Home > Newborn Disorders > Methylmalonic acidemias
Methylmalonic acidemias
Names
Methylmalonic acidemias
Methylmalonic acidemia (MMA), vitamin B-12 non-responsive
Methylmalonic aciduria, cblA Type (MMAA)
Methylmalonic aciduria, cblBType (MMAB)
Methylmalonic acidemia, racemase deficiency
Adenosylcobalamin deficiency
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 trough a series of reactions, some of which shared with the synethsis of methylcobalamin (cblF, cblC and cblD). Defects in the proximal steps (cblF, 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 A and cblB) result in isolated methylmalonic acidemia. Some of these forms respond to pharmacolocal 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
About 1/48,000 live births [Methylmalonic acidemias, B-12 responsive, info for professionals (STAR-G)]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 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.
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
- 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 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
- death
Treatment of the most severe cases prevent mortality, but the long-term outcome is still unclear. Milder cases susually repond well to treatment. Older patients have increased frequency of complications such as pancreatitis, acute kidney failure, and in rare cases cardiomyopathy.
Follow-up on positive screening test
Quantitative plasma acylcarnitine profile, plasma amino acid test, urine organic acids, plasma total homocysteine, 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/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): Medical Genetics, (801-231-3599); 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, and carnitine supplementation; special medical formulas and foods deficient in methionine, threonine, valine, isoleucine, odd chain fatty acids, and cholesterol
- 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
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
Information & Support
For Professionals
Methylmalonic acidemias, B-12 responsive, info for professionals (STAR-G)
From the Screening, Technology and Research in Genetics (STAR-G) program, 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)
From the Screening, Technology and Research in Genetics (STAR-G) program, 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 Elevated C3 Acylcarnitine (ACMG)
(
352 KB)
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.
ACT Sheets and Confirmatory Algorithms (ACMG)
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 Acute Illness Protocol (NECMP)
A guideline for healthcare 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.
Methylmalonic Acidemias (GeneReviews)
Excellent review by Charles P Venditti, MD, PhD including clinical description, differential, management, genetic counseling,
molecular genetics, and a bibliography.
Resources for methylmalonic acidemia (NLM)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more; from the National
Library of Medicine and the Genetic Alliance.
For Parents and Patients
Methylmalonic acidemias info for parents (STAR-G)
From the Screening, Technology and Research in Genetics (STAR-G) program, 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, UT 84114
Phone: 801-584-8256
Fax: 801-536-0966
http://health.utah.gov/newbornscreening
Pediatric Medical Genetics
See all Pediatric Medical 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.
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
| Reviewing Author: | Nicola Longo MD, PhD, 3/2011 |
| Compiled and edited by: | Alfred Romeo RN, PhD, 3/2007 |
| Content Last Updated: | 4/2011 |