The history of a disease can be tricky to pinpoint. An individual disease makes people ill long before the disease itself has an identity or name. Archaeologists found evidence of cancer in ancient Egyptians, though cancer didn’t get its name until 1,000 years after the ancient Egyptians.
When Was Gaucher Disease Discovered?
So it’s probably impossible to know who the first person to have Gaucher disease was. But we can trace the history of the condition all the way back to the 1880s, when Gaucher disease was discovered.
Who Discovered Gaucher Disease?
Answering “what is the history of Gaucher disease” means answering three questions: what, how, and why. Philippe Gaucher, a French doctor, answered the “what” in 1882.
Dr. Gaucher was puzzled by a patient who had an enlarged spleen. He thought the patient died of leukemia. However, during the autopsy, he discovered that the spleen wasn’t just engorged—the organ itself had enlarged cells. Those enlarged cells are now known as Gaucher cells, and the enlarged spleen is a hallmark of the disease.
Symptoms of Gaucher Disease: The List Grows
Researchers continued to build upon Dr. Gaucher’s findings, adding to the list of Gaucher disease (GD) symptoms. In addition to an enlarged spleen, doctors found:
- Enlarged liver, lungs, and kidneys
- Digestive problems
- Bone problems and fractures
- Joint pain
- Growth problems in children
- Nosebleeds, bruising, and anemia
Gaucher disease types 2 and 3 symptoms
In the 1920s, doctors noticed neurological symptoms as well, such as convulsions, intellectual disability, and muscle twitches. This type eventually became known as type 2, which doctors usually diagnose in babies at around 6 months of age. Babies with type 2 rarely live more than two years.
In the late 1950s, doctors described a third type of GD (type 3), which is characterized by late-onset neurological symptoms. People with type 3 can live into adulthood with symptoms that may include seizures, cognitive problems, and blood disorders. Today, types 2 and 3 are called neuronopathic Gaucher disease.
What Causes Gaucher Disease?
In the early 1900s, Dr. Nathan Brill, an American pathologist, answered: “How do people develop Gaucher disease?” Dr. Brill suggested that Gaucher disease is an inherited condition and that both parents had to pass on the gene for their child to develop GD. (It would take another few decades until researchers made the next genetic breakthrough—identifying one of the gene mutations that causes GD).
Dr. Brill was also the first to use the name “Gaucher disease” and the first to diagnose a living patient.
In 1934, a French chemist discovered what causes the spleens and livers to enlarge: A lipid (fatty substance) called glucocerebroside builds up in the organs. This buildup causes the symptoms of GD, such as the spleen and liver enlargement, anemia, fatigue, and bone problems.
Why Do People With Gaucher Disease Accumulate Glucocerebroside?
In the 1960s, Dr. Roscoe Brady, an American biochemist, was working with a team at the National Institute of Neurological Disorders and Stroke. His team answered the next question, “Why does glucocerebroside build up?”
Dr. Brady explored why people with GD produce too much glucocerebroside. But as he discovered, the problem isn’t with production. The problem is how the body breaks down the material.
Dr. Brady’s team realized that patients with GD lack the enzyme glucocerebrosidase, which breaks down glucocerebroside. Their bodies produce a normal amount of glucocerebroside, but the enzyme doesn’t break it down, so it accumulates.
The odd part was that the enzyme was not entirely lacking in patients with GD. It was slightly active—at 10-20% activity. And the highest level of activity was in the lysosomes, inside the cell, so GD became known as a lysosomal storage disease.
Diagnosing Gaucher Disease: A Historical Breakthrough
Until this point, the standard way to diagnose GD was through a bone marrow sample—an invasive, uncomfortable procedure. Using the newfound knowledge of the deficient enzyme, Dr. Brady and his team developed a simple blood test to diagnose GD.
Blood test for GD
The blood test analyzes the enzyme activity level. Based on the enzyme activity, doctors can identify the severity of the disease. Researchers also discovered that certain genotypes (the genetic makeup of the cells) are associated with types 1, 2, or 3. Using the genotype information, doctors can diagnose which type of GD the person has through the same blood test. Dr. Brady’s team also developed a prenatal diagnostic test.
Gaucher disease carrier testing
Diagnosis further evolved when it became possible to identify not only who has the disease, but who may be a carrier. Carriers don’t have the symptoms, but they carry the genetic mutation and can pass on the disease to their children.
Today, carrier screening is as simple as a saliva test. And carrier testing is now easier and more efficient than ever—you can even receive a “spit kit” and provide a saliva sample from the comfort of your home. NGF partners with JScreen to cover the out-of-pocket costs for carrier screening for over 200 genetic diseases. Simply request a kit and send back your saliva sample, then experts analyze it in a lab. A genetic counselor will schedule a call to discuss your results.
These breakthroughs have made it possible for people to learn information about their genetic statuses and prepare for their futures.
Changing the Face of Gaucher Disease Treatment
Now that diagnosing patients is relatively simple—and doctors pinpointed the problem of the inefficient enzyme—researchers turned to the next phase: “How can we use this information to improve treatment?”
Without knowing the cause of GD, previous treatments could only focus on symptom relief. Doctors examined the symptoms—such as enlarged spleens and livers—and tried to address those problems. Treatments included:
- Spleen removal
- Liver transplants
- Blood transfusions
- Orthopedic procedures
- Bone marrow transplants (successful in rare cases for people with type 1)
The difficulty was that these procedures didn’t address the cause, just the associated symptoms.
Developing Enzyme Replacement Therapy
The answer seemed straightforward: If a lack of something caused a condition, give the patients back what they’re missing, and their symptoms will improve.
But implementing this idea was challenging. It was difficult to find enough glucocerebrosidase from a human source and purify it. From 1966 until 1973, Dr. Brady and his team worked on extracting and purifying a sufficient amount of the enzyme.
Enzyme replacement therapy (ERT): First attempt
Finally, the team had enough enzyme to test the treatment on patients. The results were … so-so. In some patients, glucocerebroside levels decreased significantly. But in other patients, not so much. Dr. Brady’s team found that the glucocerebroside in the liver was stubborn. In more than half of the patients, the fatty material did not decrease.
What was going on? Glucocerebroside accumulates in macrophages, which are cells inside lysosomes. During the purification process, Dr. Brady’s team removed a lipid that helps activate the enzyme so it can attach to the macrophage. Without this lipid, the enzyme could not attach to the macrophage and break down the glucocerebroside.
ERT: Take two
So how to manipulate the enzyme to get all the way into the macrophages? Make it more attractive to the macrophages. The next step was to modify the enzyme.
Dr. Brady discovered that macrophages have mannose ligands, sugars that act as tiny receptors. His team decided that if the enzyme had a mannose molecule at the end of its chain, perhaps the macrophage would accept it. The team removed a different sugar molecule, oligosaccharides, from the enzyme, exposing the mannose. Dr. Brady hoped the enzyme would attach to the macrophage. These enzymes were called macrophage-targeted glucocerebrosidase.
It worked. The first person to receive this enzyme replacement therapy from Dr. Brady and his team at NIH was a young boy named Brian Berman—who is now the president and chief executive officer at the National Gaucher Foundation (NGF). See his story.
At first, ERT wasn’t successful for every patient in the trial. But when the team used a different dose of the replacement enzyme, all of the patients improved and had excellent outcomes within a few months. They experienced increased height and weight, improved anemia, decreased liver and spleen size, and less bone damage.
National Gaucher Foundation Helps Advance GD Research
NGF was involved in the initial research targeting the enzyme deficiency. The foundation has funded critical research since its inception in 1984. The NGF funded many grants for GD research and encouraged Gaucher researchers to communicate and share their information and discoveries. The NGF Medical Advisory Board, which included Dr. Brady, is a product of this desire to use knowledge to benefit the Gaucher community.
First Approved Drug for GD
And in 1991, the combined efforts of organizations like NGF and researchers including Dr. Brady paid off. The first enzyme replacement therapy received FDA approval. Doctors used a macrophage-targeted glucocerebrosidase, Ceredase, to treat patients with GD. In 1994, an improved drug called Cerezyme received FDA approval. Today, there are five FDA approved medications used to treat GD.
The medications mainly target type 1 and some of the symptoms of type 3, but not the brain and neurological symptoms of types 2 and 3. ERT and SRT can’t cross the blood-brain barrier, the barrier that prevents harmful substances from crossing over to the brain but also prevents medication from reaching it.
The work that began more than a century ago—starting with Dr. Gaucher’s puzzling patient in the 1880s—reached a life-saving milestone. Many people with GD went from living with a life-threatening disease to living with a condition that can be managed and treated with medication.
The Future of Gaucher Disease
The story of GD doesn’t end with ERT in the 1990s. Research is leading to new insights and understanding, including studying the genetic component of GD and how it works in the body. The goal of all this research is new, improved, and more effective treatments for Gaucher disease.
A small sampling of recent research includes:
- Genetics: Understanding more about the genetics of GD, including finding the mutations (more than 300 so far—and some researchers think the number of mutations may possibly top 500 ) of the glucocerebrosidase (GCase) gene
- Protein: Researching the protein alpha-synuclein, which works with the GCase enzyme, to better understand how GD works
- Treatment: Testing medicines that can cross the blood-brain barrier to find effective methods to treat types 2 and 3
- Gene therapy: Inserting a working gene to correct the ineffective enzyme in the patient’s cells
The path from “discovery” to “treatment” is never linear and requires years of research, testing, failures, and trying again. Thanks to the continued efforts of tireless researchers, organizations like NGF, and the Gaucher community, people with Gaucher disease have more hope than ever before.
- Office of NIH History. Researching Disease: Dr. Roscoe Brady & Gaucher Disease. https://history.nih.gov/exhibits/gaucher/index.html
- Gauchers Association (archived site). The History of Gaucher Disease. http://www.gaucherdisease.org.uk/brad_feb00.htm
- Icahn School of Medicine at Mount Sinai. Gaucher Disease Treatment Center. https://icahn.mssm.edu/research/gaucher
- Argosy University. Gaucher Disease: A Story of Science and Humanity. https://www.argosy.edu/our-community/blog/gaucher-disease-a-story-of-science-and-humanity