B12 releases folate from its methylated form
Expansion
B12 has exactly two reactions in humans
- Methionine synthase: homocysteine to methionine, transferring a methyl group from methyltetrahydrofolate, thereby regenerating usable folate
- Methylmalonyl-CoA mutase: methylmalonyl-CoA to succinyl-CoA
The methyl trap hypothesis explains the shared haematological picture. Without B12, folate becomes stuck as methyltetrahydrofolate and cannot be recycled into the forms needed for thymidine synthesis. DNA synthesis fails, and both deficiencies therefore produce an identical megaloblastic anaemia with hypersegmented neutrophils.
The second reaction is the one that separates them. Only B12 deficiency causes methylmalonyl-CoA to accumulate, and its abnormal incorporation into myelin lipid produces subacute combined degeneration of the cord: dorsal columns and corticospinal tracts, with loss of vibration and proprioception, brisk reflexes and extensor plantars.
Distinguishing them biochemically
| B12 deficiency | Folate deficiency | |
|---|---|---|
| Methylmalonic acid | Raised | Normal |
| Homocysteine | Raised | Raised |
“Methylmalonic acid is the discriminator.”
Replace B12 first. Folate alone accelerates haematopoiesis, consuming the little remaining B12 and precipitating or worsening cord degeneration while the blood count improves. Neurological damage can occur with a normal haemoglobin and normal MCV.