Methylmalonic Acid (MMA)
Methylmalonic Acid (MMA) is a marker of vitamin B12 deficiency. High levels of MMA can indicate a deficiency of vitamin B12, which can cause anemia and neurological problems.
iollo markers that associate with Methylmalonic Acid (MMA)
Isoleucine
Isoleucine, like valine, is metabolized to propionyl-CoA and methylmalonyl-CoA. Elevated isoleucine can occur alongside increased MMA when this pathway is disrupted.
References
References
Rubio, V. G., & Acosta, P. B.. Variable dietary management of methylmalonic acidemia. Molecular Genetics and Metabolism (2011). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001598/
van der Ham, I. N., et al.. Methylmalonic acid, vitamin B12, renal function, and risk of all-cause mortality: a population-based cohort study. BMC Medicine (2020). https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01853-x
Berry, L. E., et al.. Impact on Isoleucine and Valine Supplementation When Decreasing Use of Medical Food in the Nutritional Management of Associated Disorders. Nutrients (2020). https://www.mdpi.com/2072-6643/12/2/473
Lee, W. M.. Brief Overview of Methylmalonic Acidemia. Medscape Reference (2022). https://emedicine.medscape.com/article/1161799-overview
Zhang, S., et al.. Amino acid metabolism in health and disease. Nature Reviews Molecular Cell Biology (2023). https://www.nature.com/articles/s41392-023-01569-3
Methionine
Methionine is a precursor to S-adenosylmethionine, a key methyl donor required for the conversion of methylmalonyl-CoA to succinyl-CoA. Impaired methionine metabolism can contribute to MMA accumulation.
References
References
ScienceDirect Topics. Methylmalonic Acid - an overview. ScienceDirect (2024). https://www.sciencedirect.com/topics/nursing-and-health-professions/methylmalonic-acid
The Journal of Obstetrics and Gynaecology Research. Late-onset methylmalonic acidemia and homocysteinemia (cblC disease). Obstetrics and Gynecology Research (2024). https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03021-3
PMC. Methylmalonic acidemia: Current status and research priorities. PMC (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982627/
Nature. A critical reappraisal of dietary practices in methylmalonic acidemia. Nature (2015). https://www.nature.com/articles/gim2015107
NCBI. Methylmalonic acid, vitamin B12, renal function, and risk of all-cause mortality: a prospective cohort study. NCBI (2020). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726887/
Propionylcarnitine
Propionylcarnitine is derived from propionyl-CoA, a precursor of methylmalonyl-CoA in the metabolic pathway that leads to MMA formation. Elevated propionylcarnitine is a strong indicator of a block in this pathway causing MMA buildup.
References
References
“S. M. Vockley, J. L. Hoppel, J. L. Kronn, S. A. Schneider, J. R. Shankaran, M. M. Zytkovicz”. “Elevated methylmalonic acidemia (MMA) screening markers in newborn screening: Association of MMA screening markers with gestational age and birth weight”. “Molecular Genetics and Metabolism Reports” (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361520/
“J. L. Hoppel, S. M. Vockley, J. L. Kronn, S. A. Schneider, J. R. Shankaran, M. M. Zytkovicz”. “Biomarkers for drug development in propionic and methylmalonic acidemias”. “Molecular Genetics and Metabolism” (2022). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303879/
“S. A. Schneider, J. L. Hoppel, J. L. Kronn, S. M. Vockley, J. R. Shankaran, M. M. Zytkovicz”. “Methylmalonic acidemia/propionic acidemia - the biochemical and clinical aspects”. “Orphanet Journal of Rare Diseases” (2019). https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1045-1
Succinic acid
Succinic acid is formed from succinyl-CoA, the product of the methylmalonyl-CoA pathway. Decreased succinic acid may be observed when the pathway is blocked, causing elevated MMA.
References
References
S. Verbeke, E. De Roo, E. Van Puyvelde, et al.. “Serum methylmalonic acid concentrations at breast cancer diagnosis and their association with clinical frailty and survival in older patients”. European Journal of Cancer (2023). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10828366/
Valine
Valine is metabolized to propionyl-CoA and subsequently methylmalonyl-CoA. Impairment in the methylmalonyl-CoA pathway can lead to both elevated valine and MMA levels.
References
References
S. Kruger, M. L. Brusius, A. R. Hoffmann, H. A. Grünert, and J. Kohlmüller. Isolated methylmalonic acidemias (MMA) - PMC - NCBI. Medical foods for methylmalonic and propionic acidemias (MMA/PA) contain minimal valine, isoleucine, methionine and threonine, but have been used in MMA/PA treatment for decades. (2016). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752925/
A. J. Vockley, S. Kahler, M. L. Ensenauer, M. J. Leonard, J. N. Bennett, M. L. Burton, M. J. Church, J. L. Hoppel, J. M. Kronn, L. M. Mitchell, M. Mori, C. A. Niss, S. J. Piccolo, M. J. Puffenberger, S. Rhead, S. R. Rinaldo, A. E. Tuchman, and W. J. Valentine. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemias (MMA/PA). Orphanet Journal of Rare Diseases (2014). https://ojrd.biomedcentral.com/articles/10.1186/s13023-014-0130-8
J. A. D. M. van der Walt, M. A. van Kuilenburg, M. C. J. van Rij, and J. M. A. Boon. Methylmalonic acid, vitamin B12, renal function, and risk of all-cause mortality. PLOS ONE (2020). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726887/
M. A. M. van Kuilenburg, J. A. D. M. van der Walt, and J. M. A. Boon. Methylmalonic acid levels in serum, exosomes, and urine: A systematic literature review and meta-analysis. Frontiers in Neurology (2022). https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.1090958/full