Thursday, January 24, 2019

Mechanistic insights regarding Lesch-Nyhan syndrome

Lesch-Nyhan syndrome is characterized by choreoathetosis, dystonia, hyperuricemia, gout, self mutilatory behavior especially self biting of fingers and intellectual disability due to HGPRTase mutations.

So how does HGPRTase mutations actually cause dystonia and other extrapyramidal signs and symptoms?

1. For synthesis of dopamine tetrahydrobiopterin as a cofactor for tyrosine hydroxylase is required.
Tetrahydrobiopterin itself is derived by a series of reactions in which GTP cyclohydrolase is rate limiting enzyme.
Now HGPRTase deficiency causes depletion of GTP there by ultimately depleting tetrahydrobiopterin.

In fact GTP cyclohydrolase mutations are known to cause dopa responsive dystonia and phenotype similar to lesch-nyhan syndrome.

2. Secondly, dopamine receptors are linked to G-protein coupled receptors which alternate between GTP-GDP bound state, yet another link between GTP depletion and perturbation of dopamine signalling.

3. Adenosine deficiency due to reduction in salvage may adversely affect role of adenosine as neuroprotective agent.

Lastly, in lesch nyhan syndrome no characteristic imaging abnormalities are seen but reduced dendritic arborizations in caudate nucleus, putamen and nucleus accumbens is thought to underlie clinical manifestations.

Kirtan Patolia

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