Vitamin B12-responsive methylmalonic acidemia

Title

Other Names:

Adenosylcobalamin deficiency; Vitamin B12-responsive methylmalonic aciduria

Summary Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.

Orpha Number: 28

Disease definition

Vitamin B12-responsive methylmalonic acidemia (MA) is an inborn error of vitamin B12 (cobalamin) metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which responds to vitamin B12. There are three types: cblA, cblB and cblD-variant 2 (cblDv2).

Epidemiology

To date, over 120 patients with cblA, 66 patients with cblB and 6 patients with cblDv2 have been reported. Prevalence of 1/48,000-1/61,000 have been reported for MA of all causes in North America, and 1/26,000 in China, but only a subset of this is vitamin B12-responsive MA.

Clinical description

Patients usually present in infancy or early childhood with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, hepatomegaly and coma. They may also show signs of anemia (not megaloblastic), have potentially life-threatening ketoacidosis and/or hyperammonemia, and developmental delay and intellectual deficit, with metabolic stroke affecting the brain stem. MA frequently leads to end-stage renal failure by adolescence or adulthood. Patients with cblB are usually more severely affected than patients with cblA.

Etiology

Vitamin B12-responsive MA is caused by defects in the synthesis of adenosylcobalamin (AdoCbl). There are three distinct complementation classes, cblA, B and Dv2. cblA is caused by mutations in the MMAA gene (4q31.1-2); cblB by the MMAB gene (12q24.1); and cblDv2 by the MMADHC gene (2q23.2). The previously reported cblH disorder has been shown to be cblDv2.

Diagnostic methods

Diagnosis is based on increased methylmalonic acid in blood and urine. Neonatal screening for propionylcarnitine and/or increased propionylcarnitine-to-acetylcarnitine ratio in dried blood spots by tandem mass spectrometry (MS/MS) has become common, but specific identification of methylmalonic acid remains crucial.

Differential diagnosis

Differential diagnoses include MA with homocystinuria (see this term), caused by defects in cblC, D and F, which can be differentiated by the presence of megaloblastic anemia, or vitamin B12-unresponsive MA without homocystinuria (see this term), which also can present early in life (<1 to 4 weeks) with similar symptoms. Complementation analysis can be used to identify the group involved, or sequencing of the causative genes to identify the affected gene.

Antenatal diagnosis

Antenatal diagnosis is possible by measurement of methylmalonate in amniotic fluid and maternal urine at mid-trimester and by studies of functional mutase activity and cobalamin metabolism in cultured amniotic fluid cells. Molecular diagnosis is possible if the gene affected and the mutation(s) in the family are known.

Genetic counseling

Transmission is autosomal recessive (1 in 4 recurrence risk/pregnancy).

Management and treatment

Treatment involves a protein-restricted diet, which should be instituted as soon as life-threatening manifestations such as ketoacidosis or hyperammonemia have been resolved, and intramuscular injections of vitamin B12, with or without carnitine (mainly effective in cblA). A good response to cobalamin supplementation has been reported in most cblA patients and in nearly half cblB patients. Oral antibiotics may also be useful to reduce propionic acid from gut flora.

Prognosis

The prognosis varies with the complement involved, with cblA patients having the most favorable prognosis (most patients well at ages up to 30 years) and cblB patients less favorable. cblDv2 appears similar to cblA, although the number of patients is small. One complication in long-term surviving patients is chronic renal failure.

Visit the Orphanet disease page for more resources.

Last updated: 5/1/2012

Symptoms Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms	Other Names	Learn More: HPO ID
80%-99% of people have these symptoms
Coma		0001259
Dehydration		0001944
Failure to thrive	Faltering weight Weight faltering [ more ]	0001508
Hepatomegaly	Enlarged liver	0002240
Lethargy		0001254
Nausea and vomiting		0002017
Respiratory insufficiency	Respiratory impairment	0002093
30%-79% of people have these symptoms
Global developmental delay		0001263
Hyperammonemia	High blood ammonia levels	0001987
Intellectual disability	Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ]	0001249
Muscular hypotonia	Low or weak muscle tone	0001252
5%-29% of people have these symptoms
Anemia		0001903
Renal insufficiency	Renal failure Renal failure in adulthood [ more ]	0000083

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Last updated: 5/1/2018

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Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

In-Depth Information

The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

Related Diseases Related Diseases

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