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Disease Profile

Methylmalonic acidemia

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

#N/A

ICD-10

#N/A

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

MMA; Acidemia, methylmalonic

Categories

Kidney and Urinary Diseases; Newborn Screening

Summary

Methylmalonic acidemia refers to a group of inherited conditions in which the body can’t breakdown certain parts of proteins and fats. This leads to a build-up of toxic substances and bouts of serious illness called decompensation events or metabolic crises.[1] Symptoms of a decompensation event include poor feeding, vomiting, trouble breathing, and lack of energy (lethargy). These can occur at different ages and can range from mild to severe. Methylmalonic acidemia is caused by changes in several different genes and is inherited in an autosomal recessive fashion.[2] Treatment includes aggressive management of decompensation events, a low-protein diet, certain medications, antibiotics and, in some cases, liver and kidney transplantation. Some subtypes of methylmalonic acidemia respond to vitamin B12.[3] Long-term complications can include growth delay, intellectual disability, kidney disease, and pancreatitis.[4] Methylmalonic acidemia can be isolated or may occur along with another condition called homocystinuria.

Symptoms

Methylmalonic acidemia causes episodes of illness called decompensation events caused by the build-up of toxic substances in the blood.[1] Decompensation events can lead to brain damage if not treated quickly.[4]

Symptoms of a decompensation event usually occur a few days after birth and may include:[4]

  • Poor feeding and loss of appetite
  • Vomiting
  • Weak muscle tone (hypotonia)
  • Lack of energy (lethargy)
  • Seizures
  • Coma

Other serious complications may include:

  • Enlarged liver
  • Intellectual and motor disability
  • Poor growth
  • Kidney disease and kidney failure
  • Vision problems

Some subtypes of methylmalonic acidemia have specific symptoms. For example, methylmalonic acidemia with homocystinuria includes an unusually small head (microcephaly).[5]

Cause

Isolated methylmalonic acidemia is caused by changes in one of five genes: MMUT, MMAA, MMAB, MMADHC, or MCEE. Methylmalonic acidemia with homocystinuria is caused by mutations in the MMADHC, LMBRD1 and ABCD4 genes. Other forms of methylmalonic acidemia are caused by changes in different genes.[2][6]

Diagnosis

Methylmalonic acidemia can be diagnosed through newborn screening. Almost every state in the United States screens for this disorder. Additional testing required for diagnosis may include:

  • Biochemical testing for abnormal levels of specific chemicals
  • Testing for responsiveness to vitamin B12
  • Genetic testing for mutations in one of the genes associated with methylmalonic acidemia [2][6]

Newborn Screening

  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
  • Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
  • National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

    Treatment

    There is no specific treatment for methylmalonic acidemia.[1][3] Treatment is focused on managing the symptoms. Options include:

    • Aggressive treatment of decompensation events 
    • Special protein managed diet
    • Vitamin B12 supplementation for the vitamin B12 responsive subtypes
    • Medications such as carnitine
    • Avoidance of stressors (such as fasting or illness) that can lead to a decompensation event
    • Liver and kidney transplant in some cases

    Specialists that may be involved in the care of people with methylmalonic acidemia include:

    • Nutritionist
    • Genetics professional
    • Developmental specialist
    • Neurologist
    • Ophthalmologist
    • Audiologist
    • Nephrologist
    • Physical therapist and occupational therapist

    Management Guidelines

      Organizations

      Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

      Organizations Supporting this Disease

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
        • Genetics Home Reference (GHR) contains information on Methylmalonic acidemia. This website is maintained by the National Library of Medicine.
        • The National Human Genome Research Institute's (NHGRI) website has an information page on this topic. NHGRI is part of the National Institutes of Health and supports research on the structure and function of the human genome and its role in health and disease.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
        • The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • The New England Consortium of Metabolic Program has written medical guidelines called acute care protocols for Methylmalonic acidemia for health care professionals.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Methylmalonic acidemia. Click on the link to view a sample search on this topic.

            References

            1. Fraser JL, Venditti CP. Methylmalonic and Propionic acidemias: Clinical management and update. Curr Opin Pediatr. Dec 2016; 28(6):682-693. https://www.ncbi.nlm.nih.gov/pubmed/27653704.
            2. Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. GeneReviews. Updated Dec 1, 2016; https://www.ncbi.nlm.nih.gov/books/NBK1231/. Accessed 1/21/2020.
            3. Haijes HA, van Hasselt PM, Jans JJM, Verhoeven-Duif NM. Pathophysiology of propionic and methylmalonic acidemias. Pt 2: Treatment strategies. J Inherit Metab Dis. Sept 2019; 42(5):745-761. https://www.ncbi.nlm.nih.gov/pubmed/31119742.
            4. Haijes HA, Jans JJM, Tas SY, Verhoeven-Duif NM, van Hasselt PM. Pathophysiology of propionic and methylmalonic acidemias. Pt 1: Complications. J Inherit Metab Dis. Sept 2019; 42(5):730-744. https://www.ncbi.nlm.nih.gov/pubmed/31119747.
            5. Sloan JL, Carrillo N, Adams D & Venditti CP. Disorders of Intracellular Cobalamin Metabolism. GeneReviews. Updated September 6, 2018; https://www.ncbi.nlm.nih.gov/books/NBK1328/.
            6. Zhou X, Cui Y, Han J.. Methylmalonic acidemia: Current status and research priorities. Intractable Rare Dis Res. May 2018; 7(2):73-78. https://www.ncbi.nlm.nih.gov/pubmed/29862147.
            7. Haijes HA, Molema F, Langeveld M, Janssen MC, Bosch AM, van Spronsen F, et al. Retrospective evaluation of the Dutch pre-newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia: What to aim, expect, and evaluate from newborn screening. J Inherit Metab Dis. Dec 11, 2019; Epub ahead of print. https://www.ncbi.nlm.nih.gov/pubmed/31828787.
            8. Chace DH1, DiPerna JC, Kalas TA, Johnson RW, Naylor EW.. Rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns. Clin Chem. Nov 2001; 47(11):2020-4. https://www.ncbi.nlm.nih.gov/pubmed/11673377.
            9. Baumgartner MR, Hörster F, Dionisi-Vici C, ...and Chakrapani A. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet Journal of Rare Diseases. 2014; 9:130. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180313/.

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