The mechanism of Progressive Peripheral neuropathy in B12 deficiency - USMLE Forums
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Old 03-11-2011
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Biochemistry The mechanism of Progressive Peripheral neuropathy in B12 deficiency

Mechanism ?
myelin synthesis defect or attack by methylmalonic acid and odd chain FA ?
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Old 03-11-2011
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Vitamin B-12 role in the peripheral and central nervous systems

The neurologic manifestation of cobalamin deficiency is less well understood. CNS demyelination may play a role, but how cobalamin deficiency leads to demyelination remains unclear. Reduced SAM or elevated methylmalonic acid (MMA) may be involved.

SAM is required as the methyl donor in polyamine synthesis and transmethylation reactions. Methylation reactions are needed for myelin maintenance and synthesis. SAM deficiency results in abnormal methylated phospholipids such as phosphatidylcholine, and it is linked to central myelin defects and abnormal neuronal conduction, which may account for the encephalopathy and myelopathy. In addition, SAM influences serotonin, norepinephrine, and dopamine synthesis. This suggests that, in addition to structural consequences of vitamin B-12 deficiency, functional effects on neurotransmitter synthesis that may be relevant to mental status changes may occur. Parenthetically, SAM is being studied as a potential antidepressant.

Another possible cause of neurologic manifestations involves the other metabolically active form of cobalamin, adenosylcobalamin (see image below), a mitochondrial cofactor in the conversion of L-methylmalonyl CoA to succinyl CoA. Vitamin B-12 deficiency leads to an increase in L-methylmalonyl-CoA, which is converted to D-methylmalonyl CoA and hydrolyzed to MMA. Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination, possibly leading to defective nerve transmission.

Vitamin B-12ľassociated neurological diseases. Cobalamin deficiency leads to reduced adenosylcobalamin, which is required for production of succinyl-CoA. D-methylmalonyl-CoA is converted to methylmalonic acid.

More recent studies propose a very different paradigm: B-12 and its deficiency impact a network of cytokines and growth factors, ie, brain, spinal cord, and CSF TNF-alpha; nerve growth factor (NGF), IL-6 and epidermal growth factor (EGF), some of which are neurotrophic, others neurotoxic. Vitamin B-12 regulates IL-6 levels in rodent CSF. In rodent models of B-12 deficiency parenteral EGF or anti-NGF antibody injection prevents, like B-12 itself, the SCD-like lesions.
In the same models, the mRNAs of several cell-type specific proteins (glial fibrillary acidic protein, myelin basic protein) are decreased in a region specific manner in the CNS, but, in the PNS myelin, protein zero and peripheral myelin protein 22 mRNA remain unaltered.

In human and rodent serum and CSF, concomitantly with a vitamin B-12 decrease, EGF levels are decreased, while at the same time, TNF-alpha increases in step with homocysteine levels. These observations provide evidence that the clinical and histological changes of vitamin B-12 deficiency may result from up-regulation of neurotoxic cytokines and down-regulation of neurotrophic factors.

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