Each year, scientists take us a little closer to understanding the genetics of Parkinson’s disease (PD). Perhaps the most interesting and perplexing finding so far has been that only 10 to 15 percent of cases are associated with a change in DNA (this is known as a genetic mutation). Because of this, it is thought that Parkinson’s has both genetic and environmental influences (such as pesticides). The most common PD gene discussed by researchers is LRRK2, though others have recently emerged: PRKN, PARK7, PINK1, SNCA, UCHL1 and GBA. Genetic testing companies have made people more aware of these genetic influences and have recently made “direct to the patient” genetic testing widely available.
About the GBA Mutation
The GBA mutation has recently become the hottest on the list of potential PD-related genes. If a person has two copies of GBA (alleles), he or she will develop Gaucher’s disease. Gaucher’s affects about 1 in 40,000 people and is especially common in Eastern Europe and in Ashkenazi Jewish populations. Scientists and doctors refer to it as a lysosomal storage disease.
The GBA mutation results from a deficiency in the enzyme glucocerebrosidase. When affected, fat-like material builds up in the liver, spleen and other tissues. People with Gaucher’s disease may experience abdominal swelling, bone pain, anemia, bleeding and bruising. There is a severe neurological form of Gaucher’s disease. However, these forms are not the Gaucher’s we are talking about when we discuss Parkinson’s. It takes two copies of the GBA mutation to cause Gaucher’s disease; but if you have one copy of the GBA mutation, you enter the Parkinson’s realm. Someone with a single GBA mutation is called a GBA carrier.
There are many important links between Parkinson’s disease and GBA carriers. Researchers have shown that people with PD who are GBA carriers may be affected earlier and more severely than people with PD who are not carriers. Both Parkinson’s and GBA are associated with abnormalities in many of the same genes and proteins. While more research is needed to confirm the GBA and Parkinson’s connection, researchers speculate that the relationship between levels of alpha synuclein (found in Lewy Body protein deposits) and glucocerebrosidase may play a role in the development and progression of PD symptoms.
GBA Mutation & Cognition in Parkinson’s
Recently, scientists have begun focusing on the role of GBA in people with Parkinson’s. Clemens R. Scherzer, MD, from Harvard Medical School and colleagues from around the world pooled their information in a clinical and genetics study to examine the role of cognition and GBA carrier status in Parkinson’s. Recently publishing their work in Lancet Neurology, the team developed a cognitive risk score to predict damage within 10 years of disease onset. They concluded that “patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile.”
Today, many authors have independently concluded that the presence of the GBA mutation is associated with increased risk of thinking changes. Roberto Cilia, MD, and colleagues recently reported in the Annals of Neurology that there was an increase in dementia and mortality in Parkinson’s GBA carriers.
What People with PD & Loved Ones Should Know
Where does this leave people with Parkinson’s who are also GBA carriers? Medical professionals should educate patients and families about the potential for a worse cognitive outcome for those who are GBA carriers. However, people with PD and families should not all run out and get tested for GBA. We recommend a visit to a genetic counselor, since as many as half of people decide not to be tested for a particular gene following a genetic counseling visit.
Doctors and genetic counselors should keep in mind that there is likely a wide variability in the manifestations of GBA and not all patients experience a faster cognitive decline. The GBA status may prove important for clinical trials because screening and targeting of a single homogenous population could have many advantages for therapy development. Any future trials of enzyme replacement therapy, new medications or even potential gene therapy should be longitudinal, carefully designed and powered with enough patients to answer the critical questions facing the field.