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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 28
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 ( cblD v2).
To date, over 120 patients with cblA , 66 patients with cblB and 6 patients with cblD v2 have been reported. Prevalence of 1/48,000-1/61,000 have been reported for methylmalonic acidemia (MA) of all causes in North America, and 1/26,000 in China, but only a subset of this is vitamin B12-responsive MA.
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.
Vitamin B12-responsive MA is caused by defects in the synthesis of adenosylcobalamin (AdoCbl). There are three distinct complementation classes, cblA, B and D v2. cblA is caused by mutations in the MMAA gene (4q31.1-2); cblB by the MMAB gene (12q24.1); and cblD v2 by the MMADHC gene (2q23.2). The previously reported cblH disorder has been shown to be cblD v2.
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 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 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.
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.
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. cblD v2 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.
Source: GARD Last updated on 05-01-20
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