Gaucher disease results when an individual inherits two mutations in the GBA gene. Mutations in this same gene also play a role in developing Parkinson’s disease, a movement disorder that mostly affects older adults.
Many people who have Gaucher disease or are Gaucher carriers may be aware that they have a higher-than-average risk of developing Parkinson’s disease. For April, Parkinson’s Disease Awareness Month, we discussed that risk—and why it’s still only a low risk—with Ellen Sidransky, MD, an expert in the genetic aspects of Gaucher disease and Parkinson’s disease.
Dr. Sidransky is chief and senior investigator of the Medical Genetics Branch and head of the Molecular Neurogenetics Section of the National Human Genome Research Institute of the National Institutes of Health. She is a physician who is board-certified in pediatrics and medical genetics. Her research includes both clinical and basic research aspects of Gaucher disease and Parkinson’s disease. Her group was the first to identify glucocerebrosidase as a risk factor for parkinsonism.
She has led two large international collaborative studies on the genetics of Parkinson’s disease and dementia with Lewy bodies. She is a member of the National Gaucher Foundation’s Medical Advisory Board.
What Is Parkinson’s Disease?
Parkinson’s disease is a progressive neurodegenerative disorder, meaning it gradually impairs the nervous system. It mostly affects specific nerve cells called midbrain dopaminergic neurons. But it can impact different parts of the nervous system as it worsens.
People with Parkinson’s disease most often show signs after age 60. The most common symptoms of Parkinson’s include:
- Bradykinesia (slow movement)
- Loss of balance
- Muscle rigidity
- Resting tremor (shaking)
It can also affect health in other ways, including
- Cognitive impairment (difficulty thinking clearly)
- Impaired sleep
- Orthostatic hypotension (low blood pressure when you stand up)
- Urinary symptoms
What is Parkinsonism?
The term “parkinsonism” describes specific motor features including slowness of movement, tremor, and/or rigidity. These features occur in Parkinson’s disease as well as other neurodegenerative conditions known as Parkinson’s plus disorders or can be a side effect of certain medications.
Changes (mutations) in the GBA gene are seen in at least two other Parkinson’s-related disorders:
- Dementia with Lewy bodies (DLB): This type of dementia is characterized by Lewy bodies, clumps of proteins in the brain distributed throughout the brain. In people with DLB, cognitive issues often appear before, simultaneously, or within one year of the onset of parkinsonism. (Dementia that appears after many years of a Parkinson’s disease diagnosis is classified as Parkinson’s disease dementia or PDD.)
- REM sleep behavioral disorders (RBDs): Typically, during the deepest sleep—called rapid eye movement (REM) sleep—only the eyes move. People with RBD act out their dreams and may shout, kick or fight during this sleep stage. RBD affects about half of people with Parkinson’s disease. Doctors consider RBD a prodromal sign of Parkinson’s disease—a symptom that occurs before motor symptoms of Parkinson’s disease, which are typically used for a clinical diagnosis. Someone who has an RBD may receive a Parkinson’s disease diagnosis within 10 years.
How Are Gaucher Disease and Parkinson’s Disease Related?
Around the year 2000, doctors and researchers noticed an association between Gaucher disease and Parkinson’s disease. In 2009, researchers confirmed this association in an international multi-center collaboration. To date, GBA gene mutations are the most commonly known genetic risk factor for Parkinson’s disease.
Gaucher disease involves mutations in GBA, the gene that encodes glucocerebrosidase (GCase). GCase is an enzyme that works inside lysosomes, the part of cells that break down fats called lipids. In Gaucher disease certain lipids are not degraded and the result is a lysosomal storage disorder.
Misfolded proteins in Gaucher disease
“When you have mutations in the GBA gene, often times the GCase protein is misfolded and never gets to the lysosome,” Sidransky explains. “The lysosome’s function is to break down unneeded materials.” In Gaucher disease, people don’t have enough of the GCase enzyme, and lipids accumulate. As a result, lysosomes don’t function as well as they should. Sidransky says, “Some describe it as a vicious cycle: When the enzyme isn’t made, lipids accumulate. The lipids block other things, which contributes to the dysfunction of the lysosomes.”
Lysosomal storage disorders in Parkinson’s disease
In Parkinson’s disease associated with mutations in GBA1, the lysosomal system also may not work as it should, although researchers are still working to understand how.
Typically, people with Parkinson’s disease have elevated levels of a protein called alpha-synuclein in the brain, at the tips of certain neurons (nerve cells). In people with Parkinson’s disease, alpha-synuclein builds up in structures called Lewy bodies.
GCase levels and alpha-synuclein levels are related at a metabolic level. When GCase levels are low, alpha-synuclein accumulates. Scientists don’t yet fully understand the connection.
“We still don’t totally understand the pathogenesis (development) of Parkinson’s disease, but the protein alpha-synuclein seems to be part of the pathology,” Sidransky says. “With Parkinson’s, alpha-synuclein is degraded in the lysosome. A less-than-optimally functioning lysosome could be part of the equation.”
Some researchers think the problem in GBA-associated Parkinson’s disease is that without enough GCase enzyme, lipids accumulate, and that the lipid levels may be related to developing Parkinson’s.
“Others think that’s unlikely because Gaucher carriers generally don’t have lipid accumulation—only people with GD do,” Sidransky says. “But carriers still have a high incidence of Parkinson’s. Therefore, the GCase enzyme must have a different role.”
Increased risk of Parkinsonism in the Gaucher community
Unfortunately, people with GBA mutations that cause Gaucher disease do have a higher risk of developing Parkinson’s disease. Still, Sidransky points out that most people—including those with Gaucher disease—never develop Parkinson’s.
In the general population, a rough estimate is that Parkinson’s affects around 1% of the population over age 60. Small numbers of people receive a diagnosis at a younger age. Up to 5% of individuals (1 in 20) in the general population may develop Parkinson’s disease or related conditions by age 85.
People with a Gaucher gene mutation have:
- Higher frequency of Parkinson’s disease: As many as 9% of people with Gaucher disease may develop Parkinson’s disease. The risk is up to 3% in Gaucher carriers.
- Earlier onset of Parkinson’s disease: Parkinson’s disease may start earlier in people with the GBA gene mutation than in non-carriers. On average it may appear 6–11 years earlier in people with Gaucher and 3–6 years earlier in carriers, but there is a range.
- Greater likelihood of DLB: DLB cases may appear around 5 years earlier in Gaucher carriers and be more severe. This disorder is more likely in men than in women.
- More frequent RBDs: GBA mutations are also more common in people with RBDs. But people who have a GBA mutation and RBD don’t appear to be more likely to progress to Parkinson’s disease than those without Gaucher disease.
Ultimately, Sidransky says, “the biggest risk factor for Parkinson’s disease is aging. Lots of things go on during aging, and there are probably factors related to aging that are modifiers of the gene mutation and other risks”. “We do know that Parkinson’s disease is a disease of aging and is more frequent as you get older. There are probably other genetic risk factors that still need to be elucidated.”
Parkinson’s risk in the Ashkenazi Jewish population
Asked about Parkinson’s risk in the Ashkenazi Jewish community, Sidransky notes that this community has two fairly common genetic risk factors for Parkinson’s disease. One is GBA. The other is LRRK2 (pronounced Lark 2), which provides instructions for making a protein called dardarin.
“Over one-third of patients with Parkinson’s disease have a mutation in one of those two genes,” Sidransky says. “Of all the genes related to Parkinson’s disease, a fair amount is known about these two. Researchers are making attempts at gene-specific therapies, especially for patients with mutations in these genes.”
The future of treatments for Gaucher disease and Parkinsonism
Today, Gaucher treatments and Parkinson’s treatments don’t overlap. Parkinson’s disease affects the brain, and Parkinson’s disease treatments must cross the blood-brain barrier (BBB).
The BBB is a network of cells and blood vessels designed to keep many substances from reaching the brain. Its existence protects the brain from many types of bacteria and other foreign matter. But it makes some therapies hard to deliver.
Current Gaucher disease treatments, including enzyme replacement therapy and substrate reduction therapy, don’t cross the BBB. They don’t affect Parkinson’s. For the same reason, they don’t affect the neuronopathic symptoms of Gaucher disease types 2 and 3.
Some good news, Sidransky says, is that the link between these two disorders means that scientists are paying a lot of attention to the mechanisms that cause both conditions. That attention will lead to new therapies, including for the rarer (in the U.S.) neurologic forms of Gaucher disease.
Future treatments might involve:
Small chemical chaperones
Ordinarily, when a cell makes a protein, the protein gets folded and transported to the lysosome, where the enzyme becomes active. If it’s not folded correctly, it breaks down before it can activate. Chaperones are small molecules that can help proteins fold.
“If you can find a good chaperone, you may be able to increase folding, so even if there’s a mutation, proteins can still get into lysosomes and function at least partially,” Sidransky says.
Sidransky’s current work focuses on the association between Gaucher disease and parkinsonism. Part of that work is developing small molecule chaperones as therapy for Gaucher disease and, potentially, parkinsonism. Her team has screened a quarter-million possible molecules to increase GCase activity by chaperoning.
“We found a few possibilities, and we are hopeful that one day, they might lead to a good therapeutic approach,” she says.
“Parkinson’s disease doesn’t come in just one flavor,” Sidransky says. “There are different genetic risk factors. GBA is one, LRRK2 is another, and the gene for alpha-synuclein is a third but there are several dozen other genes identified.”
In the future, doctors might do genetic tests to tailor therapies to a specific mutation.
The concept behind gene therapy for Parkinson’s disease is that doctors might be able to increase levels of GCase by delivering using gene therapy directly to the brain. The treatment might be able to adjust levels of alpha-synuclein and decrease nerve cell dysfunction.
Those studies are in the very earliest stages, with safety still to be determined. Learn more about gene therapy for Gaucher disease.
What should you do if you carry a mutation in the GBA that may put you at higher risk for Parkinson’s?
If you’re concerned about having a higher risk of Parkinson’s due to being a Gaucher carrier or having Gaucher disease, remember: That risk is still very low.
“Genetic testing can tell you if you have a gene mutation in the GBA gene, but it can’t tell you if you’re going to develop Parkinson’s disease,” Sidransky says. “If the risk is about 2% in the general population, and people with a GBA mutation have a three-to-five-times higher risk, that risk is still under 10%. That means you still have a 90% chance of not developing Parkinson’s disease.”
For the future, that genetic information might provide helpful information about optimizing your health as you live with Gaucher disease. It also might tell you if you would qualify for some of the more targeted therapies that science may develop. Sidransky’s primary advice for people with Parkinson’s disease is to stay active. “Exercise has been shown to be quite helpful in Parkinson’s disease,” she says. “And working with a movement disorders specialist can give you access to the best conventional medications that are available right now, understanding that it is a progressive disease.” She is hopeful that “in the coming years new therapies may appear on the horizon.”
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