Methylmalonic acidemia is an inherited disorder in which the body is unable to process certain proteins and fats (lipids) properly. The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to life-threatening. Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and failure to gain weight and grow at the expected rate (failure to thrive). Long-term complications can include feeding problems, intellectual disability, chronic kidney disease, and inflammation of the pancreas (pancreatitis). Without treatment, this disorder can lead to coma and death in some cases.
This condition occurs in an estimated 1 in 50,000 to 100,000 people.
Mutations in the MMUT, MMAA, MMAB, MMADHC, and MCEE genes cause methylmalonic acidemia. The long term effects of methylmalonic acidemia depend on which gene is mutated and the severity of the mutation.
About 60 percent of methylmalonic acidemia cases are caused by mutations 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 lipids, and cholesterol. Mutations in the MMUT gene alter the enzyme's structure or reduce the amount of the enzyme, which prevents these molecules from being broken down properly. As a result, a substance called methylmalonyl CoA and other potentially toxic compounds can accumulate in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia.
Mutations in the MMUT gene that prevent the production of any functional enzyme result in a form of the condition designated mut0. Mut0 is the most severe form of methylmalonic acidemia and has the poorest outcome. Mutations that change the structure of methylmalonyl CoA mutase but do not eliminate its activity cause a form of the condition designated mut-. The mut- form is typically less severe, with more variable symptoms than the mut0 form.
Some cases of methylmalonic acidemia are caused by mutations in the MMAA, MMAB, or MMADHC gene. Proteins produced from the MMAA, MMAB, and MMADHC genes are needed for the proper function of methylmalonyl CoA mutase. Mutations that affect proteins produced from these three genes can impair the activity of methylmalonyl CoA mutase, leading to methylmalonic acidemia.
A few other cases of methylmalonic acidemia are caused by mutations in the MCEE gene. This gene provides instructions for producing an enzyme called methylmalonyl CoA epimerase. Like methylmalonyl CoA mutase, this enzyme also plays a role in the breakdown of amino acids, certain lipids, and cholesterol. Disruption in the function of methylmalonyl CoA epimerase leads to a mild form of methylmalonic acidemia.
It is likely that mutations in other, unidentified genes also cause methylmalonic acidemia.
This condition is inherited in an autosomal recessive pattern, which means both copies of the MMUT, MMAA, MMAB, MMADHC, or MCEE gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition are carriers of one copy of the mutated gene but do not show signs and symptoms of the condition.
Other Names for This Condition
- Isolated methylmalonic acidemia
- Methylmalonic aciduria
Additional Information & Resources
Genetic Testing Information
- Genetic Testing Registry: Methylmalonic acidemia
- Genetic Testing Registry: Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
- Genetic Testing Registry: Methylmalonyl-CoA epimerase deficiency
- Genetic Testing Registry: Vitamin B12-responsive methylmalonic acidemia type cblA
- Genetic Testing Registry: Vitamin B12-responsive methylmalonic acidemia type cblB
Genetic and Rare Diseases Information Center
Patient Support and Advocacy Resources
Research Studies from ClinicalTrials.gov
Scientific Articles on PubMed
- Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, Baumgartner MR, Fowler B. Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med. 2008 Apr 3;358(14):1454-64. doi: 10.1056/NEJMoa072200. Citation on PubMed
- Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C. Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):104-12. doi: 10.1002/ajmg.c.30090. Citation on PubMed
- Fowler B, Leonard JV, Baumgartner MR. Causes of and diagnostic approach to methylmalonic acidurias. J Inherit Metab Dis. 2008 Jun;31(3):350-60. doi: 10.1007/s10545-008-0839-4. Epub 2008 Jun 19. Citation on PubMed
- Horster F, Baumgartner MR, Viardot C, Suormala T, Burgard P, Fowler B, Hoffmann GF, Garbade SF, Kolker S, Baumgartner ER. Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res. 2007 Aug;62(2):225-30. doi: 10.1203/PDR.0b013e3180a0325f. Citation on PubMed
- Horster F, Hoffmann GF. Pathophysiology, diagnosis, and treatment of methylmalonic aciduria-recent advances and new challenges. Pediatr Nephrol. 2004 Oct;19(10):1071-4. doi: 10.1007/s00467-004-1572-3. Epub 2004 Aug 4. Citation on PubMed
- Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. 2005 Aug 16 [updated 2022 Sep 8]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1231/ Citation on PubMed
- Miousse IR, Watkins D, Coelho D, Rupar T, Crombez EA, Vilain E, Bernstein JA, Cowan T, Lee-Messer C, Enns GM, Fowler B, Rosenblatt DS. Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism. J Pediatr. 2009 Apr;154(4):551-6. doi: 10.1016/j.jpeds.2008.10.043. Epub 2008 Dec 5. Citation on PubMed
- Ogier de Baulny H, Saudubray JM. Branched-chain organic acidurias. Semin Neonatol. 2002 Feb;7(1):65-74. doi: 10.1053/siny.2001.0087. Citation on PubMed
- Tanpaiboon P. Methylmalonic acidemia (MMA). Mol Genet Metab. 2005 May;85(1):2-6. doi: 10.1016/j.ymgme.2005.03.008. No abstract available. Citation on PubMed
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