Biochemistry
The symptoms exhibited by most males with Lesch-Nyhan syndrome are a result of their body’s inability to produce the
enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).
Hypoxanthine-guanine Phosphoribosyltransferase (HPRT)
HPRT builds the
nucleotides inosine monophosphate (IMP) and guanine monophosphate (GMP)
from the components hypoxanthine and guanine, respectively, together with the enzyme 5-phosphoribosyl-1-pyrophosphate (PPRP).
IMP and GMP then become the basis of the nucleic acids that are used by the body to make
DNA and RNA. The production of
these nucleotides, therefore, is absolutely necessary to a person’s survival.
Recycling Pathway
Hypoxanthine and guanine are natural products of the breakdown of DNA and RNA, and our bodies have developed a way to conserve energy and resources by recycling these nucleotides through a recycling pathway. In the absence of HPRT, the enzyme PPRP, which would normally be used in recycling hypoxanthine and guanine, accumulates in the cell. The excess PPRP activates another enzyme that increases the rate of IMP and GMP production. When the levels of IMP and GMP get too high, they are broken down to form
uric acid. In addition, without HPRT’s activity hypoxanthine and guanine are not converted into their nucleotides, IMP and GMP, but instead they build up to toxic levels in the cell. This increase also leads to a large overproduction of uric acid, which can result in a build up of uric acid crystals in the kidneys, ureters or bladder.
Motor Deficits
The motor defects found in Lesch-Nyhan syndrome also result from a lack of HPRT. An increase in muscle activity requires an increase in movement through the
citric acid cycle. This usually occurs through the generation of transition molecules, such as fumarate. Fumarate is produced during the synthesis of IMP and GMP. When this cycle is not functioning correctly, such as in the absence of HPRT, fumarate is not produced and the citric acid cycle is not able to continue. This results in a severe depletion of
ATP in skeletal muscles, which results in the spasticity, choreoathetosis and hypertonic symptoms that is characteristic in Lesch-Nyhan boys.