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Prevalence of 1/48,000-1/61,000 has been reported for methylmalonic aciduria of all causes in North America, and 1/26,000 in China, but only a subset of this is vitamin B12-unresponsive methylmalonic acidemia.

Patients with vitamin B12-unresponsive methylmalonic acidemia without homocystinuria typically present very early in life (<1 to 4 weeks) with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscular hypotonia, hepatomegaly and coma. Later-onset manifestations may include developmental delay and intellectual deficit. Patients may also show signs of anemia which is not megaloblastic. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy. Later-onset and milder phenotypes have also been observed, particularly in mut- patients. Long term consequences are neurological damage due to metabolic stroke and end-stage renal failure. These complications are more frequent in mut0 than in mut-.

Vitamin B12-unresponsive methylmalonic acidemia without homocystinuria is caused by complete (mut0) or partial (mut-) deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase. This deficiency is caused by mutations in the MUT gene (6p21).

Diagnosis is based on the finding of increased methylmalonic acid in blood and urine. There is increased propionylcarnitine and/or increased propionylcarnitine-to-acetylcarnitine ratio in dried blood spots by tandem mass spectrometry (MS/MS). Diagnosis can be confirmed by somatic cell studies or molecular genetic testing.

Differential diagnoses include methylmalonic acidemia with homocystinuria, caused by defects in cblC, cblD and cblF, which can be differentiated by the presence of megaloblastic anemia, or vitamin B12-responsive methylmalonic acidemia without homocystinuria, which usually presents slightly later in life (1 month to 1 year). Complementation analysis can be used to identify the cbl or mut complement involved.

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 genetic prenatal diagnosis is also possible when the mutations segregating in the family are known.

The disorder is transmitted in an autosomal recessive manner.

Treatment involves a protein-restricted diet, which should be instituted as soon as life-threatening problems such as ketoacidosis or hyperammonemia have been resolved. Oral antibiotics may also be useful. Liver transplantation has been attempted in a limited number of patients but this does not usually offer complete protection against renal and neurological complications.

Despite dietary treatment, patients remain vulnerable to life-threatening metabolic decompensation. Other long-term complications include progressive renal failure, metabolic stroke and other neurological symptoms, as well as cardiomyopathy. Life-expectancy is decreased in mut0 patients compared to mut- patients.

Last update: March 2012 - Expert reviewer(s): Dr David ROSENBLATT