Researchers Find Genetic Clues to Rare Lesch-Nyhan Disease


Lesch-Nyhan Disease (LND) is an inherited disorder in boys caused by a deficiency of an enzyme that leads to a buildup of uric acid in all body fluids. Symptoms include poor muscle control and moderate retardation. Researchers from the University of California, San Diego School of Medicine have found clues that can explain the compulsive behavior and cognitive deficits in the rare disorder and the pathways may also add to clues regarding deficits found in other neurodegenerative disorders such as Alzheimer’s disease.

One striking feature of Lesch-Nyhan Disease, according to research by the National Institute of Neurological Disorders and Stroke (NINDS), is self-mutilating behavior, particularly lip and finger biting that begin in the second year of life. Other neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs, similar to that seen in Huntington’s disease.

The enzyme deficient in LNS is known as hypoxanthine-guanine phosphoribosyltransferase or HPRT. In addition to causing uric acid accumulation, the gene has now been liked to signaling pathway defects that are also common to Parkinson’s, Alzheimer’s and Huntington.


HPRT is expressed in most cells and was previously thought to regulate simple functions such as metabolism, but not necessarily complex processes such as embryonic and neurological development. However, Dr. Theodore Freidmann, a professor of pediatrics at UCSD’s Center for Neural Circuit and Behavior, has discovered that HPRT plays an important role in affecting how transcription factor genes are expressed, thus helping to regulate two important developmental pathways.

Specifically, HPRT-deficient cells in the Wnt signaling pathway affects vertebrate development and biological processes that include stem cell self-renewal and differentiation. Defects in the presenilin (PS-1) pathway, which interacts with the Wnt pathway, have been associated with familial forms of Alzheimer’s disease.

“Such similarities in cell function are not likely to be coincidental,” said Dr. Friedmann. “Instead, they offer important clues to cognitive defects and open up new targets for therapies to treat these diseases.”

Current treatment for LNS is only to control symptoms. Gout can be treated with allopurinol to control excessive amounts. Drugs such as carbiodopa/levodopa, diazepam, phenobarbitoal or haloperidol may help relieve some of the neurological symptoms. Unfortunately, the overall prognosis for LNS is poor. Death is usually due to renal failure in the first or second decade of life.

The research is published on-line today in the PloS ONE.