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Table of Contents<\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5888″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 1. Folate metabolism, related enzymes, and transporters.<\/b> Folate metabolism (yellow) is at the juncture of two major metabolic cycles: DNA\/RNA cycle (pink) and methylation cycle (green). This set of reactions, collectively known as folate-mediated one-carbon<\/strong> (1-C<\/strong>) metabolism, are essential for the production of, for example: (i)<\/strong> thymidine and purine precursors of nucleic acids required for DNA and RNA synthesis and repair;<\/strong> (ii)<\/strong> several amino acids required for protein synthesis<\/strong>, including serine, glycine, and methionine; and (iii)<\/strong> the S<\/em>-adenosylmethionine (SAM<\/strong>), the universal methylation agent<\/strong>, which an important methyl donor for the methylation of DNA, proteins, as well as neurotransmitters. Various folate derivatives are essential components of cell growth and survival<\/strong>, as a result, changes in folate status can disrupt normal cellular processes.<\/strong> [AHCY<\/strong>, S<\/em>-adenosylhomocysteine hydrolase; AICART<\/strong>, 5-amino-4-imidazolecarboxamide ribonucleotide transformylase; DHF<\/strong>, dihydrofolate; DHFR<\/strong>, dihydrofolate reductase; dTMP<\/strong>, deoxythymidine monophosphate; dUMP<\/strong>, deoxyuridine monophosphate; FR<\/strong>, folate receptor; GART<\/strong>, \u03b2-glycinamide ribonucleotide transformylase; MAT<\/strong>, methionine adenosyl transferase; MS<\/strong>, methionine synthase; MSR<\/strong>, methionine synthase reductase; MT<\/strong>, methionine transferase; MTHFD<\/strong>, methylenetetrahydrofolate dehydrogenase; MTHFR<\/strong>, methylenetetrahydrofolate reductase; MTHFS<\/strong>, methylenetetrahydrofolate synthase; PCFT<\/strong>, proton coupled folate transporter; RFC1<\/strong>, reduced folate carrier 1; SAH<\/strong>, S-adenosylhomocysteine; SAM<\/strong>, S<\/em>-adenosylmethionine; SHMT<\/strong>, serine hydroxymethyltransferase; THF<\/strong>, tetrahydrofolate; TYMS<\/strong>, thymidylate synthase. [Adapted and modified from: Alam et al., 2020 Trends Pharmacol Sci. May;41(5):349-361<\/em>.]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”introduction”][vc_column][vc_custom_heading text=”Introduction”][vc_column_text single_style=””]<\/p>\n Folate (vitamin B9<\/sub>) and cobalamin (vitamin B12<\/sub>) are essential for early brain development and function<\/strong>; and play a crucial role in the maintenance of central nervous system (CNS) homeostasis<\/strong> [1]. \u2018Homeostasis\u2019 is a self-regulating process by which biological systems maintain stability while adjusting to changing external conditions. Deficiency of folate and\/or cobalamin during pregnancy can cause severe malformations in the CNS such as neural tube defects<\/strong> (NTDs<\/strong>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n After birth, folate and\/or cobalamin deficiency can cause the following clinical manifestations, for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The folate and the homocysteine metabolic pathways interact at a central step where 5-methyltetrahydrofolate<\/strong> (5-methylTHF<\/strong>) donates its methyl group to homocysteine (Hcy<\/strong>, nonproteinogenic amino acid) to produce methionine (MET<\/strong>, proteinogenic amino acid) and tetrahydrofolate (THF<\/strong>, active form of folate). Methylcobalamin<\/strong> (MeCbl<\/strong>) and folate interact at this critical step.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Both micronutrients have a crucial role in de novo<\/em> synthesis of DNA or RNA<\/strong> and in biosynthesizing and delivering S<\/em>-adenosylmethionine (SAM), the universal methyl donor<\/strong>. Until now, severe and mild inherited metabolic disorders<\/strong> (IMD<\/strong>) in folate and cobalamin pathways have been described. The two groups of disorders share some commonalities, nevertheless, differ in the molecular mechanisms, metabolic dysregulation, and disease management.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n This blog summarizes selected disorders, including rare and common mutations that govern folate absorption, transport, or dependent enzymes. We will also briefly highlight the clinical significance of folate genetic defects in relation to neurodevelopmental disorders. In the upcoming blog, we will be presenting the clinical implications of cobalamin genetic defects pertaining to neurodevelopmental disorders.<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”u-orange”]<\/p>\n Most importantly, when mutations are discovered early enough<\/em><\/strong>, many of the described disorders could be easily treatable by B vitamin supplementation<\/em><\/strong>, which often prevents or reverses the clinical manifestation of the disease [2]. Consequently, the screening for mutations is recommended and should be carried out promptly and as early as possible,<\/u> for example:<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-1″][vc_column][vc_custom_heading text=”Genetic Defects in Folate Pathway”][vc_column_text single_style=”” el_class=”h3-16806″]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Folate metabolism involves absorption, transport, and intracellular reactions that result in the formation and interconversion of folate coenzymes.<\/strong><\/em> (see Figure 1; Table 1-2<\/strong>). Reduced folates act as coenzymes, which serve as one-carbon (1-C) donor or acceptor units in a variety of biochemical reactions, such as (i<\/strong>) methionine synthesis, (ii<\/strong>) histidine catabolism, (iii<\/strong>) purine ring synthesis, (iv<\/strong>) serine-glycine interconversion, and (v<\/strong>) thymidylate synthesis (a key reaction in pyrimidine synthesis). Here is the summary of folate pathway [3]:<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”u-orange”]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5886″ img_size=”full”][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_single_image image=”5887″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 2. Metabolic roles of folate coenzymes.<\/strong> [FH4<\/sub><\/strong>, tetrahydrofolate \u2013 THF; Hcy, homocysteine; MET, methionine; GLY, glycine; HIS, histidine; SER, serine; TRY, tyrosine; SAM, S<\/em>-adenosylmethionine; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; C-5, carbon 5; CO2<\/sub>, carbon dioxide]<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”h3-16806″]<\/p>\n Majority of naturally occurring dietary folates contain a polyglutamate tail<\/em><\/strong> that must be hydrolyzed into monoglutamate<\/em><\/strong> form prior to gastrointestinal absorption and transport. Dietary folates are metabolized into tetrahydrofolate (THF<\/strong>) derivatives during transit through the intestinal mucosa (in rodents) and\/or the liver (in humans). Folates in the liver are either, for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n 5-methyl THF is the predominant form of folate that circulates in the blood.<\/strong><\/em> Unbound circulating folates are delivered to the kidney for reabsorption. Folates are anionic at physiological pH; they cannot cross biological membranes through diffusion and must depend on specific transport systems for their permeability into the cells and across various epithelia. Thus far, three major folate transport pathways<\/strong><\/em> have been characterized in human tissues:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Proposed cellular localization of folate transport pathways in select tissues is illustrated and described in more detail in the following blogs. (cf. previous blogs entitled as: (i)<\/strong> \u2018Folate Transport Systems \u2013 I: Transmembrane Carriers<\/a>,\u2019 <\/em><\/u>(ii)<\/strong> \u2018Folate Transport Systems \u2013 II: Folate Receptors<\/a>,\u2019<\/em><\/u> (iii)<\/strong> \u2018Intestinal Absorption of Dietary Folates<\/a>,\u2019<\/em><\/u> (iv)<\/strong> \u2018Folate Homeostasis and Tissue Accumulation: What You Need to Know<\/a>. \u2019<\/em> )<\/u>.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-2″][vc_column][vc_custom_heading text=”Inherited Disorders of Folate Transport and Metabolism”][vc_column_text single_style=””]<\/p>\n Several inherited disorders of folate metabolism and transport have been described [4] (see Table 2<\/strong>), for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Besides, several putative inherited disorders related to folate metabolism are described in the literature, for instance:<\/p>\n [\/vc_column_text][vc_single_image image=”5885″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 3. Common genetic polymorphisms in folate-metabolizing enzymes.<\/strong><\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-3″][vc_column][vc_custom_heading text=”Neurological Consequences of Folate Deficiency”][vc_column_text single_style=””]<\/p>\n Defective or impaired folate transport is associated with various types of neurological and neurodevelopmental complications. Here we will briefly discuss five neurological disorders that have been linked to genetic defects in folate pathways and consequently to folate deficiency.<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”h3-16806″]<\/p>\n Folate deficiency in the CNS, denoted by low-levels of cerebrospinal fluid (CSF<\/strong>) 5-methyl-THF concentrations, has been implicated in disorders involving defects in folate transport systems. Hereditary folate malabsorption is caused by impaired folate transport across various epithelia such as the intestine and choroid plexus, resulting from the mutations in the SLC46A1 gene<\/strong><\/em> [5-6]. It manifests a few months after birth, causing affected newborns to develop, for example:<\/p>\n Further symptoms include, for instance:<\/p>\n<\/li>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n This disorder has been reported in about 30 patients and mostly females are affected.<\/strong><\/em> Treatment for this disorder involves parenteral administration of 5-formyl-THF<\/strong> (folinic acid<\/strong>). While this treatment approach is sufficient to correct for peripheral symptoms such as anemia, the accompanying neurological defects are not easily addressed since patients require supraphysiological folate concentrations in blood to be able to increase CSF folate. As a result, increasing folate permeability into the brain or finding alternative routes for brain folate transport can lead to significant therapeutic benefits.<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”h3-16806″]<\/p>\n Cerebral folate deficiency (CFD) is a neurological syndrome<\/em><\/strong> caused by, for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The disease is characterized by impaired folate transport across the choroid plexus, but not in the intestine<\/strong><\/em> [7]. Therefore, when dietary folate intake is sufficient, patients show normal concentrations of serum folate, but very low CSF 5-methyl-THF (<5 nM)<\/strong><\/em>. Patients appear normal at birth and throughout infancy and only exhibit the following neurological symptoms at 2 \u2013 3 years of age, for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The late onset of CFD compared with hereditary folate malabsorption could be due to the presence of normal blood folate levels, which allow for folate transport at the blood-brain barrier<\/strong><\/em> (BBB<\/strong><\/em>). However, in hereditary folate malabsorption, the presence of severe folate deficiency may limit the protective effect of the BBB.<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”u-orange”]<\/p>\n\n
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(I) Normal Folate Transport and Metabolism<\/h3>\n
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\neither 10-formyl-tetrahydrofolate (10-formyl-THF<\/strong>) or 5,10-methylene-THF.<\/li>\n
\nTable 1. Enzymes involved in the acquisition of single-carbon (1-C) units. <\/b>[FH4<\/sub>, <\/b>tetrahydrofolate – THF]<\/p>\n(II) Folate Transport Pathways<\/h3>\n
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(1) Hereditary folate malabsorption<\/h3>\n
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(2) Cerebral folate deficiency (CFD)<\/h3>\n
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