Disorders of Folate Metabolism and Transport

Folates play an essential role in one-carbon methyl transfer reactions, mediating several biological processes including DNA synthesis, regulation of gene expression through methylation reactions, embryonic central nervous system development, synthesis and breakdown of amino acids, and synthesis of thymidines, purines, and neurotransmitters (Blount et al. 1997; Linhart et al. 2009; Ghoshal et al. 2006 ; Pogribny et al. 2008 ; Fournier et al. 2002). In mammals, folates are mostly derived from exogenous sources as folate is stored in the liver for few months. The biologically active folic acid derivative is 5,6,7,8-tetrahydrofolate (THF). Dietary folate is absorbed in the intestine. In the cytoplasm, interconversion of 5,10-methylene-THF and 5,10-methenyl- THF, interconversion of 5,10-methenyl-THF and 10-formyl- THF, and reaction of THF with formate to synthesize 10-formyl- THF are mediated by the MTHFD1 gene that encodes a trifunctional protein. Metabolism of 5,10- methylene-THF to 5-methyl-THF in the liver is catalyzed by methylene- THF reductase (MTHFR). 5-methyl-THF is then widely distributed in the bloodstream. The transport of 5-methyl-THF inside the cells is mediated by different transport systems that include the proton- coupled folate transporter (PCFT), the reduced folate carrier 1 (RFC1), and the two GPI-anchored receptors, folate receptor alpha (FRα) and beta (FRβ) (Matherly and Goldman 2003). The physiological form of folate, 5-methyl-THF is actively transported to the central nervous system by FRα- mediated endocytosis in choroid epithelial cells, reaching a higher concentration in the cerebrospinal fluid when compared to the serum. FRα is a high-affinity low-capacity receptor that functions at a nanomolar range of extracellular folate concentrations (Weitman et al. 1992). Thus far, seven different inherited disorders of folate metabolism are known which lead to folate deficiency including hereditary folate malabsorption, folate receptor alpha deficiency, methylenetetrahydrofolate reductase deficiency, methenyltetrahydrofolate synthetase deficiency, dihydrofolate reductase deficiency, and methylenetetrahydrofolate dehydrogenase deficiency (Watkins and Rosenblatt 2012 ; Watkins et al. 2011). Furthermore, in some cases, an additional disorder, namely, cerebral folate deficiency (CFD) caused by FOLR1 autoantibodies has also been described (Ramaekers and Blau 2004). 

This text is an extract from “Physician´s Guide to the Diagnosis, Treatment and Follow-Up of Inherited Metabolic Diseases”, Editors: Nenad Blau, Marinus Duran, K. Michael Gibson, Carlos Dionisi-Vici, Publisher: Springer 


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