The complicated world of genetic testing for Parkinson’s disease

Genetic testing for Parkinson’s disease

Similar to other complex diseases, the reason a particular person develops Parkinson’s disease (PD) is likely a combination of genetic makeup and environment. In most people, the genetic contribution to disease development may be due to a number of different genes and the interactions between them. For only a very small percentage of people with PD, about 10%, the disease can be attributed to a single abnormal gene. Figuring out the identity and contributions of all the different genes that play a role in disease development is a very hot topic in PD research today.

Who should consider a genetic test for Parkinson’s?

There are two groups of people who might consider getting genetic testing and we will discuss each group separately.

  1. People with PD, possibly with a strong family history, who may want to know if they carry a genetic mutation that contributed to their developing PD, and if they may pass on that mutation to their children.
  2. Children and siblings of people with PD who do not have PD, but are concerned about their genetic risk of developing the disease.

Genetic testing for PD is therefore a common request and a number of commercial labs perform panels of genetic testing for PD.

Both groups are faced with two questions: Should I get genetic testing? And if so, what should I do with the results? Before we address these two questions, we need to learn more about the complexity of genetic testing in PD.

Why genetic testing for PD is complex:

  • There are many genes that are associated with the development of PD. This list continues to grow as more genes are discovered. Testing of only some of these genes is available in commercial labs.
  • The majority of people with PD, even those with a family history of PD, do not harbor one of these identified abnormal genes. The genetic contribution to PD in these people is yet to be discovered.
  • For a particular gene there may be a number of different mutations associated with disease, some of which are more common than others. Commercial testing may identify only the most common of the mutations, and therefore not capture everyone who carries a disease-causing mutation.
  • Conversely, only particular mutations in a gene may be associated with disease. Commercial testing may identify changes in a gene that may not have clinical consequences. This can be confusing for patients who even after genetic testing may not know whether they harbor a disease-causing mutation.
  • Different mutations can be enriched in different ethnic populations. For example, Ashkenazi Jews and North African Berbers have an increased risk of carrying Leucine rich repeat kinase 2 (LRRK2) mutations. Glucocerebrosidase (GBA) mutation frequency also varies greatly with ethnicity and is also increased among Ashkenazi Jews.

In addition to the above, it is important to realize that not all genes associated with PD contribute to disease in the same way:

  • Autosomal dominant inheritance means that one abnormal copy of the gene is required to cause disease
  • Autosomal recessive inheritance means that two abnormal copies of the gene are required to cause disease
  • Risk factor modifiers are genes that when mutated, increase the risk of developing PD, presumably through interactions with other genetic or environmental causes.

To make things even more complicated, in some situations, harboring one autosomal dominant or two autosomal recessive mutations is still not enough to cause disease. This phenomenon is referred to as reduced penetrance and means that a person may harbor the disease-causing mutation and not develop the disease. Additional genetic or environmental factors must also need to be in place for the disease-causing mutation to manifest itself.

Because of all this complexity, it is imperative that before you undergo genetic testing, you first meet with a genetic counselor who will explain in detail what the test can and cannot tell you. And you also need to discuss with your neurologist what you might (or might not) do with the results, as your options are quite limited.

People who already have PD: Should I get tested and what do I do with the results?

Up until recently, even people with PD with a very extensive family history of PD would not necessarily receive genetic testing because there were no clear uses for the results. There has been research directed at figuring out whether PD caused by or associated with certain mutations have particular clinical characteristics (e.g. more or less cognitive impairment, more or less dystonia). However, there remains so much variability in clinical characteristics even among people with the same PD mutation, that there are still no clear practical implications in knowing whether a PD patient harbors a particular mutation.  There is also, so far, no difference in treatment or management of PD whether or not the patient harbors one of the known mutations. That may change however, with the advent of clinical trials that target particular mutations.

There are two genes that have received particular attention recently because medications are being developed that target those with mutations of these genes.

  • GBA is a gene that increases the risk of developing PD. The gene encodes for the GBA enzyme, a protein used by the body to break down cellular products. Having two abnormal GBA genes causes Gaucher’s disease, which is characterized by the buildup of these cellular products resulting in fatigue, bone pain, easy bleeding and an enlarged spleen and liver. When a person inherits only one abnormal gene, he or she does not develop Gaucher’s disease, but does incur a small increased risk of PD. Most people with one mutated GBA gene do not develop PD.

Enzyme replacement therapy, in which the GBA protein is given intravenously, is available as a treatment for Gaucher’s disease. This protein is too big to cross the blood-brain-barrier however, and so it does not enter the brain and does not treat any symptoms caused by the abnormal buildup of cellular components in the brain. Drug companies set out to develop small molecules that can cross the blood-brain-barrier and help breakdown the accumulated cellular products. The pharmaceutical company Sanofi developed such a molecule and it is currently in clinical trials.

  • LRRK2 is a gene that causes autosomal dominant PD (only one abnormal gene is needed to cause PD), but with a reduced penetrance of 30% (only 30% of people who have the one abnormal gene will develop PD). The gene encodes the LRRK2 enzyme which adds phosphate groups onto other proteins. Mutations in LRRK2 that cause PD, increase the activity of LRRK2. The pharmaceutical company Denali developed a small molecule which inhibits the activity of LRRK2 and it is currently in clinical trials.

Of note, APDA-sponsored research of LRRK2, showed that even in PD patients without LRRK2 mutations, LRRK2 activity was increased, likely due to other biochemical changes in the cell. This implies that the medication under development may be helpful for all patients with PD and not just those with LRRK2 mutations. The clinical trial described above is therefore recruiting patients with and without the LRRK2 mutations and will compare how each group responds to the medication.

The pharmaceutical companies that are looking for clinical trial participants who have specific mutations are incorporating genetic testing into their trial design and collaborating with various partners to increase access to genetic testing. If a person is obtaining genetic testing for LRRK2 and GBA outside the context of a clinical trial, he/she should be aware that while all commercial PD genetics panels test for LRRK2 mutations, some do not include GBA. GBA testing is commercially available, but may need to be ordered separately.

Direct-to-consumer genetic testing for Parkinson’s

Direct-to-consumer genetic testing is available, without involving a physician, typically using a mailed-in saliva sample. This is different from commercial labs that provide PD genetics panels that can only be accessed with a doctor’s prescription. Some PD patients and family members may consider getting PD genetic testing via this method. A summary of direct-to-consumer genetics testing, is provided on this NIH web page.

Before you pursue this method of testing, you should consult with your neurologist and be aware of what PD genetic testing is actually being provided. For example, the standard genetic testing of the direct-to consumer company 23andme, consists of only two variants in the LRRK2 and GBA genes. Therefore, anyone who carries a mutation in another gene or who carries a less common disease-causing mutation in LRRK2 and GBA, will receive a report that they do not carry the tested mutations, and may misunderstand that they do not carry any mutation. If you do decide to pursue testing in this manner, please review the report with your neurologist to make sure that you understand it correctly.

To summarize, at this juncture, the only practical implication of genetic testing for people with PD, is potential participation in particular clinical trials. However, as we discover more about the genetics of PD, genetic testing will expand and there will likely be more and more reasons to get tested.

Family members without symptoms: Should I get tested and what do I do with the results?

Genetic testing of people with a family history of PD but no symptoms is even more tricky. As mentioned above, some mutations that cause PD have decreased penetrance and a large percentage of even those who carry the mutation will not develop the disease. For example, LRRK2 is only 30% penetrant, which means that only 30% of the people who have the mutation will develop the disease. This makes testing of asymptomatic people more complicated because even with the mutation, there is a 70% chance of never having to worry about the disease at all. The decision to get genetic testing must therefore be done after fully understanding of all the available information and with the advice of a genetic counselor.

In addition, for asymptomatic people who are at increased genetic risk of PD, there are no clinical trials to participate in and no preventative medications to take in order to reduce the future risk of developing PD. This means that there are no practical consequences of knowing about the increased genetic risk. Exercise may modify PD risk, and therefore should certainly be encouraged in people with an increased genetic risk of PD. However, exercise is valuable regardless, since it modifies many chronic health conditions. Nevertheless, if knowing about a person’s increased genetic risk of PD motivates him or her to perform regular exercise that could be considered in the decision of whether or not to be tested.

Tips and Takeaways

  • The issues surrounding genetic testing are complex and are different whether testing is being pursued by someone who has PD or someone who only has a family history of PD, without symptoms of PD.
  • Genetic testing for a number of genes that contribute to PD is available. However, there is much that is not yet known and most people with PD, even with a family history, will not carry one of these abnormal genes.
  • Before you pursue genetic testing, it is vital to meet with a genetic counselor who can explain what the testing will and will not be able to tell you.
  • As medications are developed for particular genetic mutations in PD, genetic testing for PD will likely become more commonplace.
  • If you get a positive result from genetic testing for PD, current treatment options are limited, but you might be eligible to participate in a clinical trial that is investigating the particular genetic mutation you have.

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Dr. Rebecca Gilbert

APDA Vice President and Chief Scientific Officer

Dr. Gilbert received her MD degree at Weill Medical College of Cornell University in New York and her PhD in Cell Biology and Genetics at the Weill Graduate School of Medical Sciences. She then pursued Neurology Residency training as well as Movement Disorders Fellowship training at Columbia Presbyterian Medical Center. Prior to coming to APDA, she was an Associate Professor of Neurology at NYU Langone Medical Center. In this role, she saw movement disorder patients, initiated and directed the NYU Movement Disorders Fellowship, participated in clinical trials and other research initiatives for PD and lectured widely on the disease.

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