Two studies find that mutations and variations in the GBA gene may be associated with more rapid progression of Parkinson’s disease (PD) and an increased risk for dementia|A term used to describe a group of brain disorders that cause a broad complex of symptoms such as disorientation, confusion, memory loss, impaired judgment and alterations in mood and personality.]. The studies, both of which build upon Parkinson’s Disease Foundation (PDF) supported research, appear in the August 29 online edition of JAMA Neurology and the October 3 online edition of Annals of Neurology.
As with all genes, every person carries two copies of the GBA gene, one inherited from each parent. When mutations occur in both copies of GBA, they cause Gaucher disease. When mutations occur in only one copy of GBA, it doesn’t cause Gaucher but it may increase a person’s risk of developing Parkinson's disease.
In the first study in JAMA Neurology, researchers led by Cyrus Zabetian, M.D., at the University of Washington in Seattle, looked at how specific changes to the GBA gene — mutations linked to Gaucher’s and variants with no known link to disease — affected 733 study participants with PD at seven US medical centers. Scientists detected mutations by screening DNA in participants’ blood or saliva for variations in the usual “spelling” of the GBA gene. At the beginning of the study, and regular intervals for up to three years, researchers used standard rating scales to evaluate participants’ movement and cognitive symptoms.
In the second study published in Annals of Neurology, researchers led by Stefano Goldwurm, M.D., Ph.D., at the Parkinson Institute in Milan, studied 2,764 people living with PD in Italy. Of these, 67 participants had a mutation that would cause mild Gaucher if present in two copies of the gene, and 56 had a GBA mutation linked to a severe form of the disease.
- Of the 733 study participants in the US, 58 (about eight percent) carried a mutation or other variant in one copy of the GBA gene.
- All changes found in participants’ GBA genes were associated with more rapid progression of both movement and cognitive PD symptoms.
- Variants of the GBA gene had a greater effect on balance and gait difficulties in Parkinson’s than they did on tremor.
- During the study, compared to people with normal GBA, a higher proportion of people with GBA variants progressed either from no cognitive difficulties to mild cognitive impairment (MCI)|, or from mild cognitive impairment to dementia.
- Among the 2,764 study participants in Milan, 123 (about four percent) carried one of the two GBA mutations for which they were tested.
- People with GBA mutations developed PD at an earlier age — five years younger on average — than those with normal GBA genes and had an increased risk of death at a younger age.
- Overall, GBA carriers had about three times the risk of developing dementia compared to people with PD who had no GBA mutations.
- The severity of dementia depended on the type of GBA mutation, with the “severe” GBA mutation associated with more serious dementia.
What Does It Mean?
Every person has a different experience with Parkinson’s, including the symptoms they develop, how severe those symptoms are and the rate at which they progress. These differences suggest that there might be subtypes of the disease.
These studies demonstrate that PD subtypes may exist due to genetics. Specifically, carrying mutations or variants in the GBA gene seems to affect PD progression, while carrying no mutations or variants seems to lead to milder progression.
Based upon the US study, it appears that carrying a variant in GBA, which is relatively mild change (i.e., it does not cause Gaucher if inherited from both parents) is associated with faster PD progression than in people carrying no variants. However, if one carries a more severe mutation in the GBA gene, progression of both motor and cognitive symptoms may be faster. Disease duration (time from onset of symptoms to death of any cause) is shorter.
These two independent studies highlight similar important points. First, they highlight the role of GBA variants and mutations in predicting rate of progression. In addition, they also highlight the importance of developing interventions to reverse the effect of GBA mutations. Even more interesting, such interventions may be able to help people with PD with or without GBA mutations.
Further research is needed to explain the link between GBA and PD progression, which is likely to be influenced by other genes and environmental risk factors as well. Genetic testing for GBA variants is not routinely available today outside of a research setting, but given the mounting data linking GBA mutations and PD progression, there may be a role to consider more widespread testing, especially if targeted treatments become available.
Davis, M. Y., Johnson, C. O., Leverenz, J. B., Weintraub, D., Trojanowski, J. Q., Chen-Plotkin, A., et al. (2016). Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurology. http://doi.org/10.1001/jamaneurol.2016.2245
Cilia R, Tunesi S, Marotta G, et al. (2016). Survival and Dementia in GBA-Associated Parkinson’s Disease: The Mutation Matters. Annals of Neurology DOI: 10.1002/ana.24777