Folate coenzymes participate in a number of critical single-carbon transfer reactions, including those involved in the biosynthesis of pyrimidines, purines, serine and methionine, and in the degradation of serine, glycine and histidine.
Six inherited disorders of folate transport and metabolism have been well substantiated: methylenetetrahydrofolate reductase deficiency (MIM 236250), caused by mutations in the MTHFR gene; functional methyltetrahydrofolate: homocysteine methyltransferase (methionine synthase) deficiency caused by mutations in the gene for methionine synthase reductase, MTRR (cblE; MIM 236270) or mutations in the gene for methionine synthase itself, MTR (cblG; MIM 250940); glutamate formiminotransferase deficiency (MIM 229100), caused by mutations in the FTCD gene; hereditary folate malabsorption (MIM 229050), caused by mutations in the SLC46A1 gene; and cerebral folate deficiency (MIM613068), caused by mutations in the FOLR1 gene.
Three putative inherited disorders in the literature cannot be considered to be well substantiated: dihydrofolate reductase deficiency; methenyltetrahydrofolate cyclohydrolase deficiency; and cellular uptake defects.
Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most widely studied of the inherited disorders of folate metabolism. Clinical severity correlates with the degree of enzyme deficiency. The clinical symptoms vary, with developmental delay accompanied by motor and gait abnormalities, seizures, and psychiatric manifestations being described. The age of onset has ranged from the neonatal period to adulthood. The major biochemical findings are moderate homocystinuria and hyperhomocysteinemia with low or relatively normal levels of plasma methionine. Most severely affected patients have died. Pathologic findings include vascular changes similar to those seen in classical homocystinuria and demyelination presumably due to low levels of neurotransmitters or methionine in the central nervous system. Severe MTHFR deficiency is resistant to treatment; folates, methionine, pyridoxine, cobalamin, and carnitine have all been used. Betaine has the theoretical advantage of both lowering homocysteine levels and supplementing methionine levels and has been the most promising therapeutic agent to date, particularly if started immediately after birth. Nevertheless, the prognosis is generally poor.
Functional methionine synthase deficiency due to the cblE and cblG mutations is characterized by homocystinuria and defective biosynthesis of methionine. Most patients have presented in the first few months of life with megaloblastic anemia and developmental delay. At least one patient presented in early adulthood with a misdiagnosis of multiple sclerosis. The distribution of cobalamin derivatives was altered in cultured cells, with decreased levels of methylcobalamin (MeCbl) as compared with normal fibroblasts. The cblE disorder is associated with low methionine synthase activity when the enzyme assay is performed with low levels of reducing agent, whereas the cblG disorder is associated with low activity under all assay conditions. Both diseases respond to treatment with hydroxocobalamin (OHCbl).
Glutamate formiminotransferase deficiency is a heterogeneous condition associated with elevated excretion of formiminoglutamic acid, 4-amino-5-imidazole-carboxamide, and hydantoin-5-propionate. Clinical findings have varied from mental and physical retardation to massive excretion of formiminoglutamate in the absence of retardation. Therapy with folates and methionine has been described, but given that the correlation between symptoms and formiminoglutamate excretion remains uncertain, the basis for treating these patients is unclear. ...
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