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Screening & Prevention >> Newborn Screening >> Organic Acidemias >> Methylmalonic acidemias

Methylmalonic acidemias

Disorder Category

an organic acid disorder

Screening

Finding

elevated C3 (propionyl carnitine), elevated C4 DC (methylmalonyl carnitine)

Tested By

tandem mass spectrometry (MS/MS); sensitivity=NA; specificity=NA

Names

Methylmalonic acidemias

Methylmalonic acidemia (MMA), vitamin B-12 non-responsive

Methylmalonic aciduria, cblA Type (MMAA)

Methylmalonic aciduria, cblBType (MMAB)

Adenosylcobalamin deficiency

ICD-9

270.7, Other disturbances of straight-chain amino-acid metabolism

Overview

Methylmalonic acidemia is caused by a defect in one of three mitochondrial enzymes: the vitamin B-12 non-responsive form (MMA) results from a defect in methylmalonyl-CoA mutase, which is responsible for production of adenosylcobalamin; the vitamin B-12 responsive forms (MMAA and MMAB) result from a defect in cobalamin reductase and the resulting deficiency of Cobalamin A (cblA) or a defect in cobalamin adenosyltransferase and the resulting deficiency Cobalamin B (cblB), both of which are cofactors for methylmalonyl-CoA mutase. The genes are known for each: MCM for the vitamin B-12 non-responsive form, MMAA for cobalamin A deficiency, and MMAB for cobalamin B deficiency.

Prevalence

About 1/48,000 live births [Methylmalonic acidemias, B-12 responsive, info for professionals, STAR-G]

Inheritance

autosomal recessive

Prenatal Testing

DNA testing or enzyme analysis by amniocentesis or CVS.

Clinical Characteristics

Symptom severity and onset is variable.

For MMA with treatment, 60% will die in the 1st year and 40% of survivors will be developmentally impaired. Without treatment, symptoms usually present in the first few days of life, most patients will die in the first year of life, though some will survive with deficits and a few remain assymptomatic.

For MMAA/MMAB with treatment, outcomes are generally good for those with CblA with reversal of biochemical and clinical abnormalities in 90%. For those with CblB, about a third will do well, a third will be impaired, and a third will die. Without treatment, outcomes are variable, with some dying in the newborn period, some surviving with deficits, and some remaining assymptomatic.

Symptom onset may vary from the first days of life to never. Symptoms may be triggered by fasting, stress, and illness.

Children with MMAA/MMAB often have minor facial dysmorphisms including high forehead, broad nasal bridge, epicanthal folds, long, smooth philtrum and triangular mouth. No typical phenotype is found in those with the MMA.

Initial signs/symptoms may include:
  • poor feeding;
  • failure to thrive;
  • vomiting;
  • dehydration;
  • lethargy;
  • lab findings:
    • anemia;
    • elevated ammonia levels in the blood;
    • elevated ketone levels in the urine;
    • neutropenia and thrombocytopenia; and
    • elevated glycine, methylmalonic acid, and propionic acid levels in the blood and urine.


In addition to the above, if not treated promptly, patients may experience:
  • dermatitis;
  • cutaneous candidiasis;
  • growth retardation;
  • osteoporosis;
  • liver enlargement;
  • kidney disease and failure;
  • motor skill delays;
  • dystonia;
  • spasticity;
  • stroke;
  • seizures;
  • brain damage; and
  • death.


Particulary with MMA, treatment may make little difference in the long-term outcome.

Follow-up on positive screening test

Quantitative plasma acylcarnitine profile, blood amino acid test, urine organic acids, plasma total homocysteine, serum vitamin B12 may reveal MMA or variants.

Primary care management

Upon notification of the + screen

  • Contact the family and evaluate the infant for poor feeding, lethargy, vomiting, tachnypnea, or ketonuria;
  • Provide emergency treatment/referral for signs/symptoms of ketosis, metabolic acidosis, or seizures;
  • Discontinue breast or cow milk formula feeding;
  • To confirm the diagnosis, work with the following service(s): Utah Newborn Screening Program, (801-584-8256); See also Services below;
  • For evaluation and ongoing collaborative management, consult the following service(s): Metabolic Clinic, (801-585-2457); See also Services below;

If the diagnosis is confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Methylmalonic acidemias info for parents, STAR-G for additional information);
  • In collaboration with metabolic specialists, implement a protein restricted diet, OH-Cbl injections, carnitine supplementation, and oral antibiotic therapy to decrease gut production of propionate; special medical formulas and foods deficient in methionine, threonine, valine, isoleucine, odd chain fatty acids, and cholesterol;
  • Bicarbonate and glucose may be indicated during metabolic crisis episodes;
  • Monitoring of amino acid levels through blood and urine tests may be indicated;
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Management

Initial consultation and ongoing collaboration, particularly for dietary management. Genetic counseling for the family. Liver transplant or combined liver/kidney transplant may increase metabolic control, but may not prevent neurologic complications.

Resources

Links

For Professionals

Methylmalonic acidemias, B-12 responsive, info for professionals, STAR-G
On the Screening, Technology and Research in Genetics (STAR-G) site, one of a series of Disorder Fact Sheets for Professionals; structured list of information about the condition, with links to more information.

Methylmalonic acidemias, B-12 non-responsive, info for professionals, STAR-G
On the Screening, Technology and Research in Genetics (STAR-G) site, one of a series of Disorder Fact Sheets for Professionals; structured list of information about the condition, with links to more information.

ACT Sheet for Methylmalonic acidemias from ACMG
Developed by the American College of Medical Genetics (ACMG), includes recommended responses to positive newborn screening test results, diagnostic evaluation, clinical expectations, and sources of additional information. See the ACMG ACT Sheets and Confirmatory Algorithms (link elsewhere on this page) for more info and sheets on other conditions.

ACMG ACT Sheets and Confirmatory Algorithms
The American College of Medical Genetics (ACMG) has developed ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results. This page contains a table with links to all of the ACT Sheets and related algorithms.

Methylmalonic acidemias review, GeneTests.org
Excellent review by Charles P Venditti, MD, PhD including clinical description, differential, management, genetic counseling, molecular genetics, and a bibliography.

Methylmalonic acidemias Emergency Protocol
A protocol for management of the patient with a positive screen for methylmalonic acidemias, from the New England Consortium of Metabolic Programs.

For Parents

Methylmalonic acidemias info for parents, STAR-G
From the Screening, Technology and Research in Genetics (STAR-G) site, providing information for parents about methylmalonic acidemias and links to other sites including parent support groups.

Methylmalonic acidemias, Genetics Home Reference
Excellent, detailed review aimed at patients and families from the National Library of Medicine's Genetics Home Reference site.

Organic Acidemia Association (OAA)
A non-profit organization that provides information for parents and providers; newsletters; event information; connections with other parents; a listserv; a discussion board; information about nutrition and recipes; translation of their web pages into five other languages; hosting of the Propionic Acidemia Research Network and other research funds; and links to other sites.

Services

Newborn Screening Programs

Utah Newborn Screening Program, more info...
44 Mario Capecchi Drive
Salt Lake City, UT84114
Phone: 801-584-8256
Fax: 801-536-0966
http://health.utah.gov/newbornscreening

Pediatric Genetics

Metabolic Clinic, more info...
100 Mario Capecchi Drive
Salt Lake City, UT84113
Phone: 801-585-2457
Fax: 585-7252
http://www.ped.med.utah.edu/divisions/divisions.htm

See all Pediatric Genetics services providers (3) in our database.

For other services related to this condition, browse our Services categories or search our database.

Helpful Articles

PubMed search for review articles on methylmalonic acidemias in the last 5 years.

Authors

Reviewing Author: Nicola Longo MD, PhD, 3/2007
Compiled and edited by: Alfred Romeo RN, PhD, 3/2007
Content Last Updated: 3/2008
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