Derivatives of
folic acid are involved in transfer of one-
carbon units in cellular metabolism, playing a role in synthesis of
purines and thymidylate and in the remethylation of
homocysteine to form
methionine. Five inborn errors affecting
folate transport and metabolism have been well studied:
hereditary folate malabsorption, caused by mutations in the gene encoding the
proton-coupled folate transporter (SLC46A1);
glutamate formiminotransferase deficiency, caused by mutations in the FTCD gene;
methylenetetrahydrofolate reductase deficiency, caused by mutations in the MTHFR gene; and functional
methionine synthase deficiency, either as the result of mutations affecting
methionine synthase itself (cblG, caused by mutations in the MTR gene) or affecting the accessory
protein methionine synthase reductase (cblE, caused by mutations in the MTRR gene). Recently additional inborn errors have been identified. Cerebral
folate deficiency is a clinically heterogeneous disorder, which in a few families is caused by mutations in the FOLR1 gene.
Dihydrofolate reductase deficiency is characterized by
megaloblastic anemia and cerebral
folate deficiency, with variable neurological findings. It is caused by mutations in the DHFR gene. Deficiency in the trifunctional
enzyme containing
methylenetetrahydrofolate dehydrogenase,
methenyltetrahydrofolate cyclohydrolase and
formyltetrahydrofolate synthetase activities, has been identified in a single patient with
megaloblastic anemia,
atypical hemolytic uremic syndrome and
severe combined immune deficiency. It is caused by mutations in the MTHFD1 gene.