[MCQs] Megaloblastic Anemias – Part 2

Primary function of folate compounds is to transfer single carbon moieties such as methyl and formyl groups to various organic compounds. The sources of these 1-carbon moieties is usually serine which reacts with tetrahydrofolate to produce glycine and N5,10 methylenetetrahydrofolate.

Conjugases (-glutamyl carboxypeptidases) in the gut lumen convert polyglutamates to monoand diglutamates, which are readily absorbed in the proximal jejunum

Folate is essential for the de novo synthesis of purines, deoxythymidylate monophosphate (dTMP), and methionine, serving as an intermediate carrier of 1-carbon fragments used in the biosynthesis of these compounds.

Active form of folate is tetrahydrofolate (THF).

Folate coenzymes are essential in Formate activation, Purine synthesis (formation of glycinamide ribonucleotide and formylation of aminoimidazole carboxamide ribonucleotide (AICAR), Pyrimidine synthesis (Methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP), Amino acid interconversion (serine - glycine interconversion, homocysteine to methionine and forminoglutamic acid to glutamic acid in histidine catabolism)

5,10-methylene-THF is oxidized to DHF (dihydrofolate). Enzyme DHF reductase converts DHF to THF. Methotrexate, pyrimethamine, and trimethoprim inhibit DHF reductase that prevents formation of active THF coenzymes from DHF.

Megaloblastic anemias are caused by impaired DNA synthesis in cells with rapid turnover like hematopoietic precursors & gastrointestinal epithelial cells. Cell division becomes sluggish but cytoplasmic development progresses normally, so megaloblastic cells tend to be large, with an increased ratio of RNA to DNA. Megaloblastic erythroid progenitors are destroyed in marrow whose cellularity is increased but production of RBC is decreased (ineffective erythropoiesis).

In deficiencies of either folate or cobalamin, there is failure to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), the precursor of dTTP because folate is needed as the coenzyme 5,10-methylene - THF polyglutamate for conversion of dUMP to dTMP.

THF acquires 1-carbon fragment from serine which is converted to glycine. For purine synthesis, the 1-carbon fragment is first oxidized to the level of formic acid, then transferred to substrate. For methionine synthesis, a cobalamin-requiring reaction, the 1-carbon fragment is first reduced to the level of a methyl group, then transferred to homocysteine. In these reactions the cofactor is released as THF, which can immediately participate in another 1-carbon transfer cycle. During the production of dTMP from dUMP, the 1-carbon fragment is reduced from formaldehyde to a methyl group during transfer reaction. Hydrogen atoms used for this reduction come from the cofactor, which is released, not as THF, but as dihydrofolate (DHF). To participate further in the 1-carbon transfer cycle, DHF has to be re-reduced to THF, a reaction catalyzed by dihydrofolate reductase.

Methylmalonyl CoA isomerization requires adocobalamin, and the methylation of homocysteine to methionine requires both methylcobalamin and 5-MTHF.

Most frequently affected tissue in cobalamin and folate deficiencies is the bone marrow followed by the epithelial cell surfaces of the mouth, stomach, and small intestine and the respiratory, urinary, and female genital tracts.

0.4 mg daily of folic acid provides protective effect against NTDs at conception. Folic acid (400 µg daily, should be given as a supplement before and throughout pregnancy. In women who have had a previous fetus with a neural tube defect, 5 mg daily is recommended when pregnancy is contemplated and throughout the subsequent pregnancy.

To prevent neural tube defects, folic acid supplements must be started at the time of conception and in the first 12 weeks of pregnancy. It reduces the incidence of neural tube defects (NTDs) (anencephaly, meningomyelocele, encephalocele, and spina bifida) in the fetus by 70%

Reduced activity of 5,10-methylene-THF reductase (MTHFR)

Severe homocystinuria may be due to deficiency of methionine synthase, MTHFR, or cystathionine synthase. Homocystinuria is a rare metabolic defect in the conversion of homocysteine to cystathionine. Folate deficiency is due to excessive utilization because of compensatory increased conversion of homocysteine to methionine.

Children with deficiency of enzyme methionine synthase, MHTFR or cystathionine synthase have an increased risk of vascular disease.

Meta-analysis has suggested that folic acid supplementation reduces the risk of stroke by 18%

Prophylactic folic acid in pregnancy reduces the subsequent incidence of acute lymphoblastic leukemia (ALL) in childhood.

The clinical features of cobalamin deficiency involve the blood, the gastrointestinal tract, and the nervous system.

All of the above

Initial pathology is demyelination, followed by axonal degeneration & eventual neuronal death

Sites of involvement include peripheral nerves; the spinal cord, where the posterior and lateral columns undergo demyelination; and the cerebrum itsel