Genetic Testing for GBA and LRRK2 Mutations
Date: August 2018
Prepared by SIC Member: Roy Alcalay, MD, MS, Columbia University, New York, NY, USA
Authors: Jill S. Goldman, MS, MPhil, CGC; David K. Simon, MD, PhD; Nir Giladi, MD
Blog Editor: Stella M. Papa, MD
Genetic testing is not a part of the routine evaluation of people with Parkinson’s disease (PD), and is rarely offered in late-onset PD. However, approximately 5% of the PD population of European descent carries either glucocerebrosidase (GBA) or LRRK2 mutations. Go to Discussion
Genetic testing is not a part of the routine evaluation of people with Parkinson’s disease (PD), and is rarely offered in late-onset PD. However, approximately 5% of the PD population of European descent carries either glucocerebrosidase (GBA) or LRRK2 mutations. In selected populations, such as Ashkenazi Jews and North African Berbers, mutation prevalence reaches 35-40%. Studies have clearly demonstrated a link between the genotype and phenotypic features, such as the rate of PD progression, and thus the clinical recognition of these mutations may be important to the diagnosis and management of patients. In addition, knowledge of genetic status is a prerequisite for participation in interventional studies based on genetic pathogenesis in PD. Therefore, we ask ourselves if we should use clinical testing for GBA and LRRK2 more frequently. Here, we present a discussion of this topic by three experts, Ms. Goldman, and Drs. Simon and Giladi.
1. What are the advantages and concerns in offering genetic testing to selected populations of patients with PD?
The demand for genetic testing in idiopathic PD is very real, yet many of those people who want testing are turning to direct-to-consumer (DTC) testing rather than clinical testing through their doctors. For some, this testing is just a novelty and one more piece of information for their future. But others have a real concern because they have a family history of PD or have the diagnosis. Direct-to-consumer testing poses problems for both groups. DTC does not provide testing of all pathogenic mutations in the significant late-onset genes (GBA and LRRK2), meaning that results are meaningless for many ethnicities, and often DTC does not supply pre-/post- genetic counseling to help prepare for and interpret results. Some people turn to their doctor after this testing for help with interpretation of results. What is the alternative? Testing should be coordinated by a healthcare team of a physician and a genetic counselor. However, right now, even when this is being done, testing is remarkably difficult. Very few laboratories have testing for all LRRK2 and GBA mutations on the same panel, and those that do include many other genes not pertinent to the patient’s diagnosis or family history, which could reveal potential mutations or variants of unknown significance in unrelated genes, thus opening up a can of worms. Some of these labs will allow the ordering healthcare worker to customize the panel by not including readouts of these other genes. Genetic counselors who specialize in movement disorders may know how to get around the system, but most ordering physicians will not.
An ideal situation would be to have a special panel of just GBA and LRRK2 that is easily accessible to physicians who want to order it. This would both increase access to testing and reduce cost to patients. The ordering physician should be well versed in both how to counsel patients about these tests and how to interpret the results. Alternatively, they can refer to genetic counselors specializing in adult neurology (www.nsgc.org) or to counselors working for the clinical lab.
2. Do you perceive genetic data to be useful in the management (decision on medications and surgery referral) of patients with PD?
Factors to consider before recommending genetic testing for mutations in the GBA or LRRK2 genes are whether or not the presence or absence of a mutation will affect the diagnosis, prognosis or treatment. Family planning is another potential consideration, but most PD patients are past the age of childbearing, and for those who are not it remains unclear how the presence or absence of a mutation with incomplete penetrance for a late-onset disorder should affect family planning. With regards to diagnosis, the answer is “no”. PD is a clinical diagnosis that should not be altered by the presence or absence of GBA or LRRK2 mutations. Regarding prognosis, there are data suggesting differences in certain clinical features in association with these mutations, such as accelerated cognitive decline and more frequent dementia in PD patients with GBA mutations. However, the sensitivity and specificity of a GBA mutation for predicting dementia in a PD patient who currently is without major cognitive deficits clearly is insufficient to justify clinical testing for prognosis. This is analogous to the position against routine apoE4 genetic testing despite its clear association with a higher risk of Alzheimer’s disease. Lack of a GBA mutation may be falsely reassuring because a high percentage of those PD patients may ultimately develop cognitive dysfunction, and conversely not all PD patients with GBA mutations develop dementia. Advice such as addressing vascular risk factors and promoting exercise and a healthy diet should be provided to all, regardless of their genotype. Medical treatment at this point also is not affected by mutation status. There is great hope that this will change, with strategies under development to specifically target GBA or LRRK2 mechanisms. However, no such treatments have yet been adequately tested in clinical trials, so at this point the presence or absence of GBA or LRRK2 mutations has no impact on treatment. A highly appropriate use of genetic testing for GBA and LRRK2 mutations is for determining eligibility for clinical trials targeting patients with mutations in these genes. But in this case the testing is for research purposes, not for clinical care. Thus, although some patients may want genetic testing “just to know”, at this point clinical genetic testing has little impact on clinical care, and should not be routinely recommended for PD patients. However, I envision a future when genetic testing for LRRK2 and GBA and potentially other genetic factors associated with PD will become routine for all PD patients, and will guide individualized therapy to target specific genetic mutations. But we are not there yet.
Personalized Medicine, an approach that is being increasingly embraced by researchers, clinicians and patients, promotes the idea of tailoring a treatment for each patient according to their unique physiology and life conditions. Unlike the "one-size-fits-all" approach used until now, personalized medicine takes into account patients' particular genetic background, co-morbidities, age, gender, clinical syndrome, as well as response to medications and complication profile. Parkinson's disease, where age of onset, symptoms and their severity, and disease progression vary so greatly, is a natural candidate for the personalized medicine approach.
A decade of research in Tel-Aviv and New York, focusing on Ashkenazi Jews, has recognized a genetic component among more than 1/3 of the patients, with specific clinical syndrome manifestations based on the mutations involved in the LRRK2 and GBA genes. We observed that carriers of the G2019S mutation to the LRRK2 gene experience less cognitive decline, earlier gait disturbances, better olfactory function, more insomnia and less REM sleep behavior disorders compared to patients without this mutation. On the other hand, carriers of one out of seven known mutations in the GBA gene suffer from early and more severe cognitive decline, develop dementia more frequently, and experience more frequent levodopa induced dyskinesia, more psychiatric disturbances, and more autonomic disturbances compared to patients without a known mutation associated disease. We have recently proposed that treatment should take into consideration the genetic status, of course in recruitment to clinical trials, and also during the course of the disease when treatment strategy is developed.
Based on the differences between those groups of patients, we believe that personalized medicine should be the obvious approach when facing Ashkenazi patients with PD. Genetic testing should be carried out as part of the diagnosis, and the treatment plan tailored according to the patient's genetic status. Knowing that patients with a mutation in the LRRK2 gene experience higher frequency of falls can direct us towards administering physical therapy early on to curb such tendencies and preserve existing motor skills. Knowing that freezing of gait, a motor disturbance associated with the GBA gene mutation, can direct us towards therapies to delay and prevent such functional performance disturbance, and its association with decreased motor-cognitive function. Depression and anxiety, as well as sleep disturbances, all common symptoms in PD, should be managed to prevent further physical decline, while also taking into consideration the risk of falls and the absolute need to maintain alertness in such patients. Special care should be given when referring GBA-PD patient to DBS and when prescribing drugs, or drug combinations, that are known to hamper cognition or alertness, like anticholinergics or dopamine agonists. Similarly, higher rates of autonomic disturbances in GBA-PD patients call for closer monitoring of symptoms such as orthostatic hypotension, urinary retention, constipation, or erectile dysfunction, which can be made worse by anti-parkinsonian, anti-depression, anti-psychotic or other drugs.
We believe the lesson learnt from the Ashkenazi Jews should be implemented for the entire PD population. The therapeutic strategy should be tailored to every patient, much like the case in the field of oncology, to benefit the four million PD patients living in the world today.
The discussants agree that once sufficient data are available to predict prognosis and tailor treatment based on GBA and LRRK2 status, genotyping should be routinely performed. The discussants are conflicted as to whether this point in PD research has been reached; however, the trend of clinical trials focusing on the genetic pathways points towards an encouraging future for precision medicine in PD.