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The inborn errors of folate and cobalamin (Cbl) transport and metabolism, resulting from defects in a transport system or from enzymatic deficiency, lead to decreased availability of vitamin coenzymes required for cellular metabolism. Inherited disorders of folate metabolism include those characterized by abnormal absorption and transport and those caused by enzyme deficiencies, either primary or secondary, due to Cbl coenzyme defects (Figure 19-1). Inherited disorders of Cbl metabolism are also classified as those involving absorption and transport (Figure 19-2) and those involving intracellular utilization (Figure 19-3).

FIGURE 19-1.

Summary of folate pathway. DHF, dihydrofolate; DHFR, dihydrofolate reductase; MeCbl, methylcobalamin; MTHFD1, 5,10-methylenetetrahydrofolate dehydrogenase/5,10-methenyltetrahydrofolate cyclohydrolase/10-formylteterahydrofoilate synthetase (trifunctional enzyme); MTHFR, 5,10-methylenetetrahydrofolate; MTR, methionine synthase; MTRR, methionine synthase reductase; THF, tetrahydrofolate.

FIGURE 19-2.

Summary of cobalamin absorption, transport and cellular uptake. Cbl, cobalamin; Cbl/HC, cobalamin haptocorrin complex; Cbl/IF, cobalamin intrinsic factor complex; Cbl/TC, cobalamin TC complex; Cubam, ileal receptors made up of cubilin and amnionless proteins; HC, haptocorrin; TC, transcobalamin.

FIGURE 19-3.

Intracellular cobalamin metabolism. AdoCbl, adenosylcobalamin; ATR, cobalamin adenosyltransferase, (product of MMAB gene); Cbl, cobalamin; HCFC1, products of the HCFC1 gene, co-regulators of MMACHC expression; LMBD1, ABCD4, products of the LMBRD1 and ABCD4 genes (lysosomal membrane proteins); MeCbl, methylcobalamin; MMAA, MMAA gene product MMACHC, product of the MMACHC gene; MMADHC, product of the MMADHC gene; MTRR, methionine synthase reductase; TC/Cbl, transcobalamin-cobalamin complex; TC, transcobalamin; TCblR, transcobalamin receptor; THF, tetrahydrofolate.


Folate metabolism consists of several steps, including intestinal uptake and transport across the blood–brain barrier, cellular uptake, and conversion to biologically active derivatives and their use in a variety of reactions. Derivatives of folic acid act as acceptors and donors of single-carbon units in cellular metabolism (Figure 19-1). Tetrahydrofolate (THF) and its one-carbon substituted derivatives play a role in a variety of processes, including homocysteine remethylation, purine ring biosynthesis, thymidylate synthesis, serine and glycine interconversion, and histidine catabolism.1,2,3

AT-A-GLANCE Inborn Errors of Folate and Cobalamin Transport and Metabolism

The inborn errors of folate and cobalamin (Cbl) transport and metabolism result from either defects in a transport system or from enzymatic deficiency, and they lead to decreased availability of vitamin-derived coenzymes. Biochemical features depend on which part of the pathway is affected. Functional deficiencies of methionine synthase (folate pathway) lead to homocystinuria and hyperhomocysteinemia, whereas functional deficiencies of methylmalonyl-CoA mutase lead to methylmalonic aciduria and acidemia. Combined functional deficiencies lead to both biochemical abnormalities. Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inborn error of folate metabolism, and the cblC disorder is the most common defect of Cbl metabolism. When the folate pathway is ...

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