What substrate is utilized by the defective enzyme in a disorder characterized by developmental delay, self-mutilation, and orange crystals in diapers, with a 98% loss of enzyme activity, specifically affecting purine metabolism, involving enzymes such as hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which acts on substrates like hypoxanthine, guanosine, or other related compounds?

From the Guidelines

The defective enzyme in this disorder would normally utilize hypoxanthine as a substrate. This clinical presentation describes Lesch-Nyhan syndrome, a rare X-linked recessive disorder caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) 1. HGPRT is responsible for the salvage pathway of purine metabolism, specifically converting hypoxanthine to IMP and guanine to GMP. When this enzyme is deficient, hypoxanthine accumulates and is converted to uric acid, leading to hyperuricemia and the characteristic orange crystals (uric acid) in the diapers. The neurological manifestations, including developmental delay and self-mutilating behaviors like lip and finger biting, are hallmarks of Lesch-Nyhan syndrome, as described in the study by Siegel et al. 1. These symptoms result from the disruption of normal purine metabolism in the brain. The almost complete absence of enzyme activity (98% loss) is consistent with the classical form of Lesch-Nyhan syndrome rather than partial deficiency variants. Key features of Lesch-Nyhan syndrome include:

• Mild to moderate intellectual disability
• Chronic, compulsive, self-injurious behaviors resulting in self-mutilation: biting, eye poking, fingernail pulling, psychogenic vomiting, arching, head snapping, head banging
• Language pattern: repeated ambivalent statements with anxiety and vulgarity
• Frequent compulsive aggression toward others (grabbing and pinching) 1.

From the Research

Defective Enzyme Substrate

The defective enzyme in this disorder is hypoxanthine-guanine phosphoribosyltransferase (HPRT) 2, 3, 4, 5, 6.

• The substrates of this enzyme are:
  • Hypoxanthine
  • Guanine
• The enzyme HPRT is involved in the purine metabolism pathway, where it catalyzes the conversion of hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP) 2, 3, 4, 5, 6.

Relevant Substrate Options

Based on the provided options, the correct substrates of the defective enzyme HPRT are:

• Hypoxanthine
• Guanine Note that the other options (adenine, adenosine, guanosine, AMP, GMP) are not the primary substrates of the HPRT enzyme, although some of them may be related to the purine metabolism pathway 2, 3, 4, 5, 6.