Chapter 100. Megaloblastic Anemias (Part 5)

An underlying maternal folate metabolic abnormality has also been postulated. One abnormality has been identified: reduced activity of the enzyme 5,10-methylene-THF reductase (MTHFR) (Fig. 100-1) caused by a common 677CÆT polymorphism in the MTHFR gene. In one study, the prevalence of this polymorphism was found to be higher in the parents of NTD fetuses and in the fetuses themselves: homozygosity for the TT mutation was found in 13% compared with 5% in control subjects. The polymorphism codes for a thermolabile form of MTHFR. The homozygous state results in a lower mean serum and red cell folate level compared with...
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Chapter 100. Megaloblastic Anemias (Part 5) Chapter 100. Megaloblastic Anemias (Part 5) An underlying maternal folate metabolic abnormality has also beenpostulated. One abnormality has been identified: reduced activity of the enzyme5,10-methylene-THF reductase (MTHFR) (Fig. 100-1) caused by a common677CÆT polymorphism in the MTHFR gene. In one study, the prevalence of thispolymorphism was found to be higher in the parents of NTD fetuses and in thefetuses themselves: homozygosity for the TT mutation was found in 13%compared with 5% in control subjects. The polymorphism codes for a thermolabileform of MTHFR. The homozygous state results in a lower mean serum and redcell folate level compared with control subjects, as well as significantly higherserum homocysteine levels. Tests for mutations in other enzymes possiblyassociated with NTDs, e.g., methionine synthase or serine–glycinehydroxymethylase, have been negative. Autoantibodies to folate receptors have, however, been detected in 9 of 12women who were or had been pregnant with a fetus with a NTD, but in only 2 of20 control women. Antiserum to folate receptors results in resorption or multipledevelopmental abnormalities in mouse embryos. It is possible, therefore, that theassociation of antibodies to maternal folate receptors and NTDs reflects a causalrelation. Cardiovascular Disease Children with severe homocystinuria (blood levels ≥100 µmol/L) due todeficiency of one of three enzymes, methionine synthase, MHTFR, orcystathionine synthase (Fig. 100-1), suffer from vascular disease, e.g., ischemicheart disease, cerebrovascular disease, or pulmonary embolus as teenagers or inyoung adulthood. Lesser degrees of raised serum homocysteine and low levels ofserum folate have been found to be associated with cerebrovascular, peripheralvascular, and coronary heart disease and with deep vein thrombosis. Prospectiverandomized trials of lowering homocysteine levels with supplements of folic acid,vitamin B12, and vitamin B6 against placebo over a 5-year period in patients withvascular disease or diabetes have not, however, shown a reduction of majorcardiovascular events, nor have these supplements reduced the risk of recurrentcardiovascular disease after an acute myocardial infarct. It is possible that thesetrials were not sufficiently powered to detect a small (e.g., 10%) benefit or thatsome other underlying factor is responsible for both the vascular damage and theraised homocysteine. Alternatively, the beneficial effects of loweringhomocysteine were offset in these trials by the vitamins stimulating endothelialcell proliferation. The results of longer and larger trials are needed to resolve theseuncertainties. Malignancy Prophylactic folic acid in pregnancy has been found to reduce thesubsequent incidence of acute lymphoblastic leukemia (ALL) in childhood. Asignificant negative association has also been found with the MTHFR677(C→T)polymorphism and leukemias with mixed lineage leukemia (MLL) translocations,but a positive association with hyperdiploidy in infants with ALL or acute myeloidleukemia or with childhood ALL. A second polymorphism in the MHTFR gene,A1298C, is also strongly associated with hyperdiploid leukemia. There are variouspositive and negative associations between polymorphisms in folate-dependentenzymes and the incidence of adult ALL. The C677T polymorphism is thought tolead to increased thymidine pools and better quality of DNA synthesis byshunting 1-carbon groups towards thymidine and purine synthesis. This mayexplain its reported association with a lower risk for colorectal cancer. Othertumors that have been associated with folate polymorphisms or status includefollicular lymphoma, breast cancer, and gastric cancer. Neurologic Manifestations Cobalamin deficiency may cause a bilateral peripheral neuropathy ordegeneration (demyelination) of the posterior and pyramidal tracts of the spinalcord and, less frequently, optic atrophy or cerebral symptoms. The patient, more frequently male, presents with paresthesias, muscleweakness, or difficulty in walking and sometimes dementia, psychoticdisturbances, or visual impairment. Long-term nutritional cobalamin deficiency ininfancy leads to poor brain development and impaired intellectual development.Folate deficiency has been suggested to cause organic nervous disease but this isuncertain, although methotrexate injected into the cerebrospinal fluid may causebrain or spinal cord damage. An important clinical problem is the nonanemic patient with neurologic orpsychiatric abnormalities and a low or borderline serum cobalamin level. In suchpatients, it is necessary to try to establi ...