Methylmalonic Acidemias

Other Names

Methylmalonic acidemia (MMA)), mutase deficiency

Methylmalonic aciduria, cblA Type (MMAA)

Methylmalonic aciduria, cblB Type (MMAB)

Methylmalonic acidemia, racemase deficiency

Adenosylcobalamin deficiency

Diagnosis Coding

E71.120, methylmalonic acidemia

Disorder Category

An organic acidemia

Screening

Finding

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

Tested By

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

Overview

Methylmalonic acidemia is caused by a defect in methylmalonyl-CoA mutase, racemase or one of the enzymes involved in the synthesis of adenosylcobalamin, the essential cofactor of methylmalonyl-CoA mutase (cblA and cblB). Adenosylcobalamin is synthesized from vitamin B-12 through a series of reactions, some of which are shared with the synthesis of methylcobalamin (cblF, cblJ, cblC, and cblD). Defects in the proximal steps (cblF, cblJ, cblC, and some forms of cblD) result in combined methylmalonic acidemia-homocystinuria (due to defects in methionine synthase, the enzyme requiring methylcobalamin). Defects in the distal steps (some forms of cblD, cblA, and cblB) result in isolated methylmalonic acidemia. Some of these forms respond to pharmacological amounts of vitamin B-12 (provided as injectable hydroxycobalamin). The genes for all these conditions have been identified, but there are additional steps in vitamin B12 metabolism that are still unknown.

Prevalence

The prevalence of methylmalonic acidemia falls between 1:50,000 and 1:100,000. [Chace: 2001] [Shigematsu: 2002]

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing by amniocentesis or CVS

Clinical Characteristics

Symptom severity and onset is variable.

For MMA with treatment, some will die in the 1st year and many of the survivors will be developmentally impaired. Outcome is dependent on the severity of enzymatic impairment, with those with milder mutations (mut-) doing better than those with no residual activity (mut0). 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 (mut-) remain asymptomatic. 

For MMAA/MMAB with treatment, outcomes are generally good for those with CblA with good response to therapy 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 experience severe complications early in life. Without treatment, outcomes are variable, with some still dying in the newborn period, some surviving with deficits, and some having few symptoms. 

Symptom onset may vary from the first days of life to later in life. Symptoms may be triggered by fasting, stress, and illness. No typical facial phenotype is found in patients those with any form of methylmalonic acidemia.

Initial signs and symptoms may include:
  • Poor feeding
  • Hypotonia followed by spasticity
  • Failure to thrive
  • Vomiting
  • Dehydration
  • Lethargy
  • Lab findings:
    • Metabolic acidosis
    • Anemia
    • Elevated ammonia levels in the blood
    • Elevated ketone levels in the urine
    • Neutropenia and thrombocytopenia
    • Elevated glycine, methylmalonic acid, and methylcitric 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
  • Death
Treatment consists of a low-protein diet; medical foods restricted of isoleucine, methionine, threonine and valine, odd-chain fatty acids and cholesterol; administration of pharmacological amounts on injectable hydroxycobalamin; and carnitine supplements. Treatment of the most severe cases prevents mortality, but the long-term outcome is still unclear. Milder cases usually respond well to treatment. Older patients have increased frequency of complications, such as pancreatitis, kidney failure, and cardiomyopathy in older individuals. Liver transplantation can prevent metabolic crises, but its effect on chronic complications is still unclear. A combined liver-kidney transplant can be performed in children presenting with kidney failure.

Follow-up Testing after Positive Screen

Follow up with quantitative plasma acylcarnitine profile, plasma amino acid test, urine organic acids, plasma total homocysteine, serum methylmalonic acid, and serum vitamin B12 (to exclude vitamin B12 deficiency). If vitamin B12 deficiency is suspected, the mother should also be tested.

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 or symptoms of ketosis, metabolic acidosis, or seizures.
  • Discontinue breast or cow milk formula feeding.
  • To confirm the diagnosis, work with the following service(s): see all Newborn Screening Programs services providers (3) in our database.
  • For evaluation and ongoing collaborative management, consult the following service(s): see all Pediatric Genetics services providers (8) in our database.

If the Diagnosis is Confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Methylmalonic Acidemia - Information for Parents (STAR-G) for additional information).
  • In collaboration with metabolic specialists, implement a protein-restricted diet; OH-Cbl injections; carnitine supplementation; special medical formulas deficient in methionine, threonine, valine, isoleucine, odd chain fatty acids, and cholesterol; and a low protein diet.
  • Bicarbonate, intralipids, glucose and insulin may be indicated during metabolic crisis episodes.
  • Monitoring of plasma amino acid levels is indicated.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Collaboration

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

Resources

Information & Support

For Professionals

Methylmalonic Acidemia, B-12 Non-Responsive - Information for Professionals (STAR-G)
Structured list of information about the condition and links to more information; Screening, Technology, and Research in Genetics.

Isolated Methylmalonic Acidemia (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

National Newborn Screening & Global Resource Center (NNSGRC)
Fact sheets, data reports, publications, and information for clinicians about genetic screening that includes links to state genetic contacts.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Utah Newborn Screening Program (UDOH)
Provides information about the program, related legislation, training for practices, and newborn conditions; Utah Department of Health.

For Parents and Patients

Support

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.

General

Methylmalonic Acidemia (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

Methylmalonic Acidemia - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

Baby's First Test (Genetic Alliance)
A clearinghouse for newborn screening information. Provides resources about screening at the local, state, and national levels and ways for people to share their viewpoints and questions about newborn screening; supported by the U.S. Department of Health and Human Services.

Newborn Screening Information for Families (NNSGRC)
Information for families about genetic screening. Links to support groups, advocacy groups, and state genetic contacts; National Newborn Screening and Global Resource Center.

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.

Center for Parent Information and Resources (DOE)
A large resource library related to children with disabilities. Parent Centers in every state provide training to parents of children with disabilities and provide information about local conferences, support groups, and finding schools and other local services; Department of Education, Office of Special Education.

Tools

ACT Sheet for Elevated C3 Acylcarnitine (ACMG) (PDF Document 352 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithms for Elevated C3 Acylcarnitine (ACMG) (PDF Document)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Methylmalonic Acidemia Acute Illness Protocol (NECMP)
A guideline for health care professionals treating the sick infant/child who has previously been diagnosed with methylmalonic acidemia; developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs.

Services

Genetics-related clinical services throughout the world can be found through Genetics Clinic Directory (GeneTests).

Newborn Screening Programs

See all Newborn Screening Programs services providers (3) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (8) in our database.

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

Helpful Articles

PubMed search for methylmalonic acidemias and neonatal screening, last 5 years.

Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C.
Methylmalonic and propionic aciduria.
Am J Med Genet C Semin Med Genet. 2006;142C(2):104-12. PubMed abstract
Methylmalonic and propionic aciduria (PA) are the most frequent forms of branched-chain organic acidurias. The recent implementation of neonatal screening by electrospray tandem mass spectrometry has decreased early mortality and improved the short-term outcome.

Authors

Author: Nicola Longo, MD, PhD - 3/2011
Reviewing Author: Nicola Longo, MD, PhD - 7/2017
Compiled and edited by: Alfred Romeo, RN, PhD - 3/2007
Content Last Updated: 7/2017

Page Bibliography

Chace DH, 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. 2001;47(11):2040-4. PubMed abstract

Shigematsu Y, Hirano S, Hata I, Tanaka Y, Sudo M, Sakura N, Tajima T, Yamaguchi S.
Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan.
J Chromatogr B Analyt Technol Biomed Life Sci. 2002;776(1):39-48. PubMed abstract