[ZucchiniFlower]

"Only about 10 percent of patients diagnosed with Parkinson's disease have a strong family history of the disease, and Mayo Clinic researchers in Florida have been part of a worldwide effort to discover whether common genes may explain the origin of the other 90 percent, the so-called "sporadic" form. In 2004, they were part of a team that discovered that the LRRK2 gene is linked to both familial and non-familial cases of the disease.

Since then, they have found LRRK2 mutations that can cause the same clinical manifestations of Parkinson's disease in people with and without a family history – discoveries that "have caused a paradigm shift in the field," says Dr. Ross. For example, a mutation labeled G2019S causes both familial and non-familial Parkinson's disease in a high number of Berber Arabs and Ashkenazi Jews. "This shows that the effect of mutations in different areas of the Lrrk2 protein lead to the same disease, although it may not manifest in each generation and so did not appear to be familial," he says."


Different Mutations In Single Gene Suggest Parkinson's Is Primarily An Inherited Genetic Disorder

ScienceDaily (Apr. 16, 2008) — Two new international studies by researchers at the Mayo Clinic site in Florida are rounding out the notion that Parkinson's disease is largely caused by inherited genetic mutations that pass through scores of related generations over hundreds, if not thousands of years. These genetic influences, which can be small but additive, or large and causative, overturn common beliefs that the neurodegenerative disease mostly occurs in a random fashion or is due to undetermined environmental factors.

These latest studies bring the total of number of disease-related mutations in an as yet poorly understood gene, leucine-rich repeat kinase 2 (LRRK2), to seven, all of which are linked, either weakly or strongly, to typical, late onset development of Parkinson's disease in people around the world. One mutation (R1628P) doubles the risk of Parkinson's disease in ethnic Chinese, according to a study published on April 16, 2008 in the online edition of the Annals of Neurology. The second study, published April 15 in Neurology, demonstrates that another very rare mutation (R1441C), found in people on three continents, increases risk by more than 10-fold..........

"The picture that is emerging of Parkinson's disease is one in which genetic risk factors, passed down through the population for hundreds or thousands of years, add up to substantial susceptibility within a single individual, and, with some possible environmental influences, can result in disease," says Mayo Clinic neuroscientist Owen A. Ross, Ph.D., first author on the Annals of Neurology study.......



"These types of mutations are important because the goal of this research is to be able to screen people who are most at risk because of their genetic profiles, and design therapies that interfere with the disease process," Dr. Ross says.

The stronger R1441C mutation, also currently being reported, originated from several different "founders" and is now found in 20 families on three continents. It is relatively causative in nature, meaning the majority of people with the mutation are likely to develop the disease.

"Parkinson's disease is fascinating to study because we can now roughly trace when and where mutations occur, and how they travel through offspring and in populations," says Kristoffer Haugarvoll, M.D., a visiting scientist at Mayo Clinic and lead author on the Neurology study. "It also shows us that disease that appears to be the same in the majority of patients can originate from different genetic mutations – either genes that increase risk substantially, or by several risk factors, genetic and environmental, that each have minor but additive effects.".....

Generations that carry rare but critical mutations

In the Neurology study, Dr. Haugarvoll, who is from Norway, worked with researchers from a number of countries to collect genetic information from discrete populations of people representing three continents who had previously been found to be carriers of the R1441C mutation. "This was a completely collaborative effort," he says. "Rare mutations affect relatively few patients, but if we join forces in a worldwide initiative, we have larger samples to look at, and that is the only way you can advance the science."

The scientists identified 33 affected and 15 unaffected R1441C mutations from 20 families, including four patients with no family history of Parkinsonism. These patients all developed disease that mimicked the typical, late onset disease normally seen in non-familial, sporadic Parkinson's disease, Haugarvoll says. The scientists believe the same disease-causing mutation has occurred independently on several occasions; however, most patients seem to originate from two different founders. One variant was found in Italian, German, Spanish, and American patients. The second was discovered in patients from Belgium and from a single American family, located in Nebraska.

Dr. Haugarvoll says the region of R1441C appears to be "a hotspot for mutation events" because other mutations occur in this general area. What is most interesting, he says, is that "even though there are familial mutations in different locations of the gene, it produces the same effect, the same disease."

"It seems like mutations are occurring in a few founders, and that these founders have a lot of offspring over generations that carry the mutation. Even in sporadic disease, then, familial genes are inherited but symptoms may skip some generations, making the disease appear sporadic" Dr. Haugarvoll says.

http://www.sciencedaily.com/releases...0416104317.htm