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-   -   Lesch Nyhan Syndrome and Allopurinol (https://www.usmle-forums.com/usmle-step-1-forum/3234-lesch-nyhan-syndrome-allopurinol.html)

doctorF 07-09-2010 04:34 PM

Lesch Nyhan Syndrome and Allopurinol
 
A 1-year-old male has a normal birth and infantile history except for delay in sitting up, crawling, and standing (delayed motor milestones). He begins the unusual habit of chewing on his fingers and lips, and in one instance bites through the lip and leaves a large wound. His physician documents an elevated serum uric acid and suspects Lesch-Nyhan syndrome . In considering potential therapy, the physician reads that purines are overproduced in gout and Lesch-Nyhan syndrome, causing hyperuricemia, yet the hypoxanthine analogue allopurinol is only effective in gout. Allopurinol does not treat the neurologic symptoms of Lesch-Nyhan syndrome because it does not do which the following?

A. Decrease de novo purine synthesis
B. Decrease de novo pyrimidine synthesis
C. Diminish urate synthesis
D. Increase phosphoribosylpyrophosphate (PRPP) levels
E. Inhibit xanthine oxidase

doc_study 07-10-2010 02:04 AM

hmmm.... its a tricky one i will have to revise biochemistry.

doc_study 07-10-2010 06:53 AM

Lesch Nyhan Syndrome and Allopurino
 
Correct option is,

A. Decrease de novo purine synthesis

Allopurinol is structural isomer of hypoxanthine and acts by two mechanisms:

(1) it inhibits xanthine oxidase, which catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid

(2) it also inhibits the purine synthesis by inhibiting the rate limiting enzyme PRPP amidotransferase. As it is a purine analogue, allopurinol must be converted to its respective nucleotide by HGPRT to inhibit this enzyme.

So it needs an intact HGPRT. As in Lesch Nyhan Syndrome there is complete deficiency of this enzyme so it cannot inhibit purine synthesis & which continues unchecked.

inder 07-11-2010 12:24 AM

I am guessing A

doctorF 07-11-2010 01:22 AM

YEP A!!


Most forms of gout are probably X-linked recessive with deficiencies in phosphoribosyl pyrophosphate (PRPP) synthase, the first step of purine synthesis . Some patients may have a partial deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRTase), which salvages hypoxanthine and guanine by transferring the purine ribonucleotide of PRPP to the bases and forming inosinate and guanylate, respectively. In all of these patients, the hypoxanthine analogue allopurinol has two actions: (1) it inhibits xanthine oxidase, which catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid stones and tissue deposits; and (2) it forms an inactive allopurinol ribonucleotide from PRPP in a reaction catalyzed by HGPRTase, thereby decreasing the rate of purine synthesis. In contrast, because of the total loss of HGPRTase activity in Lesch-Nyhan patients, the allopurinol ribonucleotide cannot be formed. Thus, PRPP levels are not decreased and de novo purine synthesis continues unabated. The gouty arthritis caused by urate crystal formation is relieved in Lesch-Nyhan patients, but their neurological symptoms (mental deficiency, self-mutilation with compulsive chewing of fingers and lips) are not.


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