USMLE Step 1 Question 301

Question:

A 4-year-old male with intellectual disability, self-mutilation, and hyperuricemia is likely to have a deficiency of an enzyme involved in which of the following processes?

Correct Answer: D.  Recycling of guanine and hypoxanthine

Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) is an enzyme of the purine salvage pathway for recycling guanine and hypoxanthine (D) that is deficient in individuals with the X-linked recessive disorder Lesch-Nyhan syndrome. This disorder is characterized by excess uric acid production, which may produce symptoms of gout, intellectual disability, spasticity, self-mutilation, and aggressive behavior.

Purine synthesis involves adding carbons and nitrogens to ribose 5-phosphate (R5P), which is a product of the hexose monophosphate (HMP) shunt. R5P is then converted to ribose phosphate pyrophosphate (RPPP), which is subsequently converted to 5′-phosphoribosylamine, the latter step being the committed step in purine nucleotide biosynthesis. Through a series of steps RPPP is converted to inosine 5′-monophosphate (IMP). Several of these biochemical steps involve transferring methyl groups from folate. This is important because folate analogues, such as methotrexate, inhibit DNA synthesis, especially in rapidly growing tumor cells, by inhibiting purine synthesis. Finally IMP is converted into either AMP or GMP. These last biochemical steps are also connected to biochemical reactions that involve adenosine deaminase, an enzyme that is deficient in individuals with the autosomal recessive form of SCID, and hypoxanthine-guanine phosphoribosyl transferase (HGPRT), a deficiency of which will produce Lesch-Nyhan Syndrome as described above. In contrast, a deficiency of homogentisic oxidase, which is involved in the conversion of homogentisic acid to methylacetoacetate, is associated with alkaptonuria. Abnormal degradation of galactocerebroside is seen in Krabbe’s disease, while abnormal breakdown of branched-chain amino acids is seen in maple syrup urine disease.