Defective HGPRT Production: Lesch Nyhan Syndrome

An expected result of a defect in the production or activity of HGPRT is an increase in both hypoxanthine and guanine, which are ultimately degraded to uric acid. But there is also an accumulation of PRPP,  which allosterically stimulates amidophosphoribosyl transferase activity ("feedforward activation") thus increasing the production of the purine nucleotides, and consequently increasing the breakdown products, and ultimately the uric acid level. When the ability of the kidneys to excrete uric acid is exceeded, the uric acid will precipitate in the joints, kidneys and urinary tract, as described in the discussion of gout. However, with severe deficiency of HGPRT, not only does gout result, but also a host of other neurologic abnormalities, including mental retardation, spasticity ("cerebral palsy"), aggressive and destructive behavior and self-mutilation. 

Allopurinol is effective in relieving  gout but has no effect on the neurologic abnormalities. Although the pathophysiology of the neurologic defects has yet to be worked out, the resulting disease, "Lesch-Nyhan Syndrome", has importance as the first neuropsychiatric abnormality which could be attributed to a specific enzyme defect. Since the description of the biochemical abnormality in Lesch-Nyhan Syndrome, other genes that are linked to depression, alcoholism and schizophrenia have been identified.