Different mutations in single gene suggest Parkinson's is primarily an inherited genetic disorder

“Inheriting one or both of these mutations doesn’t mean that a person will develop Parkinson’s disease, but that an individual’s risk is increased,” he says. “The basis of population genetics is that disease is familial; people are so distantly related that they don’t know they may have inherited specific genes. While there may be an environmental component to development of the disease, none have been identified that have risks as large as those seen by the LRRK2 gene mutations.”

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.

Major funding for both studies came from NIH (including the Morris K. Udall Center for Excellence in Parkinson’s Disease Research at the Mayo Clinic) and several international funding agencies.

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