When folate is deficient , maintenance of methylation of histones and cytosine may be inadequate . 12 Low levels of plasma folate have been correlated with shorter telomere length in older males . 12 It has been suggested that folate deficiency might induce telomere attrition and / or telomere dysfunction by molecular mechanisms , such as the metabolism of DNA , uracil misincorporation within the telomere , and inefficient binding of the shelterin proteins to the telomeric DNA . 12
Pregnancy has been recognised as a time when folate requirements are increased to sustain the demand for rapid cell replication and growth of foetal , placental , and maternal tissue , relating to the critical role it plays in DNA , RNA , and protein synthesis . 11 A deficiency of folate during preconception and during early pregnancy
9 , 11 , 14 , 32
can lead to neural tube defects . Maintaining an adequate folate status throughout pregnancy is important not only for the mother ’ s health but also for the developing infant . 11
Mthfr Polymorphism
5,10-methylene tetrahydrofolate reductase ( MTHFR ), methionine synthase ( MTR ), and methionine synthase reductase ( MTRR ) are critical enzymes in the metabolism of folate . 15 5,10-methylenetetrahydrofolate reductase ( MTHFR ) catalyses the irreversible reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate ( 5- MTHF ), 15 , 22 , 26 , 33-35 the primary form of folate . 22 , 25 This conversion produces a methyl donor for the conversion of homocysteine to methionine 15 , 21 , 22 and S-adenosylmethionine ( SAMe ). 36 It is catalysed by methionine synthase , where vitamin B12 is a cofactor , 15 , 21 in the presence of either reduced flavin adenine dinucleotide ( FAD ) ( derived from vitamin B2 ) or reduced nicotinamide adenine dinucleotide ( NAD ) ( derived from vitamin B3 ). 33 Furthermore , homocysteine can be converted to cysteine via the vitamin B6-dependent trans-sulphuration pathway . 21 MTHFR is essential for the metabolism of singlecarbon units 15 , 22 , 35 ( transmethylation reactions ), such as the methylation of DNA and synthesis of purine and pyrimidine , the process of covalent addition of a methyl group to cytosine . 37 The occurrence of polymorphisms in enzyme-encoding genes of the folate pathway provides a functional impact on metabolism . 15 In people with an MTHFR polymorphism , there is a lack of response to short-term folate supplementation . 27 Folate status should be monitored .
The MTHFR gene has been identified as possessing 14 common or rare single nucleotide polymorphisms that are associated with enzymatic deficiency . Among them , C677T ( rs1801133 ) and A1298C ( rs1801131 ) are the most commonly occurring and reported polymorphisms that may reduce the
15 , 22 , 35
MTHFR activity in various degrees . Altered MTHFR activity is the most common inherited disorder of folate metabolism , where there is an impairment in the ability to process and metabolise folate effectively . 18 , 38 All people have two MTHFR genes , one inherited from each parent . Some people have a genetic mutation in one or both of their MTHFR genes . People with mutations in one MTHFR gene are called “ heterozygous ” for the MTHFR mutation , whereas a person is “ homozygous ” for the mutation when mutations are present in both genes . 38 In people with C677T polymorphism , homozygotes have 25-30 % enzyme activity , 20 , 22 while heterozygotes have 65-67 % of MTHFR enzyme activity . 20 , 22 In people with the MTHFR 1298 CC genotype , there is approximately
22 , 39
60 % MTHFR activity in homozygotes and approximately 83 % enzyme activity in heterozygotes . 22 There is also compound heterozygous , where there is one mutated allele on both the 677 and 1298 base position , accompanied by approximately 48 % enzyme activity . 22
As consequences of a polymorphism of MTHFR , reduction of MTHFR enzymatic activity would cause impaired methylation as well as deficiency of folate . 22 An MTHFR polymorphism represents a potential risk factor for numerous health conditions and diseases , including , but not limited to , cardiovascular disease , 15-17 coronary artery disease , 17 peripheral arterial disease , 17 , 40 hypertension , 41 ischaemic or haemorrhagic stroke , 21 thrombosis , 15 hyperhomocysteinaemia , 15 , 17 , 18 diabetes , 15 polycystic ovary syndrome , 42 cervical dysplasia , 43 15 , 19
neural tube defects , pregnancy complications , 15 , 19 recurrent pregnancy loss , 15 hypertension in pregnancy , 44 birth defects , 16 infertility , 15 depression , 20-22 risk of postmenopausal depression , 22 schizophrenia , 20-22 bipolar disorder , 20-22 autism spectrum , 22 attention deficit hyperactivity disorder ( ADHD ), 22 neurological symptoms , 45 inflammatory bowel disease , 46 non-alcoholic fatty liver disease , 47 pain , 48 fatigue , 48 sleeplessness , 48 osteoporosis , 49 osteopaenia , 49 fracture risk , 50 migraine , 21 , 48 psoriasis , 15 , 51 cancer risk , 15 breast cancer risk , 15 colorectal cancer , 29 , 52 and severity of atrophic gastritis , 15 gastric cancer , 21 , 53 and inflammation . 35 C677T polymorphism of MTHFR has an influence on symptoms of schizophrenia . 22 Men with a C677T polymorphism have a risk for altered spermatogenesis . 9 Folic acid supplementation has been demonstrated as an aggravating factor in men carrying a C677T polymorphism . 9
Conclusion
Folate is an essential water-soluble vitamin . It is essential for numerous functions in the body , such as normal healthy growth and development and playing a critical role in cell growth and division . Some of the symptoms of folate deficiency include megaloblastic anaemia , peripheral neuropathy , cardiovascular disease , hyperhomocysteinaemia , depression , cognitive dysfunction and decline , among others . An MTHFR polymorphism affects folate metabolism and represents a potential risk factor for numerous health conditions and diseases . For people presenting with various health conditions associated with folate metabolism and deficiency , a polymorphism of MTHFR should be considered . Appropriate management , along with active folate 5-MTHF and cofactors , should be utilised .
26 | vol29 | no1 | JATMS