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PubMed This is a summary of 8 peer-reviewed journal articles Updated
Medical Genetics

Diagnosing CMAMMA and Understanding Lab Reports

At a Glance

Combined Malonic and Methylmalonic Acidemia (CMAMMA) is diagnosed through a combination of biochemical lab tests and genetic screening. Key diagnostic steps include checking for elevated malonic and methylmalonic acids in urine, verifying the plasma MA/MMA ratio, and confirming ACSF3 gene mutations.

Confirming a diagnosis of Combined Malonic and Methylmalonic Acidemia (CMAMMA) requires a combination of biochemical tests (blood and urine) and genetic confirmation. Because CMAMMA can look like other conditions on paper, specialized lab work is essential to ensure the diagnosis is accurate [1][2].

The First Step: Urine Organic Acid Analysis

The initial clue for CMAMMA usually comes from a urine organic acid test. This test looks for chemical markers that the body produces when it isn’t processing acids correctly [3].

  • Elevated Markers: In CMAMMA, both malonic acid (MA) and methylmalonic acid (MMA) are elevated in the urine [4][5].
  • The Detection Challenge: Malonic acid can be technically difficult for labs to detect. Its levels can fluctuate or be “hidden” by other chemicals in the urine, which is why CMAMMA is sometimes missed on standard screenings [1][4].
  • A Unique Pattern: Unlike “classic” MMA, where only methylmalonic acid is high, CMAMMA patients typically show levels of MMA that are higher than the levels of MA, but both remain above the normal range [2].

The Differentiator: Plasma MA/MMA Ratio

The most important tool for distinguishing CMAMMA from the more severe “classic” MMA is the plasma MA/MMA ratio [1].

  • How it Works: By measuring the exact amounts of both acids in the blood (specifically the plasma—the liquid portion of a standard blood draw) and dividing the malonic acid level by the methylmalonic acid level, doctors can determine which enzyme is malfunctioning [1].
  • Why it Matters: This ratio acts as a “molecular fingerprint.” A specific ratio indicates the ACSF3 enzyme is at fault, which confirms CMAMMA and rules out the higher-risk classic forms of methylmalonic acidemia [1][2].

The Confirmation: ACSF3 Genetic Testing

While biochemical tests show what is happening, genetic testing shows why. To confirm the diagnosis, a doctor will order molecular genetic testing to look for mutations in the ACSF3 gene [2][6].

  • Biallelic Variants: To have CMAMMA, a person must have biallelic variants—meaning one mutation was inherited from each parent [3][4].
  • Types of Variants: The report might list different types of mutations, such as missense (a single “letter” change) or nonsense (a change that stops the gene from being read correctly) [2][7].

Lab Report Checklist

When reviewing your or your child’s laboratory results, look for the following items. If any are missing, ask your doctor:

  1. Urine Organic Acids: Are both malonic acid and methylmalonic acid listed as “Elevated” or “High”? [3]
  2. Plasma Amino Acids/Acylcarnitines: Is there a calculation for the MA/MMA ratio? [1]
  3. Genetic Results: Is the ACSF3 gene mentioned? Are there two mutations (variants) found? [2]
  4. Variant Classification: Are the genetic changes listed as “Pathogenic” (disease-causing) or “Likely Pathogenic”? [5]

If the genetic test only finds one mutation or the lab results are borderline, your doctor may suggest further testing or monitoring over time [4][8].

Common questions in this guide

What blood and urine tests are used to diagnose CMAMMA?
Doctors use a urine organic acid test to check for elevated levels of malonic and methylmalonic acids. They also measure the plasma MA/MMA ratio in your blood to differentiate CMAMMA from other similar metabolic conditions.
What does the plasma MA/MMA ratio mean?
The plasma MA/MMA ratio compares the exact amounts of malonic and methylmalonic acids in your blood. This calculation acts like a molecular fingerprint to confirm CMAMMA and rule out more severe forms of classic methylmalonic acidemia.
What does it mean to have biallelic variants on an ACSF3 genetic test?
Having biallelic variants means that a mutation in the ACSF3 gene was inherited from both your mother and your father. Finding two of these disease-causing mutations is required to genetically confirm a diagnosis of CMAMMA.
What if my genetic test shows a Variant of Uncertain Significance (VUS)?
A VUS means a change was found in the gene, but it is currently unknown if it causes the condition. If you have borderline lab results or a VUS, your doctor may suggest further testing or monitoring over time to clarify the diagnosis.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.On my urine report, were both malonic and methylmalonic acids elevated, and what were the exact numbers compared to the 'normal' range?
  2. 2.Can you confirm that my plasma MA/MMA ratio was calculated and that it specifically points to CMAMMA rather than classic MMA?
  3. 3.Does my genetic report show 'biallelic' variants, meaning I have a mutation on both copies of the ACSF3 gene?
  4. 4.If any of my genetic findings are listed as a 'Variant of Uncertain Significance' (VUS), how does that affect the certainty of my diagnosis?

Questions For You

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References

References (8)
  1. 1

    A New Approach for Fast Metabolic Diagnostics in CMAMMA.

    de Sain-van der Velden MG, van der Ham M, Jans JJ, et al.

    JIMD reports 2016; (30()):15-22 doi:10.1007/8904_2016_531.

    PMID: 26915364
  2. 2

    Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort.

    Levtova A, Waters PJ, Buhas D, et al.

    Journal of inherited metabolic disease 2019; (42(1)):107-116 doi:10.1002/jimd.12032.

    PMID: 30740739
  3. 3

    A Deep Clinical and Biochemical Characterization of a Patient With Combined Malonic and Methylmalonic Aciduria (CMAMMA).

    Gragnaniello V, Galderisi A, Tucci S, et al.

    JIMD reports 2025; (66(6)):e70045 doi:10.1002/jmd2.70045.

    PMID: 41030468
  4. 4

    Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients.

    Wang P, Shu J, Gu C, et al.

    Frontiers in pediatrics 2021; (9()):751895 doi:10.3389/fped.2021.751895.

    PMID: 34900860
  5. 5

    Biallelic ACSF3 variants with combined malonic and methylmalonic acidemia and associated developmental epileptic encephalopathy phenotype: A novel genotype-phenotype correlation.

    Curry J, Bonkowski E, Mefford H, et al.

    Seizure 2025; (133()):16-19 doi:10.1016/j.seizure.2025.09.015.

    PMID: 41075375
  6. 6

    Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria.

    Gabriel MC, Rice SM, Sloan JL, et al.

    Molecular genetics & genomic medicine 2021; (9(4)):e1621 doi:10.1002/mgg3.1621.

    PMID: 33625768
  7. 7

    Dual molecular genetic diagnosis with combined malonic and methylmalonic aciduria (CMAMMA): implications of coexisting genetic disorders on clinical presentation.

    Ersoy M, Abali ZY, Papatya Cakir ED, et al.

    Journal of pediatric endocrinology & metabolism : JPEM 2025; (38(12)):1340-1349 doi:10.1515/jpem-2025-0208.

    PMID: 40960910
  8. 8

    Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program.

    Navarrete R, Leal F, Vega AI, et al.

    European journal of human genetics : EJHG 2019; (27(4)):556-562 doi:10.1038/s41431-018-0330-0.

    PMID: 30626930

This page explains CMAMMA diagnostic and genetic testing terminology for educational purposes only. Always consult your medical geneticist or primary doctor to interpret your specific laboratory results.

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