Folate deficiency

Douglas J Lanska MD FAAN MS MSPH (Dr. Lanska of the Great Lakes VA Healthcare System and the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.)
Originally released November 6, 2012; last updated January 29, 2017; expires January 29, 2020

This article includes discussion of folate deficiency and folate deficiency associated neural tube defects. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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 1930 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 (Wills 1931; Anonymous 1964; Wadsworth 1988; Roe 1978; Bastian 2008; Lanska 2010).

Image: English physician Lucy Wills (1888–1964)
Subsequent studies resulted in isolation of the missing dietary factor and determination of its structure (Angier et al 1946). The first patient with a genetic disorder resulting in specific inability to absorb dietary folate was described in 1961 (Luhby et al 1961).

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

Image: Folic acid (chemical structure, skeleton formula)
Image: Three-dimensional ball-and-stick model of folic acid
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.

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