14/12/21 10:08 MDS SIC Blog: Genetic Testing for GBA and LRRK2 Mutations

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Genetic Testing for GBA and LRRK2

Mutations

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About the Authors

Jill S. Goldman, MS, MPhil, CGC

Genetic Counselor

Columbia University

New York, NY

David K. Simon, MD, PhD

Professor of Neurology

Beth Israel Deaconess Medical Center and Harvard Medical School

Boston, MA

Nir Giladi, MD

Professor of Neurology

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Tel-Aviv Sourasky Medical Center

Tel Aviv, Israel

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

About the Contributors

 
Blog prepared by SIC member:

Roy Alcalay, MD, MS, Columbia University, New York, NY, USA

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?

Ms. Goldman

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
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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?

Dr. Simon

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

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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.

Dr. Giladi

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

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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.

SUMMARY

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.

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