B₁₂/Folate Problem set

Question 8: B₁₂deficiency

Abnormal findings in patients with a vitamin B₁₂ deficiency may include:

A. methylmalonic aciduria
B. homocystinuria
C. megaloblastic anemia
D. hypersegmented nuclei in leucocytes
E. sensory neuropathy

Tutorial

B12Uptake Animation (3.4MB)

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This module has now come full circle from the first question ñ lack of B₁₂ traps folate in the N⁵-methyl form. For the affected patient, this means that the functions of both B₁₂ and folate are disrupted. To explain the symptoms:

1)	methylmalonic aciduria - This is perhaps the only real way to distinguish a B12 deficiency from a folate deficiency (biochemically, at least). The enzyme methylmalonyl CoA mutase requires B12 (but not folate) as a cofactor, so its reactant (methylmalonyl CoA) accumulates only in a B12 deficiency. Incidently, the CoA group is stripped off for other uses and free methylmalonic acid is what leaves the cell for excretion in the urine.
2)	homocystinuria - This and the next three symptoms can all be found in both B12 and folate deficiencies. This particular symptom is perhaps the easiest to explain, since the enzyme methionine synthase requires a form of both B12 and folate. This is also where the folate trap occurs, since N5-methyl THF can only return to the folate pool by donating its methyl to B12. Obviously this cannot occur when there is no B12 around. [To be continued in 5) below...]
3)	megaloblastic anemia - One of the main reasons for this is the requirement of folate derivatives for DNA/RNA synthesis. This shows up in reticulocytes because these cells must be constantly replenished via new synthesis of DNA and RNA. Exactly why impaired DNA synthesis causes these cells to be "megaloblastic" is beyond the scope of this discussion.	Megaloblastic anemia
4)	hypersegmented nuclei in leucocytes - This finding is presumably also related to impaired DNA synthesis. Again, the only part of the mechanism we will consider here is the requirement for folate derivatives in DNA/RNA synthesis.
5)	sensory neuropathy - Continuing the story from 2), the methyl group from N5-methyl THF is supposed to pass on to form the following compounds (in order): methyl-B12 -> methionine -> S-adenosyl methionine (SAM) -> neural membrane lipids (see overview figure or tutorial figure for question # 3 for a depiction of this). Obviously, the lack of B12 nips this in the bud pretty effectively! Myelin sheaths are particularly affected by this interruption in the supply of membrane lipids, presumably due to their high rate of turnover.