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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Medical Genetics

Diagnosis and Understanding Lab Reports

At a Glance

A high C3 newborn screen suggests, but does not prove, Propionic Acidemia. Doctors compare C3/C2, methylcitric acid, MMA, B12, and homocysteine results, then use PCCA/PCCB genetic testing or enzyme testing to confirm the diagnosis and monitor crises.

The journey to a Propionic Acidemia (PA) diagnosis often begins with a phone call regarding a newborn screening or an urgent hospital admission. Understanding the lab reports can feel like learning a new language, but these tests are the tools your medical team uses to keep your child safe and stable [1][2].

Note: Never alter your child’s diet or medication based on a single lab result without consulting your metabolic team. Lab ranges change based on age, illness, and the specific laboratory.

The First Step: Newborn Screening

Newborn screening (NBS) is a “hint,” not a final diagnosis. It looks for a specific marker called propionylcarnitine (C3) [2][3].

  • The C3 Marker: C3 is a substance that builds up when the body cannot break down certain proteins. However, C3 can be high for several reasons, including prematurity, cobalamin (B12) disorders, or maternal vitamin B12 deficiency [4][5].
  • The C3/C2 Ratio: To be more accurate, labs often look at the ratio between C3 and another marker called C2 (acetylcarnitine). A high C3/C2 ratio is a stronger signal that the body is struggling with the propionic acid pathway [2][5].

Differentiating “Look-Alike” Conditions

Because an elevated C3 can point to several different conditions, doctors use “second-tier” testing to narrow it down.

  • Methylcitric Acid (2-MCA): This marker often supports a diagnosis of a propionyl-CoA disorder. While it is usually elevated in PA, it can also be abnormal in methylmalonic acidemia (MMA) and cobalamin-related disorders [6][4].
  • Methylmalonic Acid (MMA): Doctors check MMA to help differentiate PA from Methylmalonic Acidemia. While a normal MMA is typical in PA, it does not absolutely rule out other conditions in every context [7][6].
  • Homocysteine & B12: Doctors evaluate infant and maternal B12 status and homocysteine levels. Some cobalamin-processing disorders are genetic, while others are related to acquired B12 deficiency [8].

No single marker confirms or excludes PA. The overall biochemical pattern is interpreted together by a metabolic specialist.

Confirmatory Testing

Once the biochemistry suggests PA, doctors use definitive tests to confirm it.

  1. Genetic Testing: This looks for changes in the PCCA or PCCB genes. An individual must have two changes (one from each parent) to have PA [9][10]. Sometimes, a standard test misses a small piece of missing DNA, requiring more specialized “deletion/duplication” testing [11][10].
  2. Enzyme Activity Testing: In cases where genetic results are unclear, a lab can test the PCC enzyme directly in a sample of skin cells or white blood cells to see how well it functions [12].

Reading the “Daily” Lab Reports

Once a diagnosis is made, you will see several types of labs regularly.

Lab Test What it Indicates Why it Matters in PA
Ammonia Toxic waste product of protein breakdown High levels (hyperammonemia) can cause brain swelling and severe sleepiness [7][13].
Blood Gas (pH/Bicarbonate) The acidity of the blood Low pH or low bicarbonate indicates metabolic acidosis, a sign of a metabolic crisis [7][14].
Anion Gap A calculation of chemical balance A “high anion gap” means there is an buildup of unmeasured acids (like propionic acid) [7].
Plasma Amino Acids Levels of specific protein building blocks Used to adjust the medical formula and natural protein intake [15][7].
Acylcarnitine Profile Measures carnitines (like C3 and C2) Tracks how well the body is handling toxins and if carnitine supplements are working.
Lactate A byproduct of stressed cells High lactate can occur during a crisis even if ammonia is normal [7][16].

Short Glossary

  • C3 (Propionylcarnitine): A metabolite that builds up when the propionic acid pathway is blocked.
  • C2 (Acetylcarnitine): Used in a ratio with C3 to improve screening accuracy.
  • 2-MCA (Methylcitric Acid): A second-tier marker used to evaluate propionate pathway disorders.
  • MMA (Methylmalonic Acid): A marker used to help distinguish PA from Methylmalonic Acidemia.
  • Metabolic Acidosis: A dangerous condition where the blood becomes too acidic.

Diagnosis Completeness Checklist

To ensure your medical team has evaluated all possibilities, you can ask if the overall pattern of the following tests is consistent with PA:

  • [ ] Acylcarnitine profile evaluated.
  • [ ] Urine organic acids checked.
  • [ ] Methylmalonic acid (MMA) and Homocysteine evaluated.
  • [ ] Vitamin B12 status of mother and baby checked.
  • [ ] Genetic sequencing (and deletion/duplication testing if needed) of PCCA and PCCB completed.

Common questions in this guide

Does a high C3 newborn screening result mean my baby has Propionic Acidemia?
No. A high propionylcarnitine, or C3, result is a screening signal rather than a final diagnosis. Prematurity and vitamin B12-related problems can also raise C3, so doctors use follow-up biochemical and genetic tests to interpret the result.
Could vitamin B12 deficiency affect my baby’s Propionic Acidemia screening result?
Yes. A baby’s or mother’s vitamin B12 deficiency, as well as some inherited B12-processing disorders, can affect C3 and related screening results. Doctors may check vitamin B12 and homocysteine levels while evaluating an abnormal screen.
Which tests help distinguish Propionic Acidemia from similar disorders?
Doctors may compare the C3/C2 ratio, methylcitric acid, methylmalonic acid, homocysteine, vitamin B12, acylcarnitine results, and urine organic acids. These results help distinguish Propionic Acidemia from methylmalonic acidemia and B12-related conditions, but no single marker is definitive.
How is Propionic Acidemia confirmed after an abnormal screen?
Confirmation commonly includes genetic testing for changes in the PCCA or PCCB genes, with disease-causing changes affecting both gene copies. If genetic testing finds only one change or the result is unclear, deletion and duplication testing or direct testing of PCC enzyme activity may be considered.
What do ammonia and blood gas results show in Propionic Acidemia?
High ammonia can occur during a metabolic crisis and may cause severe sleepiness or brain swelling. Low blood pH or bicarbonate suggests metabolic acidosis, while a high anion gap can indicate a buildup of acids; the metabolic team compares these results with the child’s healthy baseline.
Which lab tests are monitored regularly after a Propionic Acidemia diagnosis?
Monitoring may include ammonia, blood gas, anion gap, plasma amino acids, acylcarnitines, and lactate. These results help the care team recognize stress or crisis and adjust medical formula, protein intake, or supplements when needed.
Should I change my child’s diet or medication because of one lab result?
No. Lab ranges can vary with age, illness, and the laboratory, and one result may not show the full picture. Contact the metabolic team before changing your child’s diet, medical formula, supplements, or medication.

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Were second-tier tests like methylcitric acid (2-MCA) performed to help evaluate the newborn screening result?
  2. 2.Does my child have a diagnosis of PCCA or PCCB, and have both copies of the gene been identified?
  3. 3.If only one genetic variant was found, have we performed deletion/duplication testing or enzyme activity testing?
  4. 4.How do my child's ammonia and blood gas levels today compare to their 'baseline' when they are healthy?
  5. 5.Could my child's screening results have been affected by maternal vitamin B12 levels?

References

References (16)
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    Assessing Gut Microbiota in an Infant with Congenital Propionic Acidemia before and after Probiotic Supplementation.

    Bordugo A, Salvetti E, Rodella G, et al.

    Microorganisms 2021; (9(12)) doi:10.3390/microorganisms9122599.

    PMID: 34946200
  2. 2

    Too Early to Tell? Balancing Diagnostic Accuracy of Newborn Screening for Propionic Acidemia Versus a Timely Referral.

    Meijer NWF, Huidekoper HH, Koop K, et al.

    International journal of neonatal screening 2025; (12(1)) doi:10.3390/ijns12010001.

    PMID: 41562797
  3. 3

    The markers of the organic acidemias and their ratios in healthy neonates in Serbian population.

    Beletić A, Tijanić A, Chrastina P, et al.

    Drug metabolism and personalized therapy 2022; (37(3)):271-275 doi:10.1515/dmpt-2021-0218.

    PMID: 35254746
  4. 4

    Quantification of 2-methylcitric acid in dried blood spots improves newborn screening for propionic and methylmalonic acidemias.

    Al-Dirbashi OY, McIntosh N, Chakraborty P

    Journal of medical screening 2017; (24(2)):58-61 doi:10.1177/0969141316645824.

    PMID: 27216769
  5. 5

    A False-Positive Case of Methylmalonic Aciduria by Tandem Mass Spectrometry Newborn Screening Dependent on Maternal Malnutrition in Pregnancy.

    Rossi C, Cicalini I, Rizzo C, et al.

    International journal of environmental research and public health 2020; (17(10)) doi:10.3390/ijerph17103601.

    PMID: 32443888
  6. 6

    Simultaneous determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in dried blood spots: Second-tier LC-MS/MS assay for newborn screening of propionic acidemia, methylmalonic acidemias and combined remethylation disorders.

    Monostori P, Klinke G, Richter S, et al.

    PloS one 2017; (12(9)):e0184897 doi:10.1371/journal.pone.0184897.

    PMID: 28915261
  7. 7

    A Rare Case of Propionic Acidemia in a Six Months Female Child.

    Irum S, Rehman A, Aamir M, et al.

    Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 2022; (32(8)):S180-S182 doi:10.29271/jcpsp.2022.Supp2.S180.

    PMID: 36210688
  8. 8

    Implementation of second-tier tests in newborn screening for the detection of vitamin B12 related acquired and genetic disorders: results on 258,637 newborns.

    Pajares S, Arranz JA, Ormazabal A, et al.

    Orphanet journal of rare diseases 2021; (16(1)):195 doi:10.1186/s13023-021-01784-7.

    PMID: 33931066
  9. 9

    A novel delins (c.773_819+47delinsAA) mutation of the PCCA gene associated with neonatal-onset propionic acidemia: a case report.

    Wang HR, Liu YQ, He XL, et al.

    BMC medical genetics 2020; (21(1)):166 doi:10.1186/s12881-020-01102-1.

    PMID: 32819290
  10. 10

    Novel variants of the PCCB gene in Chinese patients with propionic acidemia.

    Yang X, Li D, Tu C, et al.

    Clinica chimica acta; international journal of clinical chemistry 2021; (519()):18-25 doi:10.1016/j.cca.2021.03.019.

    PMID: 33798502
  11. 11

    Combinations of exonic deletions and rare mutations lead to misdiagnosis of propionic acidemia.

    Wang H, Meng L, Li W, et al.

    Clinica chimica acta; international journal of clinical chemistry 2020; (502()):153-158 doi:10.1016/j.cca.2019.12.021.

    PMID: 31893529
  12. 12

    Measuring propionyl-CoA carboxylase activity in phytohemagglutinin stimulated lymphocytes using high performance liquid chromatography.

    Liu YN, Liu TT, Fan YL, et al.

    Clinica chimica acta; international journal of clinical chemistry 2016; (453()):13-20.

    PMID: 26620954
  13. 13

    Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories.

    Häberle J, Chakrapani A, Ah Mew N, Longo N

    Orphanet journal of rare diseases 2018; (13(1)):219 doi:10.1186/s13023-018-0963-7.

    PMID: 30522498
  14. 14

    Liver transplantation in propionic and methylmalonic acidemia: A single center study with literature review.

    Pillai NR, Stroup BM, Poliner A, et al.

    Molecular genetics and metabolism 2019; (128(4)):431-443 doi:10.1016/j.ymgme.2019.11.001.

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    Interorgan amino acid interchange in propionic acidemia: the missing key to understanding its physiopathology.

    Stanescu S, Belanger-Quintana A, Fernandez-Felix BM, et al.

    Amino acids 2022; (54(5)):777-786 doi:10.1007/s00726-022-03128-6.

    PMID: 35098378
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    Mitochondrial Dysfunction in Propionic Acidemia: A Case-Report and Review of the Literature.

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    JIMD reports 2026; (67(2)):e70073 doi:10.1002/jmd2.70073.

    PMID: 41647652

This page is for informational purposes only and does not constitute medical advice about your child’s Propionic Acidemia testing. Do not change your child’s diet or medication based on one result; ask your metabolic team to interpret the complete pattern.