A rare condition affecting about 1 in 40,000 live births, Gaucher disease has not always been a research priority. But times are changing. Since 1998, Dr. Ellen Sidransky, head of the Molecular Neurogenetics Section in the National Human Genome Research Institute of the National Institutes of Health in Maryland, has been at the forefront of proving a connection between Gaucher disease and Parkinson disease, a more common, progressive neurological disorder that affects about 1.5% of the population over age 65. In the process, her work has shined a light on Gaucher disease.

Serendipity Leads to Proven Tie Between Gaucher and Parkinson Diseases

Dating back to the 1990s, researchers noticed a trend towards comorbidity between Gaucher disease and Parkinson disease. At first researchers thought the link was nothing more than coincidence. But the findings persisted, and in 2001, Dr. Sidransky published an article about the connection.

Several years later, serendipity led to a deeper understanding of this relationship. A former student of Dr. Sidransky’s performed an autopsy on a Parkinson patient and noticed the patient also had Gaucher disease. Since the former student was aware of Dr. Sidransky’s interest in the subject, she offered to send her a brain sample from the autopsy. Dr. Sidranky requested that she also send brain samples of individuals who had “run of the mill Parkinson disease,” so the two types of samples could be compared.

The results were surprising. “It turned out one of them had two Gaucher mutations, like we had expected because he had Gaucher disease. But the other two were also Gaucher carriers, which was really strange,” she said.

She then ordered Parkinson brain samples from brain banks around the country. Out of 58, about 12 had mutations of the Gaucher gene, a fact that caught the interest of many Parkinson disease researchers. In 2008, 16 Parkinson centers came together and screened more than 5,000 patients with Parkinson disease and an equal number of matched controls without the disease for mutations in the Gaucher gene, glucocerebrosidase. The combined results showed that patients with Parkinson disease were over five times more likely to carry a mutation. A subsequent study found that for related disorder, dementia with Lewy bodies, the risk for having a mutation was even higher—over eight times that found in controls. While earlier studies uncovered a connection between Gaucher and Parkinson patients, it soon became clear that carriers, too, were at greater risk.

Comorbidity with Parkinson: The Risks for Gaucher Carriers

So why do Gaucher carriers and patients develop Parkinson disease more often? At this point, researchers aren’t entirely sure. One theory is that, like Gaucher, Parkinson disease may be related to the body’s inability to bring the enzyme glucocerebrosidase to the lysosome. In recent years, some evidence has also indicated that those with a Gaucher mutation may have an earlier onset of Parkinson disease than those without mutations, and that they may experience more severe symptoms.

As an advocate for the Gaucher community, Dr. Sidransky is mindful that the connection between these two diseases may trigger fear.

“I think it’s important for the Gaucher community to realize that just because you have Gaucher disease doesn’t mean you are going to develop Parkinson disease, but you are at a slightly increased risk,” she explained. “So, awareness is key.”

She added that even if a Gaucher patient or carrier develops Parkinson, it does not necessarily mean symptoms will be more severe.

Hope for Gaucher Community: Potential Treatments for Both Conditions

With growing awareness of the ties between these two conditions, medical researchers are working to develop new treatments.

• Small Molecule Chaperones: When glucocerebrosidase is made, it must be “folded” and transported to the lysosome. When patients have the Gaucher mutation, it does not get properly “folded,” and never makes it to the lysosome. Researchers are looking for a chemical, known as a molecular chaperone, which can bind to the mutant enzyme and stabilize it. Drug companies were interested in this concept even before connections to Parkinson were known. They are even more interested now.
• Focus on Siblings: Dr. Sidransky and her team are currently following different sibling pairs who have Gaucher disease. In each pair, only one sibling has developed Parkinson disease. They are looking at genes, clinical parameters and PET scans to identify factors that might protect an individual from getting Parkinson disease.
• Blood-Brain Barrier: It is interesting to note that because Parkinson disease affects the brain, and research is being done on getting the enzyme glucocerebrosidase to the lysosome in the brain, this may help those with neuronopathic forms of Gaucher disease, namely type 2 and type 3.

Dr. Sidransky’s work has helped bring new attention not only to Gaucher disease, but also to the importance of studying rare conditions.

“There’s now a lot of interest in this enzyme,” said Dr. Sidransky. “The more we learn about it, the more drug companies will focus their efforts on developing agents to target it—and that will benefit all people with Gaucher disease.”