Neurology

    While the overproduction of uric acid is thought to be the major cause of many of the motor and renal abnormalities, it has not been shown to be the cause of the neurological conditions. If a buildup of uric acid was the cause of the neurological conditions in LNS patients, then an increase in the amount of uric acid in the cerebrospinal fluid (CSF) would be expected. However, amounts of uric acid have been found to be normal in the CSF of patients with LNS. HPRT’s role in the production of purine nucleotides and its effects on the central nervous system still remains unknown. Studies have shown that normal HPRT activity is higher in the brain when compared to other tissues.

(above:  Arrows indicate flow of CSF)

Dopamine

Evidence seems to suggest there is a significant decrease in the brain cells that contain dopamine The substantia nigra, the control center for dopamine regulation, contained 71% of the normal concentration of dopamine. It is also believed that dopamine function is decreased in the nucleus accumbens, the pleasure center of the brain. It is therefore thought that the decrease in dopamine levels is what leads to the self-mutilation that occurs in boys with Lesch-Nyhan syndrome. It is also known that the destructive nature of these patients is not related to a dysfunction of sensory receptors, nor to the transmission of nociceptive (the unconscious awareness of pain) information.

Serotonin

Another possible explanation lies in a difference in serotonin functions in the brain. While no studies have looked at the actual evidence that could support this hypothesis, two pieces of evidence suggest that serotonin plays a significant role in the self-mutilating behavior of Lesch-Nyhan syndrome. When compared to patients with (OCD), who are known to have changes in the function of serotonin and to be successfully treated with drugs that increase serotonin function, both OCD and LNS patients exhibited

“…intrusive and irresistible urges to commit an act that the individual may perceive as senseless, mounting tension associated with attempts to resist the behavior, and relief from anxiety following commission of the act.”

Even though the relief experienced in Lesch-Nyhan patients is replaced with physical pain, the overall experience of compulsive behaviors is similar between both sets of patients. Perhaps the best evidence for serotonin’s role in self-mutilating behaviors comes from treatment with a form of serotonin. Oral administration of 1-8mg/kg/day doses of this drug resulted in a dramatic reduction of self-mutilating behaviors within three days of treatment. When the drug was discontinued, destructive behavior returned within fifteen hours.