http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/restless-legs-syndrome/what-is-rls/causes.html

 

Unexpectedly, Iron deficiency can cause restless leg syndrome. Supposedly iron may be needed by the neuromelanin cells in the substantial nigra to synthesise dopamine.

 

How does this work? Is iron a co-factor for tyrosine hydroxylase or dopa decarboxylase?

 

Also does this imply iron supplements may help extrapyramidal akathisia when using antipsychotics?

I do not think that a direct mechanistic link can be drawn at this point. More recently low serum zinc levels have also been associated with restless leg syndrome, for example. Also, the precise pathophysiology is (to my knowledge) not completely elucidated which makes it harder to develop a coherent model of the role and interaction of iron and dopamine in this disease.

That being said, the tyrosine hydroxylase actually has iron as a co-factor, but in animal studies actually increased hydroxylase levels were found in neurons with diminished iron content (rather than a reduction, as one may expect due to the limitation in co-factor).

 

The most complete model (again, derived from animal experiments) indicates that activation of the HIF pathway by iron deficiency may be a key element. Increased HIF was found in the substantia nigra and could increase the expression of the HIF-responsive tyrosine hydroxylase. Another part of the model deals with how HIF activation may still lead to intracellular iron deficiency which probably happens via the MEIS1 hub.

 

There may be more complete models out there, but that would be outside of my expertise.

It's interesting, and has the advantage of being testable- measuring blood/serum Fe and Zn levels is easy enough.

 

Just a quick word of warning, Excess Fe is rather toxic.

I should add that iron deficiency on the serum level can, but does not have to be present while displaying symptoms. It is assumed that even transient deficiency can cause the tissue levels to be depleted. IIRC it is hypothesized that activation of MEIS1 leads to partitioning of iron into the mitochondria, causing cellular deficiency while serum levels can be back to normal levels.