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  • Updated 05.23.2023
  • Released 11.06.2012
  • Expires For CME 05.23.2026

Folate deficiency



Folate deficiency is characterized by megaloblastic anemia and less frequently by neurologic problems, usually forgetfulness and irritability, but sometimes by neuropathy or myelopathy. Maternal folate deficiency early in pregnancy is also a major risk factor for fetal neural tube defects. Folate deficiency may arise as the result of dietary deficiency or generalized malabsorption, such as in sprue or celiac disease. A small number of affected individuals have hereditary folate malabsorption due to mutations in the SLC46A1 gene, which encodes the proton-coupled folate transporter responsible for folate transport across the intestinal epithelia and the blood-brain barrier.

Key points

• Derivatives of folic acid are required for nucleic acid and amino acid metabolism.

• Folate deficiency results in megaloblastic anemia and neurologic problems.

• Folate deficiency is observed in individuals with insufficient dietary folate, decreased uptake due to intestinal disease, or alcoholism.

• Folic acid fortification of cereal grains in the United States and some other countries means that dietary folate deficiency is becoming less common.

• A small number of patients with hereditary folate malabsorption due to mutations in the SLC46A1 gene have been identified.

Historical note and terminology

Dietary folate deficiency was first reported in 1931 by English physician Lucy Wills (1888–1964), who described megaloblastic anemia, identical to that seen in patients with pernicious anemia, among nutritionally deficient women at a hospital in India (158; 07; 151; 118; 17; 84).

English physician Lucy Wills (1888-1964)

In 1931, Wills described megaloblastic anemia, identical to that seen in patients with pernicious anemia, among nutritionally deficient women at a hospital in India. This nutritional deficiency was later shown to be due to fola...

Subsequent studies resulted in isolation of the missing dietary factor and determination of its structure (06). The first patient with a genetic disorder resulting in specific inability to absorb dietary folate was described in 1961 (91).

The classic study of experimental human folate deficiency was self-experimentation by American hematologist Victor Herbert (1927-2002) (66; 61). Decreased serum folate concentrations could be detected after 3 weeks of folate deprivation. Hypersegmented neutrophils were the first evident hematological anomaly, after 7 weeks of deprivation. Macrocytosis of circulating red cells was observed after 18 weeks. Anemia developed rapidly after 4.5 months on a folate-deficient diet. In this case, leukopenia and thrombocytopenia did not occur. Sleeplessness and forgetfulness occurred during the fourth month of folate deprivation, and irritability occurred during the fifth month; this latter problem became progressively worse. All of these manifestations of folate deficiency responded rapidly to oral therapy with folic acid.

Folic acid (also called pteroylglutamic acid) is a stable molecule that is not itself active metabolically.

It must be converted within cells to a number of reduced derivatives that are required for 1-carbon transfer reactions involved in cellular intermediary metabolism. The term “folate” refers to folic acid and its derivatives.

The term “folate” is frequently used in a generic sense to designate any member of the pteroylglutamate family or their derivatives, which have various reduction levels of the pteridine ring, as well as different numbers of glutamate residues and 1-carbon substitutions (147). The term, therefore, includes folic acid, the biologically active form tetrahydrofolate (THF), the main circulating form 5-methyltetrahydrofolate (5-MTHF), folinic acid (5-formyltetrahydrofolate; leucovorin), and others.

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