Methylenetetrahydrofolate reductase defect

Fig. 2.2.1 Outline of homocysteine metabolism in man. BMT Betaine methyltransferase, cblC cobalamin defect type C, cblD cobalamin defect type D, GNMT def glycine N-methyltransferase deficiency, MAT methionine adenosyl transferase, MeCbl methylcobalamin, Met Synth methionine synthase, MTHFR methylenetetrahydrofolate reductase, SAH Hyd dc/S-adenosylhomocys-...

Melnick, M. and Marazita, M. L. (1998). Neural tube defects, methylenetetrahydrofolate reductase mutation, and north/south dietary differences in China. J. Craniofac Genet. Dev. Biol. 18(4), 233-235. 

Figure 8 Extended folate metabolism, including compartmentation. MTHFR, methylenetetrahydrofolate reductase SHMT, serine hydroxymethyltransferase BHMT, betaine homocysteine methyltransferase, MAT, methionine adenosyltransferase SAH-hydrolase, S-adenosylhomocysteine hydrolase MT, methyltransferase CBS, cystathionine /i-synthase SAM, S-adenosylmethionine SAH, S-aden-osylhomocysteine THF, tetrahydrofolate and 5-MeTHF, 5-methyltetrahydrofolate. (Reproduced from Van der Put etal. (2001) Folate, homocysteine and neural tube defects An overview. Experimental Biology and Medicine 226 243-270.)...

Kang SS, Passen EL, Ruggie N, Wong PW, Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1993 88 1463-9. 

Homocyslinuiia is an autosomal recessive condition caused by a deficiency of the enzyme, cystalhionine-p-synthase (CBS), which results in the accumulation of homocysteine and methionine and a deficiency of cystathionine and cysteine. There are other disorders to consider when an elevated homocysteine concentration is identified. These disorders include vitanun Bn uptake or activation defects, which may or may not have associated elevated methylmalonic acid, severe 5,10-methylenetetrahydrofolate reductase deficiency, and 5-methyl-THF-homocysteine meth-yltransferase deficiency. The latter two are typically associated with an elevated homocysteine, but low methionine concentrations, so it is relatively easy to disaiminate these conditions from homocystinuria. It is also important to consider that nongenetic causes of hyperhomocyste-inemia exist, such as dietary deficiencies, end-stage renal disease, and administration of several drugs [6]. 

The deficiencies of cystathionine )5-synthase (CBS), sulfite oxidase, and methylenetetrahydrofolate reductase (MTHFR) may all result in central nervous system dysfunction, in particular mental retardation [1-3]. Defects of CBS and sulfite oxidase both cause dislocated lenses of the eyes, but the phenotypes are different otherwise. The manifestations of CBS deficiency, the most common of these disorders, and MTHFR deficiency range from severely affected to asymptomatic patients both may cause vascular occlusion. Deficiency of sulfite oxidase is clinically uniform, but genetically heterogeneous, and functional deficiency of the enzyme can result from several inherited defects of molybdenum cofactor biosynthesis [2, 4]. Hereditary folate malabsorption and defects of cobalamin transport (transcobala-min II deficiency) or cobalamin cofactor biosynthesis (cblC-G diseases) may cause megaloblastic anemia, in addition to CNS dysfunction [3, 5, 6]. 

Fig. 10.1. Defects of transmethylation (methioninehomocysteine), transsulfuration (methionine sulfate), and remethylation (homocysteine - methionine) enzymes of sulfur amino acid metabolism 10.1, methionine adenosyltransferase 10.2, cystathionine ) -synthase 10.3, y-cystathionase 10.4, sulfite oxidase 10.5, molybdenum cofactor 10.6, methylenetetrahydrofolate reductase 10.7 and 10.8, methionine synthase.

The metliylenetetraliydrofolate reductase enzyme reduces 5,10-methylenetetrahydrofolate to form 5-methyltetrahy-drofolate, which provides methyl groups necessary for homocysteine remetliylation to methionine. The severity of the enzyme defect and of clinical symptoms varies considerably. Completely absent enzyme activity results in neonatal apneic episodes, myoclonus leading to coma, and death, whereas partial deficiency may result in mental retardation and seizures. Premature cardiovascular disease or peripheral neuropathy could be the only manifestation. A common polymorphism (677C>T) is associated with enzyme thermal lability and mild elevation of homocysteine in the presence of folate insufficiency, implicating a risk for both vascular disease and neural tube defects. ... 

---