The Role of Genetics in Personalized Medicine for Parkinson's Disease
There is increasing evidence that each of us is physiologically unique, and personalized medicine has become a concept that is embraced by the health world, albeit not yet fully practiced. This relatively new approach to treatment is especially relevant when it comes to Parkinson's disease. With over four million* people living with Parkinson's disease in the world today, no two cases are alike. Patients as young as thirty and forty years old are diagnosed with the disease, as well as people who are well into their eighties, and more recently even in their nineties. The disease can progress rapidly or very slowly, start with a single symptom of rest tremor, or with walking disturbances that pose a greater risk to the patient. A decade of research in Tel-Aviv, Israel 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 7 known mutations in the GBA gene suffer from early and more severe cognitive decline, develop Lewy Body Dementia more frequently, and experience more frequent levodopa induced dyskinesia, psychiatric and 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 an Ashkenazi patient with Parkinson's disease. Genetic testing should be carried out as part of the diagnosis, and a treatment plan tailored according to the patient's genetic status should be generated. Our awareness of the higher frequency of falls in patients with a mutation in the LRRK2 gene can direct us towards administering physical therapy to curb such tendencies and preserve existing motor skills. 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 Parkinson's disease, 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 in prescribing drug therapies to GBA patients, whose cognitive state is more easily compromised, and may be contraindicated for certain anti parkinsonian drugs, or drug combinations, that are known to hamper cognition, like anti-cholinergics. Similarly, higher rates of autonomic disturbances in GBA-PD patients call for closer monitoring of symptoms such as urinary retention, constipation, erectile dysfunction, which can be made worse by many of the anti-parkinsonian drugs.
Knowledge of a patient's genotype may provide an invaluable tool to custom fit an effective treatment, and avoid certain therapeutic related complications that would be hard to avoid otherwise. We believe the lesson learnt from the Ashkenazi Jews should be adopted for the entire Parkinson's disease population. Therapeutic strategy should be tailored to every patient based on the genetic background, co-morbidities, age, gender, clinical syndrome as well as response to medications and complication profile. Such personalized approach well accepted in oncology should be implemented in the treatment of Parkinson's disease NOW.
*NOTE: The WPC cites the number of 10 million people living with Parkinson's globally, as per the US-based Parkinson's Foundation. This is just evidence that we need to do more work to determine as accurate number of people living with PD around the world.
Nir Giladi MD, served on the program committee for the Fourth World Parkinson Congress in Portland, Oregon and presented at the First World Parkinson Congress in Washington DC: the Second World Parkinson Congress in Glasgow, Scotland: and the Third World Parkinson Congress in Montreal, Canada. He is currently a Full Professor and the Shiratzki Chair in Neurology at the Sackler School of Medicine and Sagol School of Neurosciences. He is also Director of the Neurological Institute at Tel Aviv Medical Center.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®