is usually low or absent in CPS1 deficiency and very high in OTC deficiency.
What genetic testing is used to confirm CPS1 deficiency?
A multigene panel commonly examines CPS1, NAGS, and OTC, which can cause similar findings. Additional copy-number analysis can find larger missing pieces of the CPS1 gene, and RNA sequencing may help when standard DNA results are unclear.
What does an unclear CPS1 genetic result mean?
A negative or unclear result does not always settle the diagnosis. Doctors may combine the lab pattern with functional studies, testing in parents, or other biochemical evidence; a variant of uncertain significance means the effect of a genetic change is not yet known.
Could sample handling change an ammonia result?
Ammonia results can be affected by collection and transport, so the sample should be kept cold and analyzed promptly. If a result seems inconsistent with the child’s condition, ask the care team whether the sample was handled this way and whether repeat testing is needed.
Should treatment begin before genetic testing is finished?
Yes. High ammonia can damage the brain, so emergency biochemical treatment should not be delayed while genetic results are pending. The medical team can continue to refine the diagnosis as testing returns.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Was my child’s ammonia test performed on a sample that was kept on ice and run immediately?
  2. 2.How low was my child’s citrulline level, and does that suggest a proximal urea cycle disorder?
  3. 3.Has a multigene panel been ordered to rule out NAGS and OTC deficiency?
  4. 4.Did the genetic testing include 'copy-number-variation analysis' to look for missing pieces of the CPS1 gene?
  5. 5.If the genetic results are unclear, is RNA sequencing an option for us to clarify the findings?

Questions For You

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References

References (14)
  1. 1

    Clinical findings of patients with hyperammonemia affected by urea cycle disorders with hepatic encephalopathy.

    Lopes FF, Sitta A, de Moura Coelho D, et al.

    International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 2022; (82(8)):772-788 doi:10.1002/jdn.10229.

    PMID: 36129623
  2. 2

    Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision.

    Häberle J, Burlina A, Chakrapani A, et al.

    Journal of inherited metabolic disease 2019; (42(6)):1192-1230 doi:10.1002/jimd.12100.

    PMID: 30982989
  3. 3

    Considering Proximal Urea Cycle Disorders in Expanded Newborn Screening.

    Vasquez-Loarte T, Thompson JD, Merritt JL

    International journal of neonatal screening 2020; (6(4)) doi:10.3390/ijns6040077.

    PMID: 33124615
  4. 4

    Long-term follow-up of children with carbamoyl phosphate synthase 1 deficiency detected in newborn screening.

    Zhang Z, Tong F, Chen C, et al.

    Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 2023; (52(6)):721-726 doi:10.3724/zdxbyxb-2023-0359.

    PMID: 37986659
  5. 5

    A Four-Year Prospective Pilot Study of Newborn Screening for Late-Onset Proximal Urea-Cycle Disorders in Hyogo Prefecture in Japan.

    Lee T, Matsui M, Yokoyama Y, et al.

    International journal of neonatal screening 2026; (12(2)) doi:10.3390/ijns12020039.

    PMID: 42346728
  6. 6

    Carbamoylphosphate synthetase 1 (CPS1) deficiency: clinical, biochemical, and molecular characterization in Malaysian patients.

    Ali EZ, Khalid MK, Yunus ZM, et al.

    European journal of pediatrics 2016; (175(3)):339-46 doi:10.1007/s00431-015-2644-z.

    PMID: 26440671
  7. 7

    Novel Pathogenic Variant (c.580C>T) in the CPS1 Gene in a Newborn With Carbamoyl Phosphate Synthetase 1 Deficiency Identified by Whole Exome Sequencing.

    Choi R, Park HD, Yang M, et al.

    Annals of laboratory medicine 2017; (37(1)):58-62 doi:10.3343/alm.2017.37.1.58.

    PMID: 27834067
  8. 8

    The Application of Next-Generation Sequencing (NGS) in Neonatal-Onset Urea Cycle Disorders (UCDs): Clinical Course, Metabolomic Profiling, and Genetic Findings in Nine Chinese Hyperammonemia Patients.

    Zhou Q, Huang H, Ma L, Zhu T

    BioMed research international 2020; (2020()):5690915 doi:10.1155/2020/5690915.

    PMID: 32934962
  9. 9

    Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing.

    Isler J, Rüfenacht V, Gemperle C, et al.

    JIMD reports 2020; (52(1)):28-34 doi:10.1002/jmd2.12091.

    PMID: 32154057
  10. 10

    N-acetylglutamate synthase deficiency with associated 3-methylglutaconic aciduria: A case report.

    Selvanathan A, Demetriou K, Lynch M, et al.

    JIMD reports 2022; (63(5)):420-424 doi:10.1002/jmd2.12318.

    PMID: 36101823
  11. 11

    The efficacy of Carbamylglutamate impacts the nutritional management of patients with N-Acetylglutamate synthase deficiency.

    Singh RH, Bourdages MH, Kurtz A, et al.

    Orphanet journal of rare diseases 2024; (19(1)):168 doi:10.1186/s13023-024-03167-0.

    PMID: 38637895
  12. 12

    Carbamoyl phosphate synthetase 1 deficiency diagnosed by whole exome sequencing.

    Zhang G, Chen Y, Ju H, et al.

    Journal of clinical laboratory analysis 2018; (32(2)) doi:10.1002/jcla.22241.

    PMID: 28444906
  13. 13

    Is there any relationship between mutation in CPS1 Gene and pregnancy loss?

    Talebi M, Yahya Vahidi Mehrjardi M, Kalhor K, Dehghani M

    International journal of reproductive biomedicine 2019; (17(5)) doi:10.18502/ijrm.v17i5.4604.

    PMID: 31435610
  14. 14

    Novel compound heterozygote variants: c.4193_4206delinsG (p.Leu1398Argfs*25), c.793C > A (p.Pro265Thr), in the CPS1 gene (NM_001875.4) causing late onset carbamoyl phosphate synthetase 1 deficiency-Lessons learned.

    Lin HT, Enchautegui-Colon Y, Huang YR, et al.

    Molecular genetics and metabolism reports 2022; (33()):100942 doi:10.1016/j.ymgmr.2022.100942.

    PMID: 36466970

This page explains CPS1 deficiency testing and lab patterns for informational purposes only and does not constitute medical advice. Your metabolic and genetics team should interpret your child’s results and guide urgent care.

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