The way Gaucher disease affects different individuals can seem like a mystery. Even in the same family, some people have only mild signs and symptoms, while others face devastating outcomes.
Now, researchers are unraveling the genetic changes that cause Gaucher disease. Their work tells patients and families more about how genes influence Gaucher disease—and how doctors might be able to tailor treatment to individuals.
Just in time for Rare Disease Day on Feb. 28, we spoke with Dr. Gregory Grabowski, one of four authors of a forthcoming research paper. The paper, “Gaucher disease: Basic and translational science needs for more complete therapy and management,” examines current scientific knowledge about Gaucher disease. It also offers a roadmap for the future.
Dr. Grabowski is professor emeritus of Pediatrics and of Molecular Genetics, Biochemistry, and Microbiology at the University of Cincinnati College of Medicine and the Cincinnati Children’s Hospital Medical Center. He has published more than 350 scholarly works on the science of lysosomal diseases, including Gaucher disease. For more than 25 years, he has worked with a philanthropic program to treat Gaucher disease patients in Egypt and other countries. He is a member of the National Gaucher Foundation’s Medical Advisory Board.
The Continuum Hypothesis and Gaucher Signs and Symptoms
The continuum hypothesis is a theory about how Gaucher disease affects individuals. This hypothesis assumes that the severity of Gaucher disease relates directly to how much enzyme activity you have in your cells. That is, having less enzyme activity would cause more severe effects. And people with more enzyme activity would have milder manifestations.
No test can measure or predict the level of enzyme activity. But doctors can predict Gaucher severity using the continuum hypothesis.
The manuscript by Dr. Grabowski and the other three authors provides guidance based on existing literature. It also suggests topics for future study, to help doctors understand why some people with the same type of Gaucher have different degrees of involvement.
With more information, doctors can make better predictions about how Gaucher disease might progress in a specific individual’s body. And, hopefully, they can offer more personalized treatments.
Why Research the Continuum Hypothesis?
Dr. Grabowski’s team examined the bases of the continuum hypothesis and whether it provides a forecast for an individual’s path with Gaucher disease. To do so, they reviewed past studies and considered their experience with hundreds of patients.
They looked at whether they could reasonably predict:
- How severe Gaucher disease could be for an individual
- When individuals should start enzyme replacement therapy or substrate reduction therapy
- How Gaucher disease might differ in multiple family members
The Three Types of Gaucher Disease
Understanding Dr. Grabowski’s work requires a refresher on Gaucher disease. Classically, specialists describe three types of Gaucher disease:
- Gaucher disease type 1 is the most common form of the disease in Western countries. Learn more about Gaucher disease type 1.
- Gaucher disease type 2, a rare type, causes severe, irreversible brain damage that is usually fatal by age 2.
- Gaucher disease type 3 is the most common form of the disease outside the U.S. and Europe. Learn more about Gaucher disease types 2 and 3.
How Gaucher disease affects the body
With all types of Gaucher disease, people have too little of the enzyme glucocerebrosidase (GCase). Because of this deficiency, a substance called glucosylceramide builds up in tissues.
This buildup results in damage to different body parts, depending on the form of Gaucher disease. It can affect:
- Organs, such as the spleen and liver, which may become enlarged (all types)
- Bones, causing fragile bones and bone breaks (types 1 and 3)
- Central nervous system (CNS), or the brain and nerves (types 2 and 3)
But people with the same type of Gaucher disease don’t all have the same Gaucher disease symptoms and signs. And these signs and symptoms don’t always appear at the same point in time or with the same severity.
In medical terms, a sign is objective evidence, such as an enlarged organ, low platelet count, or osteopenia. A symptom is subjective—something that a test can’t measure—such as pain or fatigue.
Gaucher Disease Genotypes and Phenotypes
Gaucher disease results from a genetic mutation (change) in the glucocerebrosidase gene, GBA1. There are hundreds of possible mutations to this gene. Many are rare mutations, but the N370S and L444P mutations are the most common.
The L444P mutation is likely the most common worldwide, whereas the N370S mutation is most common in people with European ancestry. The L444P mutation seems to happen again and again, while the N370S mutation appears to have occurred just twice in the Ashkenazi Jewish populations several hundred years ago.
Each person inherits two copies of the GBA1 gene, one from each biological parent. Individuals may have no mutation, two copies of the same mutation, or two different mutations.
Doctors study two aspects of these gene mutations to understand how Gaucher affects an individual:
- Genotype refers to the specific gene mutations an individual has.
- Phenotype (gene expression) refers to what traits or symptoms the individual has.
Each combination of gene mutations can have different effects. And in some cases, even siblings with identical mutations (genotype) can have vastly different signs or symptoms (phenotype).
Genotype/Phenotype Correlation in Gaucher Disease
Dr. Grabowski and his team closely examined the link between Gaucher signs and genotype. To do so, they reviewed genotype and phenotype information from a registry of about 2,000 people.
They focused on registry participants with Gaucher disease type 1. This focus provided a large population of untreated patients with either two N370S genes or at least one N370S mutation and another mutation that made very little enzyme.
The team looked at:
- Onset: When did the disease start or when was it diagnosed? How old was each patient at diagnosis?
- Gene mutations: Was there a relationship between the GBA1 mutations and the patient’s onset or other Gaucher disease signs?
Once they had filtered the data by genotype, the researchers reviewed measures such as liver size, spleen size, and bone manifestations.
“Then we asked, ‘Does this set of signs correlate with the genotype?’” Dr. Grabowski says. “It turned out that it did.”
How the Genotype/Phenotype Correlation Impacts Treatment
As the team reviewed data for these type 1 patients, they found they could make important predictions:
- Age of onset: In those with the matching genotypes for Gaucher, the disease appears to start at similar times. People with two copies of the N370S mutation received a diagnosis around age 32. In people with one copy of N370S and one copy of a different gene mutation that made little or no enzyme, the disease caused symptoms much earlier. The specific age correlated with the genotype.
- Enzyme activity: Based on the new data about genotypes, researchers can better estimate the effects of different levels of enzyme that are active in these patients. Gaucher patients diagnosed at age 5 probably have much less enzyme activity than people who develop symptoms at age 32.
For patients and families, this correlation could provide vital information. Families and patients may now be able to understand, sooner and more accurately, the potential severity of their form of Gaucher disease.
It is important to note that patients with two copies of the N370S mutation can have a very wide spectrum in the age at onset. Those with one N370S and one different GD gene mutation had earlier onset and narrower spectrum of the age of onset.
Next Steps in Genotype/Phenotype Research
The work in the research paper uses a patient registry developed as part of a 2006 study. The team selected this registry for its size and completeness. Today, genetic information is readily available.
“In the U.S. and Europe, genetic testing is the standard of care,” Dr. Grabowski says. “In the future, having that much more data will make it easier to see trends and determine the right care for each patient.”
Learning more about the factors that influence phenotypes
A major unanswered question is what other genetic or environmental factors affect the severity of GD within and between families. One area scientists will continue to study is how variations in such factors or modifier genes and enzyme regulation affect the phenotype—the way the disease presents and progresses.
Environmental factors that could affect Gaucher include infections and autoimmune response, changes in nutrition, and oxidative stress (an imbalance in how your body handles free radicals, or unstable elements in the body). Modifier genes affect the expression of a specific allele (gene). In Gaucher disease, modifier genes could play a role in whether and how much enzymes work.
In Gaucher type 3, for instance, the most common genotype is two copies of the L444P mutation. Dr. Grabowski explains, “As part of my work in Egypt, I have seen several hundred patients with that particular genotype—but the results between families and within families are astounding. Within the common genotype, there is a wide spectrum of involvement that can’t be explained by the Gaucher disease mutations alone.”
Enzyme replacement therapy (ERT) and genetic variation
For Gaucher disease type 1, ERT has clear benefits. For type 2, there is no direct brain benefit because the therapy can’t cross the blood-brain barrier into the brain to address neurological effects.
For type 3, ERT is more complex. But doctors do know the therapy has a profound effect on how the disease manifests, Dr. Grabowski explains. And it can change the course of the disease early on.
ERT doesn’t reach the brain, but it can impact “how immunologically active organs like the spleen put out inflammatory compounds, such as cytokines and chemokines, that have a direct effect on the brain,” he says. “This effect is well-known in the field of degenerative neurologic disease. For instance, someone with Alzheimer’s or Parkinson’s disease could have a visceral (organ) infection that causes an enormous inflammatory response and causes more neurological symptoms. But once the infection is treated, they go back to their baseline.”
In people with Gaucher disease type 3, treatment modifies phenotype in ways doctors wouldn’t necessarily predict. Ultimately, it seems, treating type 3 with ERT helps prevent some of the organ damage associated with Gaucher disease. And treatment may also have a protective effect on patients’ intellectual condition.
The Gaucher–Parkinson’s relationship
An essential question in Gaucher disease research relates to the link between Gaucher disease and Parkinson’s disease. Researchers continue to heavily study the genetics of Parkinson’s and Gaucher disease.
“Certainly we know there’s something special about GBA1 mutant alleles and Parkinson’s disease,” says Dr. Grabowski. “We know from animal models that having more normal GBA in a brain changes things for the better in terms of Parkinson’s.”
Where to Learn More About Gaucher Disease Genetic Research
You can take steps to learn more:
- Get the paper: The research paper by Dr. Grabowski and his team aims to provide a roadmap for Gaucher research and treatment. Its conclusions also apply to other lysosomal storage disorders. The paper is available from the journal Molecular Genetics and Metabolism, or search: “Gaucher disease: Basic and translational science needs for more complete therapy and management.” A. Grabowski, A. H. M. Antommaria, E. H. Kolodny, and P. K. Mistry. Mol Genet Metab 2021 Vol. 132 Issue 2 Pages 59-75.
- Join a registry: If you and your family are interested in participating in a patient data registry, talk to your Gaucher specialist. There are opportunities for patients and physicians to take part. Learn more about joining a Gaucher registry.
- Get involved with Rare Disease Day: This annual celebration takes place on the last day in February. It offers opportunities to raise awareness and celebrate our community. Make a gift or learn more about Rare Disease Day.
- Jakóbkiewicz-Banecka J, Gabig-Cimińska M, Banecka-Majkutewicz Z, Banecki B, Węgrzyn A, Węgrzyn G. Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases. Metab Brain Dis. 2014;29(1):1-8. doi:10.1007/s11011-013-9455-6 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930848/
- Roshan Lal T, Sidransky E. The Spectrum of Neurological Manifestations Associated with Gaucher Disease. Diseases. 2017;5(1):10. Published 2017 Mar 2. doi:10.3390/diseases5010010 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456331/
- Stanford Encyclopedia of Philosophy – The Genotype/Phenotype Distinction – https://plato.stanford.edu/entries/genotype-phenotype/
- Technology Networks – Genotype vs. phenotype –https://www.technologynetworks.com/genomics/articles/genotype-vs-phenotype-examples-and-definitions-318446