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Methylmalonic acidemia
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Methylmalonic acidemia

Methylmalonic acidemia is a rare inherited disorder that impairs the body’s ability to break down proteins and fats, often leading to severe metabolic crises in infants.

Overview

Methylmalonic acidemia is a group of inherited disorders that prevent the body from breaking down proteins and fats (lipids) properly. The effects usually appear in early infancy and can range from mild to life‑threatening. Affected infants may experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delays, lethargy, hepatomegaly, and failure to thrive. Long‑term complications can include feeding problems, intellectual disabilities, movement disorders, chronic kidney disease, and pancreatitis. Frequent episodes of metabolic acidosis can cause serious health complications, and without treatment, the disorder can lead to coma and death.

Frequency

Methylmalonic acidemia occurs in an estimated 1 in 50,000 to 100,000 people.

Causes & Risk Factors

Variants (mutations) in the MMUT, MMAA, MMAB, MMADHC, and MCEE genes cause methylmalonic acidemia. The long‑term effects depend on which gene is altered and the severity of the variant.

Genetic Causes

  • MMUT – provides instructions for methylmalonyl‑CoA mutase, an enzyme that works with vitamin B12 to break down certain amino acids, lipids, and cholesterol. About 60 % of individuals have variants in this gene.
  • MMUT variants can be classified as:
    • mut0 – no functional enzyme; most severe form.
    • mut‑ – reduced activity; less severe with variable symptoms.
  • MMAA, MMAB, MMADHC – encode proteins that regulate vitamin B12 production and delivery to methylmalonyl‑CoA mutase. Variants impair enzyme activity.
  • MCEE – encodes methylmalonyl‑CoA epimerase, another enzyme involved in amino acid, lipid, and cholesterol breakdown. Variants lead to a form with varied signs and symptoms.

Because these variants only elevate methylmalonic acid levels, the condition is sometimes called isolated methylmalonic acidemia, distinguishing it from related disorders such as methylmalonic acidemia with homocystinuria.

Inheritance

This condition is inherited in an autosomal recessive pattern, meaning both copies of the affected gene in each cell must have a variant to cause the disorder. Parents of an individual with an autosomal recessive condition each carry one copy of the altered gene but typically do not show signs or symptoms.

Other Names

  • Isolated methylmalonic acidemia
  • Methylmalonic aciduria
  • MMA

Additional Information & Resources

Genetic Testing

  • Genetic Testing Registry: Methylmalonic acidemia due to methylmalonyl‑CoA epimerase deficiency
  • Genetic Testing Registry: Methylmalonic aciduria, cblA type
  • Genetic Testing Registry: Methylmalonic aciduria, cblB type
  • Genetic Testing Registry: Methylmalonic acidemia
  • Genetic Testing Registry: Methylmalonic aciduria due to methylmalonyl‑CoA mutase deficiency

Support & Advocacy

  • National Organization for Rare Disorders (NORD)

Clinical Trials

  • ClinicalTrials.gov

Scientific Literature

  • Almasi T, Guey LT, Lukacs C, Csetneki K, Voko Z, Zelei T. Systematic literature review and meta‑analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl‑CoA mutase (mut) deficiency. Orphanet J Rare Dis. 2019 Apr 25;14(1):84.
  • Chandler RJ, Venditti CP. Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future. Hum Gene Ther. 2019 Oct;30(10):1236‑1244.
  • Forny P, Horster F, Ballhausen D, et al. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision. J Inherit Metab Dis. 2021 May;44(3):566‑592.
  • Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical management update. Curr Opin Pediatr. 2016 Dec;28(6):682‑693.
  • Haijes HA, Jans JJM, Tas SY, et al. Pathophysiology of propionic and methylmalonic acidemias. Part 1: Complications. J Inherit Metab Dis. 2019 Sep;42(5):730‑744.
  • Haijes HA, van Hasselt PM, Jans JJM, et al. Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies. J Inherit Metab Dis. 2019 Sep;42(5):745‑761.
  • Horster F, Baumgartner MR, Viardot C, et al. Long‑term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut‑, cblA, cblB). Pediatr Res. 2007 Aug;62(2):225‑230.
  • Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. GeneReviews. 2005 Aug 16; updated 2022 Sep 8.

Frequently Asked Questions

targeted gene panel or whole‑exome sequencing that includes MMUT, MMAA, MMAB, MMADHC, and MCEE should be performed on the affected child. Once the pathogenic variant is identified, carrier testing can be offered to parents and siblings. For future pregnancies, options include pre‑implantation genetic testing (PGT‑M) with IVF, prenatal chorionic villus sampling, or early newborn screening, allowing you to make informed decisions before birth.
Look for sudden vomiting, poor feeding, lethargy, rapid breathing, dehydration, low muscle tone, or a change in urine color. These symptoms can appear within hours and often precede a drop in blood pH. Prompt measurement of blood gases and serum ammonia, followed by emergency treatment, can prevent coma.
Infants usually require a low‑protein diet that limits branched‑chain amino acids (isoleucine, valine, methionine, threonine) and odd‑chain fatty acids. Many patients benefit from oral hydroxocobalamin (vitamin B12) injections, carnitine supplementation, and a medical formula specially designed for organic acidemias. Regular follow‑up with a metabolic dietitian is essential to adjust calories and protein as the child grows.
If the child develops any combination of vomiting, lethargy, rapid breathing, or a seizure, call 911 or go to the nearest emergency department immediately—treatment must start within the first few hours. If symptoms are mild (e.g., slight irritability or mild vomiting) but you cannot reach the specialist within an hour, still seek emergency care, as delayed treatment increases the risk of permanent neurologic injury.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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