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Methylmalonic Acidemias

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Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Adenosylcobalamin deficiency
Methylmalonic acidemia (MMA), mutase deficiency
Methylmalonic acidemia, racemase deficiency
Methylmalonic aciduria, cblA Type (MMAA)
Methylmalonic aciduria, cblB Type (MMAB)

ICD-10 Coding

E71.120, Methylmalonic acidemia

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Elevated C3 (propionyl carnitine)

Tested By

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

Description

Methylmalonic acidemia (MMA) is caused by a defect in methylmalonyl-CoA mutase, racemase, or one of the enzymes involved in the synthesis of adenosylcobalamin (cblA and cblB), the essential cofactor of methylmalonyl-CoA mutase. Toxicity is caused by the accumulation of methylmalonic acid and other toxic metabolites, which in infantile MMA (mut 0 ) most classically presents in neonates with lethargy, tachypnea, and vomiting that can rapidly progress to metabolic acidosis and hyperammonemic encephalopathy. However, partial deficiencies (mut – enzymatic subtype) and the cobalamin synthesis disorders (cblA, cblB, and cblD-MMA) can have a more mild insidious presentation with developmental delay with regression, failure to thrive, hypotonia, and feeding difficulties.

Clinical Characteristics

Symptom severity and onset are variable. Symptom onset may vary from the first days of life to late adult presentations. Symptoms and further decompensation are commonly triggered by prolonged fasting, excess protein consumption, and infectious illnesses.
Initial signs and symptoms may include:
  • Poor feeding
  • Seizures
  • Hypotonia
  • Visual and cognitive impairment
  • Failure to thrive
  • Vomiting
  • Dehydration
  • Lethargy
  • Lab findings:
    • Metabolic acidosis
    • Elevated ammonia
    • Elevated ketones
    • Anemia, neutropenia, and thrombocytopenia
    • Elevated methylmalonic acid, glycine, and propionylcarnitine (C3) in plasma
    • Elevated methylmalonic acid, methylcitric acid, and tiglylglycine in urine
In addition to the above, if not treated promptly, patients may experience:
  • Liver steatosis/fibrosis
  • Kidney disease
  • Dystonia
  • Strokes
  • Seizures
  • Coma
  • Death
With treatment for methylmalonic acidemia, the prognosis will still depend primarily on the severity of the disease and response to early therapies. Despite proper therapy, some with infantile MMA (mut0 ) will not survive beyond the 1st year, while most of the survivors will have some degree of developmental disability. Early treatment significantly reduces mortality and results in favorable developmental outcomes. Alternatively, those with milder forms of isolated MMA are typically responsive to vitamin B12 injections with hydroxycobalamin and may not have any disability while on treatment. The expected response to treatment is particularly good for cblA and more variable for cblB.
Without treatment, those with infantile MMA (mut0 ) will not survive the initial metabolic crisis. More mild forms of MMA can present at any stage of life, assuming the right circumstances and trigger, which can present with a life-threatening crisis or more slow progressive cognitive disabilities and dystonia.
Treatment should be managed closely by a medical geneticist and metabolic dietitian. The proper approach may include any combination of fasting avoidance, a low-protein diet, specialized medical formulas, and administration of pharmacological amounts of injectable hydroxycobalamin, carnitine supplements, and antibiotics to prevent intestinal bacteria overgrowth. In more severe cases, either isolated or combined liver and kidney transplantation may be performed. Notably, transplantation is not curative but does reduce the frequency of metabolic decompensations and may improve developmental outcomes.

Incidence

The prevalence of methylmalonic acidemia in the US is reported as 1:159,614. [Therrell: 2014] [Chapman: 2018]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for poor feeding, lethargy, vomiting, tachypnea, or ketonuria.
  • Provide emergency treatment/referral for signs or symptoms of ketosis, metabolic acidosis, or seizures.
  • Discontinue breast or cow milk formula feeding.

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see NW providers [1]).
  • Follow-up testing will include 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.

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Medical Genetics (see NW providers [1]).
  • Provide initial consultation and ongoing collaboration, particularly for dietary management.
  • Refer family for Genetic Testing and Counseling (see NW providers [6]).
  • Educate the family regarding signs and symptoms for the condition (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 when indicated.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.
  • Liver transplant or combined liver/kidney transplant may increase metabolic control but may not prevent neurologic complications.

Specialty Care Collaboration

  • Provide initial consultation and ongoing collaboration, particularly for dietary management.
  • Refer for genetic counseling for the family: Genetic Testing and Counseling (see NW providers [6]).
  • Liver transplant or combined liver/kidney transplant may increase metabolic control but may not prevent neurologic complications.

Resources

Information & Support

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Isolated Methylmalonic Acidemia (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

For Parents and Patients

Methylmalonic Acidemia (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the 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)
Clearinghouse for local, state, and national newborn screening education, programs, policies, and resources. Also, provides many ways for people to connect and share their viewpoints and questions about newborn screening, supported by the U.S. Department of Health and Human Services.

Center for Parent Information and Resources (DOE)
Parent Centers in every state provide training to parents of children with disabilities and provide information about special education, transition to adulthood, health care, support groups, local conferences, and other federal, state, and local services. See the "Find Your Parent Center Link" to find the parent center in your state.

Tools

ACT Sheet for Elevated C3-Acylcarnitine (ACMG) (PDF Document 347 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 194 KB)
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 (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 for Patients & Families Nationwide (NW)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Studies

Methylmalonic Acidemia in Children (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

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 & Reviewers

Initial publication: March 2007; last update/revision: April 2024
Current Authors and Reviewers:
Author: Emily Ramos, MD, MPH
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2017: update: Nicola Longo, MD, Ph.D.A
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Chapman KA, Gramer G, Viall S, Summar ML.
Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data.
Mol Genet Metab Rep. 2018;15:106-109. PubMed abstract / Full Text

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.

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text