• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Methylmalonic Acidemia

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Last updated: 05/17/2024
Years published: 1987, 1988, 1990, 2000, 2002, 2007, 2024


Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, Brazilian MD, MS, National Organization for Rare Disorders, for assistance in the preparation of this report.


Disease Overview

Methylmalonic acidemia (MMA) is a group of genetic disorders in which the body can’t breakdown (metabolize) proteins and fats properly. This results in an abnormally high level of acid in the blood (acidemia) and body tissues. This condition varies in severity from mild to life-threatening. Infants with this condition typically have drowsiness, vomiting, dehydration, weak muscle tone (hypotonia) and excessive tiredness (lethargy). Without treatment, MMA can lead to coma and death in some patients. MMA is inherited in an autosomal recessive pattern.

Newborn screening can identify affected infants early in life. This is important because dietary changes and supplements can prevent some of the harmful effects of this disorder.

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Synonyms

  • methylmalonic aciduria
  • MMA
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Signs & Symptoms

The onset of MMA is usually during the first few months of life, but onset throughout childhood has been described. Babies may appear normal at birth, but develop symptoms once they start eating more protein, which can cause the condition to get worse. 

Symptoms may include excessive tiredness (lethargy), not growing and gaining weight at the expected rate (failure to thrive), recurrent vomiting, a condition where there is too much acid in the body (acidosis), dehydration, respiratory distress, diminished muscle tone (hypotonia), developmental delay, seizures and/or an enlarged liver. Affected children may have a brain disease that gets worse (progressive encephalopathy) and intellectual disability. These symptoms can appear after an infection or change in feeding habits. Some children may suffer from strokes.

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Causes

Methylmalonic academia is caused by changes (variants) in several different genes including MMUT, MMAA, MMAB, MMADHC and MCEE.

Most people with MMA have variants in the MMUT gene. This gene provides instructions for making an enzyme called methylmalonyl-CoA mutase. This enzyme works with vitamin B12 (also called cobalamin) to break down several protein building blocks (amino acids), certain fats (lipids) and cholesterol. Variants in the MMUT gene can prevent the production of this enzyme or affect its function. This leads to a buildup of methylmalonic acid and other potentially toxic compounds in the body and this leads to the signs and symptoms of MMA.

Some variants in the MMUT gene prevent the production of any functional methylmalonyl-CoA mutase enzyme. This results in a form of MMA called mut0, the most severe form of MMA. Variants that change the structure of this enzyme but do not eliminate its activity result in a form of MMA called mut-.  The mut- form is usually less severe, with more variable symptoms than the mut0 form.

Some patients with MMA have variants in the MMAA, MMAB or MMADHC genes. Proteins produced by these genes help produce and regulate vitamin B12 and are needed for the methylmalonyl-CoA mutase enzyme to function normally.

Rarely, MMA can be caused by variants in the MCEE gene. This gene provides instructions for making the methylmalonyl CoA epimerase enzyme. Like methylmalonyl CoA mutase, this enzyme plays a role in the breakdown of amino acids, certain lipids and cholesterol. Abnormal function of methylmalonyl CoA epimerase leads to a form of MMA with varied signs and symptoms.

MMA is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Methylmalonic acidemia occurs in 1 in 50,000 to 1 in 100,000 livebirths. Based on a large study, the detection of MMA was below 2 cases per 100,000 newborns in North America, Europe and Asia-Pacific regions. 

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Diagnosis

Methylmalonic acidemia can be identified at birth on a blood spot through expanded newborn screening with tandem mass spectrometry. A baby with high levels of acylcarnitines, methylmalomic acid and methylcitiric acid may have MMA. Additional testing on blood, urine and sometimes skin is needed to confirm a diagnosis of MMA. Magnetic resonance imaging (MRI) and computed tomography (CT) imaging studies show several alterations in the brain. Genetic testing for variants in the MMUT, MMAA, MMAB, MMADHC and MCEE genes can also confirm the diagnosis.

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Standard Therapies

Treatment

A special diet is important to prevent some of the health problems associated with MMA. This includes a diet low in certain proteins and fats, special formulas and medical foods and regular meals and snacks. Children with some forms of MMA may need vitamin B-12 supplements and some affected children may need carnitine supplements. Children with MMA who are treated early in life may still have learning difficulties and intellectual disability.

Genetic counseling is recommended for families of an affected child.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Almási T, Guey LT, Lukacs C, Csetneki K, Vokó 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;14(1):84. Published 2019 Apr 25. doi:10.1186/s13023-019-1063-z 

INTERNET

Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. 2005 Aug 16 [Updated 2022 Sep 8]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1231/ Accessed May 15, 2024.

Methylmalonic Aciduria. Online Mendelian Inheritance in Man (OMIM). Entry No: 251000; Last Update: 03/11/2024. https://www.omim.org/entry/251000 Accessed May 15, 2024.

Lee B. Genetics of Methylmalonic Acidemia. Updated: Mar 15, 2019. www.emedicine.com/ped/topic1438.htm Accessed May 15, 2024.

Methylmalonic acidemia. MedlinePlus. July 17, 2023. https://medlineplus.gov/download/genetics/condition/methylmalonic-acidemia.pdf Accessed May 15, 2024.

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Programs & Resources

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Patient Organizations


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