Thursday, January 24, 2019

Mechanistic insights regarding Lesch-Nyhan syndrome

Hello friends! Let's refresh our biochemistry knowledge today.

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 do HGPRTase mutations actually cause dystonia and other extrapyramidal signs and symptoms?

1.)  For the 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 a rate-limiting enzyme.
Now HGPRTase deficiency causes depletion of GTP thereby 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 states, yet another link between GTP depletion and perturbation of dopamine signaling.

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

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

So to summarise, Lesch Nyhan syndrome can be considered as one of the basal ganglia disorders with Wilson's disease and Huntington's disease being the other notable ones.

Have a great day!

-Kirtan Patolia

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