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

ICD-10 Coding

E71.120, Methylmalonic acidemia

Disorder Category

Organic acidemia

Screening

Abnormal Finding

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

Tested By

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

Description

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.

Clinical Characteristics

Symptom severity and onset are variable.
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 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
With treatment for methylmalonic acidemia, 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; those with milder mutations (mut-) do better than those with no residual activity (mut0). Without treatment, symptoms usually present in the first few days of life; most will die in the first year, though some will survive with deficits and a few (mut-) remain asymptomatic.

With treatment for methylmalonic acidemia, mutase deficiency/ methylmalonic aciduria, cblB type, outcomes are generally good for those with CblA with good response to therapy of biochemical and clinical abnormalities in 90%. For those with methylmalonic aciduria, cblB type, 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.
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.

Incidence

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

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 NV providers [2]).
  • 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 NV providers [5]).
  • Provide initial consultation and ongoing collaboration, particularly for dietary management.
  • Refer family for Genetic Testing and Counseling (see NV providers [12]).
  • 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.

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

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 (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; 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.

NV ACT Sheet for Methylmalonic Acidemia (PDF Document 157 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; 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 (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 in Nevada (NV)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

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: July 2017
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Authoring history
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

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