
Researchers have discovered a gene that, when mutated, causes cognitive and behavioral defects seen in Lesch-Nyhan disease, a rare neurological disease that affects children.
“We understand how this gene affects normal brain function, and that is a new facet to this disease,” pediatrics professor Theodore Friedmann said.
The gene mutations can cause defects in two signaling pathways, which have also been associated with other neurodegenerative diseases like Alzheimer’s disease.
“We’d like to think that the clues we are getting from this disease may be telling us something about how the brain becomes deregulated or upset in other diseases,” Friedmann said.
Lesch-Nyhan disease is a disorder caused by a deficiency in the HGPRT enzyme. This is caused by mutations in the HPRT gene on the X chromosome, which leads to a build-up of uric acid in bodily fluids and damages neurological pathways.
The HPRT gene is expressed in most healthy cells and was previously thought to regulate metabolism, rather than embryonic and neurological development. However, in 2009, Friedmann’s team found that HPRT plays an important role in regulating developmental pathways.
LND affects mainly children, causing cognitive and behavioral deficiencies like uncontrollable and involuntary compulsive self-mutilating behaviors, like lip- and- finger-biting.
The research team discovered a similarity in the genes to those related to other neurological disorders, like Alzheimer’s, Parkinson’s and Huntington’s disease. Studying the common mechanisms defective in LND can tell researchers how it works in more common diseases such as Parkinson’s.
“We’ve been working with this disease for forty years,” Friedmann said. “[Until this study] came along, we had no clue about how genetic defects cause brain defects.”
Friedmann and his team also identified abnormal purine metabolism in LND patients caused defects in the PS-1 and Wnt pathways. The interactions between these two pathways suggest they are associated with other neurodegenerative diseases.
Lesch-Nyhan disease affects one in 100,000 children. Researchers hope to identify treatments, as there currently are none. Since they know which genes are interfering, Friedmann said gene therapy or design drugs are possible to target the secondary defects as a result of the mutation.
“This is a very complicated mechanism,” Friedmann said. “A single gene leads to a string of secondary defects — these are the targets for treatment.”
Using this model, researchers can also extend treatments to adults with neurological diseases. Their goal is to correct defects caused by LND.