Methylenetetrahydrofolate reductase deficiency

Rozen, R. (1996) Molecular genetics of methylenetetrahydrofolate reductase deficiency. Journal of Inherited Metabolic Disease. 19, 589-594. 

Goyette R et al, Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/ phenotype correlations in severe methylenetetrahydrofolate reductase deficiency, Am J Hum Genet 1995 56(5) 1052-1059. 

I I Kluijtmans LA, et al, Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency. Eur J Hum Genet 1998 6(3) 257-265. 

Brouwer OF, Onkenhout W, Edelbroek PM, et al Increased neurotoxicity of arsenic in methylenetetrahydrofolate reductase deficiency. Clin Neurol Neurosurg 94 307-310, 1992... 

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]. 

Table 10.6. Methylenetetrahydrofolate reductase deficiency (approx. 50 patients)...

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-...

Fig. 6 Methyl trap hypothesis 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetiahy-drofolate in an irreversible reaction. When vitamin Bn is deficient, methyl groups are trapped as 5-methyltetrahydrofolate, resulting in decreased substrates for DNA synthesis and neural lipid methylation. MTHFR, methylenetetrahydrofolate reductase DHFR, dihydrofolate reductase MS, Methionine synthase TS, thymidylate synthase SAM, S-adenosyl-methionine dUMP, deoxyuridine 5 -monophosphate dTTP, deoxythymidine 5 -monophosphate...

Kluijtmans LA, et al. Homozygous cystathionine beta-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. Blood. 1998 91(6) 2015-8. 

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]. 

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. ... 

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