Gaucher Disease: A Rare Disease Sheds Light on More Common Conditions

When Pramod Mistry, MD, a Yale Medicine expert in inherited liver diseases, cared for his first patient with Gaucher disease 35 years ago, he didn’t anticipate that his work with this rare genetic disorder might illuminate the understanding of more common conditions such as multiple myeloma and Parkinson’s disease.

Dr. Mistry, director of the National Gaucher Disease Treatment Center at Yale, has focused his career on Gaucher, which affects one in 40,000 people worldwide. The disease is characterized by fat-filled cells that accumulate in parts of the body including the liver, spleen, and bone marrow; in some forms of the disorder, the brain, lungs, and lymph nodes are also affected. This buildup causes inflammation, enlarged organs, bone pain, and other disabling symptoms, while also raising the risk for fracture.

In 2001, a patient of Dr. Mistry’s with Gaucher disease also developed multiple myeloma, a type of blood cancer, which affects plasma cells in the bone marrow. “Why did I get multiple myeloma?” the patient asked Dr. Mistry. It was a good question. At that time, there were a few isolated case reports of people with Gaucher being diagnosed with multiple myeloma, but the connection was not understood.

Dr. Mistry’s patient, a physician, followed up by also asking, “What is the mechanism here, and what can be done about it?”

“I took that question to heart,” Dr. Mistry says. “Everything starts and ends with patients. First, we conducted a Yale-focused study in one of the largest groups of patients in the world and then expanded to an international cohort. Our research taught us that the fat-filled cells called macrophages talk to immune cells called B-lymphocytes, which produce excessive amounts of antibodies, and unchecked, it leads to multiple myeloma.”

The Yale study, published in 2009, was the first comprehensive analysis demonstrating that Gaucher disease increased the risk of myeloma by 25-fold compared to the general population, Dr. Mistry says. The next step was to take this information to the laboratory and develop intricate mouse models of Gaucher disease. “We learned that the accumulation of this fatty material in macrophages, the scavenger cells of the body, triggers an inflammation of the immune system to be activated in such a way that B-Lymphocyte, starts to make antibodies to the lipid,” he says.

Based on the lab study, that activation of the immune system is believed to eventually cause a sequence of events, he explains, that leads to the development of multiple myeloma. With a hypothesis to explain this process, Dr. Mistry led an international clinical trial testing a pill that slows the Gaucher disease process, replacing the traditional biweekly infusion treatments. This drug, eliglustat (Cerdelga®), was FDA-approved in 2014, marking a significant advance in Gaucher disease therapy. Further studies indicated that this pill not only treated Gaucher symptoms but also reduced the precancerous conditions associated with multiple myeloma. Dr. Mistry believes such treatment strategies could prevent multiple myeloma in future generations of Gaucher patients.

“When it comes to discoveries and research questions, every single major question that we've pursued in the laboratory has started with a patient asking the question,” Dr. Mistry says. “We then study it in a larger number of patients and then take it into the lab to apply the most cutting-edge technology to dissect the problem. Among the most important skills I try to teach my medical students is that they must develop the art of listening to their patients, because they define very fundamental questions about their disease.”

In the Q&A interview below, Dr. Mistry describes how research focusing on rare diseases can provide valuable insights into more common diseases.

A rare disease, by definition, affects fewer than 200,000 individuals in the United States. This definition is derived from the Orphan Drug Act, which President Ronald Reagan signed in 1983, to promote the development of therapies for rare diseases.

Approximately one in 10 Americans suffers from a rare disease, and there are more than 7,000 rare diseases in total. Although each disease is individually rare, collectively they form a mighty community, yet patients often suffer in silence and isolation. Since the enactment of the Orphan Drug Act, the rare disease community has made significant strides, yet many patients still endure a prolonged diagnostic odyssey, feeling underserved and often isolated.

Gaucher disease is caused by an enzyme deficiency in the lysosomes. Lysosomes are cell components that act like a garbage factory for the body, because they contain enzymes that break down waste materials and cellular debris.

In Gaucher, there is a genetic deficiency of an enzyme called glucocerbrosidase, which is responsible for breaking down a fatty substance called glucocerebroside. If this chemical, or lipid, builds up in the lysosomes, the cells get engorged and they collect in various parts of the body, including the liver, spleen, bone marrow, and lungs.

This accumulation causes symptoms including a swollen belly, bone pain (and increased fracture risk), anemia (low red blood cell count), fatigue, bleeding (frequent nosebleeds, gum bleeding), and bruising (resulting from a decrease in blood platelets caused by an enlarged spleen). In some forms of the disease, the brain is also involved, causing neurological symptoms such as seizures or Parkinson’s disease.

Gaucher is an inherited disease. To get it, you must have two mutations, one from your mother and one from your father, of a gene called GBA. It is present at birth, but symptoms may not occur until later, even into adulthood. Gaucher disease is most common among those of Ashkenazi Jewish descent. Due to certain genetic factors, it affects approximately one in 450 people in this population.

The program we have built at Yale, called the National Gaucher Disease Treatment Center, is a destination program that is ranked among the top in the world. We started it in 2001, and there’s still a need for more centers like this, but unfortunately, there are very few. Our center is unique, in that alongside offering holistic care, we have a vibrant clinical and lab research program that is helping to shape the modern clinical care for this disease.

When patients come to us from long distances, they can see all the specialists that they may need in consecutive appointments in one stop, in one day. This includes me, hematologists, neurologists, orthopedists, and genetic counselors.

We have a more than two-decade history of focusing on Gaucher disease, but Gaucher is one of about 40 lysosomal diseases, and we look after patients with all the different forms of these diseases. For about half a dozen of the lysosomal diseases, we have enzyme treatments, and our goal is to understand the biology of the disease so that we can also help to advance those treatments.

Although Gaucher disease is a rare disease, it has immense potential to inform the understanding and treatment of more common diseases. For example, while multiple myeloma is considered a rare cancer, it affects about 170,000 individuals around the country. And what we've learned is that the mechanism that we outlined for Gaucher disease operates in about one-third of patients with multiple myeloma as well. Stimulated by our work, another group found out that the Gaucher disease genetic defect occurs more frequently in people with multiple myeloma.

Gaucher disease research has similarly illuminated the understanding of Parkinson’s disease, a central nervous system disorder that affects movement, and Lewy body dementia, a brain disorder that causes cognitive decline, behavioral changes, and movement issues.

After observing an unexpectedly high prevalence of Parkinson’s in Gaucher patients—21 times greater than in the general population—myself and other researchers identified key shared biological mechanisms. These insights are helping scientists develop therapies aimed at halting the progression of Parkinson’s disease, offering hope for a cure where previously treatments only managed symptoms.

Here, too, we study models in our lab, including stem cells models, to understand the mechanism. And we've learned that this lipid, this fatty material that builds up in Gaucher disease, drives the fundamental process that harms neurons in the substantia nigra, the part of the brain that is damaged in Parkinson's disease.

As we create new treatments for Gaucher, we can potentially help tens of thousands of people with Parkinson’s disease who are carriers of the Gaucher disease mutation. For Parkinson’s, there are no therapies. All you can do is give medicine to control symptoms, but patients die of dementia and of severe frailty. But what we have learned from Gaucher disease is that you can arrest the disease process itself with disease-modifying therapies that we are attempting to create.

Living with a rare disease can be extremely challenging. Often, patients find themselves in the difficult position of having to educate their own doctors about their condition. This situation leads many patients to seek community with others experiencing similar challenges, sharing insights and support through online forums, LISTSERVs, and social media groups.

Physicians can and should be part of these communities. Personally, I have found that engaging with patient-led communities provides invaluable insights into the lived experiences and practical realities of the disease—insights I wouldn't gain from clinical interactions alone.

It's crucial that we never view patients merely as interesting genetic cases; they are individuals experiencing real suffering. Psychological and emotional health is a fundamental component of patient care. I've observed that when we build trust and establish genuine connections with our patients, our interactions themselves can become part of the healing process.

Patients with rare diseases are sometimes unfairly labeled as medical "enigmas." Such terminology is distressing and isolating. It highlights our own professional limitations rather than the complexity of the disease itself. With today's advanced diagnostic technologies and medical imaging capabilities, we have powerful tools to unravel the complexities of these conditions. No patient should ever remain an enigma. Our goal must always be to understand fully the root causes of their condition and to use our knowledge and technology to provide real solutions.