NGF Community Blog

2018 NGF Patient Symposium: Q&A

At a recent symposium on Gaucher disease, nationally and internationally renowned Gaucher disease experts answered a variety of questions about the condition. Topics touched on everything from advances in gene therapy to the role of diet in Gaucher disease treatment to whether people with Gaucher disease have certain biological advantages. Read the Gaucher disease Q&A to find out what the experts had to say.

Meet the Gaucher Disease Experts

Answering questions during the Gaucher disease Q&A session:

  • Heather Lau, M.D., M.S., is the director of the Lysosomal Storage Disease Program and associate director of the Division of Neurogenetics at New York University (NYU) School of medicine.
  • Pramod Mistry, M.D., Ph.D., FRCP, is a professor of Pediatrics, Medicine, and Cellular and Molecular Physiology at Yale School of Medicine. Dr. Mistry is the director of the National Gaucher Disease Treatment Center and a member of the National Gaucher Foundation Medical Advisory Board.
  • Neal Weinreb, M.D., is an associate professor of Human Genetics and Hematology at the University of Miami Miller School of Medicine, a member of the National Gaucher Foundation Medical Advisory Board, and the director of the University Research Foundation for Lysosomal Storage Diseases in Coral Springs, Fla.

Read the information on Gaucher disease covered during the symposium:

Should All Individuals, Even Those Mildly Affected, See a Gaucher Disease Specialist?

The short answer: yes.

The longer answer:

“It’s just mild Gaucher disease”

Sometimes, people may have a mild presentation of Gaucher disease (GD). The GD may remain mild throughout their lifetime, or it may worsen over time. These individuals may not have severe organ problems—perhaps the splenomegaly (spleen enlargement) is so mild we can only detect it through an MRI or ultrasound.

However, it’s possible that a person with a mild presentation of GD has more significant bone involvement—problems which we can only detect using specialized assessments. A Gaucher disease specialist has the experience and training to consider which tests are necessary to best monitor and manage the person’s health.

In particular, children who seem to have a mild presentation may experience growth delays and begin to show signs of osteopenia (reduced bone density). Their pediatricians often don’t realize that these are significant symptoms of GD. They recommend that the parents bring their children to an endocrinologist rather than to a Gaucher specialist.

The parents, because they are told the condition is “mild,” do not independently seek out a Gaucher specialist for care. The endocrinologist, who is most likely unfamiliar with GD, may prescribe growth hormone to address the growth delay. At best, this may be unnecessary. At worst, this approach could lead to serious complications as the GD progresses without proper treatment.

GD specialists look at the big picture

However, growth hormone treats just one aspect of GD without considering the whole person. And then we have a situation where young adults who are 18, 19, or 20 years old—who should be building bone density and hitting growth spurts—are instead experiencing abnormal growth and possibly irreversible bone damage.

A Gaucher specialist has the training and experience to see that big picture—all the symptoms, future risks, and benefits vs. risks of treatment—and create a comprehensive treatment plan that will lead to the patient’s best health. This specialist looks at the metabolic defect, the Gaucher disease, not simply the growth issue.

It’s possible that, after a comprehensive assessment directed by experts, the result of the discussion among the Gaucher disease team, parents, and child will be to delay treatment and monitor symptoms instead. But the parents and the child need the full picture to make an informed, educated decision about the child’s care.

Part of the Gaucher specialist’s job is to educate not only patients, but physicians as well. When a person presents with symptoms of Gaucher disease, no matter how mild, a Gaucher specialist needs to be part of the treatment team and ongoing care.

Fatigue in Patients With GD

Fatigue is a common symptom for patients with Gaucher disease. There’s no simple answer for how to treat fatigue or even the reason behind it. The fatigue may be directly related to the disease—caused by the inflammatory chemicals released by the Gaucher cells. We know that fatigue commonly occurs in patients who have chronic inflammation due to diseases such as rheumatoid arthritis or inflammatory bowel disease.

And while we don’t know the answer yet or how to treat fatigue effectively, we know that it deserves more attention in clinical trials.

  • Studying fatigue: There are few reliable tools for studying Gaucher-related fatigue. The tools used to study fatigue in general are too intertwined with all the other non-Gaucher-related fatigue issues.
  • Teenagers with Gaucher disease: When adolescents have Gaucher disease, it can be even trickier to tease out what’s Gaucher-related fatigue and what’s simply normal teenager fatigue due to poor sleep habits or stress.
  • ERT and fatigue: It’s unclear whether enzyme replacement therapy (ERT) helps with fatigue itself, or helps improve anemia, which improves energy. Or whether short term positive effects are simply a placebo effect. Some patients report that ERT causes even more fatigue, though that could be related to the frequent trips to the infusion center to receive the treatment.

Advances in Gene Therapy for Gaucher Disease

An exciting emerging development in Gaucher disease treatment is gene therapy, which is getting closer and closer to reality. While there is some talk of using gene therapy to cure the condition, currently, researchers are studying gene therapy as an additional but non-curative treatment option for type 1 Gaucher disease.

How does gene therapy for Gaucher disease work?

Gene therapy is essentially a superior form of enzyme replacement therapy. The goal of gene therapy for GD is to help the patient’s cells produce and secrete a normal amount of the glucocerebrosidase enzyme into the blood stream and internal organs.

How gene therapies achieve that:

  1. Insert the gene: Insert a corrected glucocerebrosidase gene into committed stem cells, which are a reservoir for replacing blood or liver cells as they wear out.
  2. Genes replicate: Inserting the healthy gene into the DNA of stem cells creates a tiny, internal factory to produce enzymes. The cells replicate and create a population of either blood or liver cells that continuously secrete normal enzymes into the blood and to body organs.
  3. Repeat the process as necessary: The corrected stem cells can live for a long time but they may not persist forever. A new infusion of stem cells might be necessary to continue effective treatment.

The advantage of gene therapy is that the enzyme is being produced continuously rather than once every two weeks as with ERT, making it more efficient and eliminating the need for the biweekly infusions.

However, gene therapy still has the limitations of ERT—which include the treatment not crossing the blood-brain barrier to reach the brain and possibly not reaching other organs as well.

What are the limitations of gene therapy for Gaucher disease?

The stem cells that are currently being used for gene therapy of various hereditary diseases are called committed stem cells. These stem cells can produce either blood cells or liver cells but cannot turn into any cell type, such as a heart or brain cell. Those cells will still have the Gaucher gene.

We also don’t know if these cells are truly “immortal.” At some point, the stem cells may stop replicating, and the person will need a second booster treatment.

What is the future of gene therapy for Gaucher disease?

To perform “curative” enzyme therapy—to use gene therapy not to treat, but to cure GD—we would need to correct the deficiency in the embryo and then implant the embryo. If we could do that, all the cells in the body would likely be corrected. However, this method is not (yet) viable, because it comes with many risks and unknowns.

An interesting trial to keep an eye on is one for Fabry disease. This condition is another lysosomal storage disease, which in many ways is more severe than GD. And gene therapy trials for Fabry disease have begun, which could have significant implications for Gaucher disease treatment.

Who is a good candidate for gene therapy for GD?

We’ll need to seriously consider who can be a candidate for gene therapy and at what age to do it. Although gene therapy is becoming safer, there are still some risks that doctors need to carefully weigh when advising such treatments, either in clinical trials or eventually in routine use.

For example, should doctors consider gene therapy for a 4-year-old who has type 1 GD but no symptoms? This child could possibly live a normal life and never develop symptoms. On the other hand, he or she could develop severe symptoms. We don’t know who’s going to develop symptoms and how severe they will be, so it’s hard to pinpoint who should receive the therapy and when.

A recent study focused on the neurological symptoms of GD. Researchers injected a healthy gene in the brain of a mouse fetus with GD. Instead of dying quickly after birth, the mouse functioned well and had a longer life expectancy.

However, when the researchers gave this treatment to a newborn mouse, the treatment was not nearly as effective. So it’s possible that gene therapy will have to be done very early in life if it’s going to be effective, which presents a challenge to doctors.

The Effect of Diet and Nutrition on Gaucher Disease Symptoms

Adequate sleep, a balanced diet, and regular exercise have many benefits, increasing a person’s overall health and well-being. But do they have a specific benefit for people with GD?

Can a low-fat diet help?

Since GD is caused by a buildup of a fatty substance, perhaps eating a low-fat diet can help reduce the buildup. But it’s not that simple.

Glucocerebroside, the fatty substance that accumulates in patients with GD, is not like cholesterol or triglycerides. A person can control those types of fats fairly effectively through diet, exercise, and sometimes drug therapy. Glucocerebroside is made inside our cells, so it’s harder to control through outside influences like diet.

One intriguing aspect to study is whether there is a difference in how GD presents itself in people who have different diets, such as vegetarian or kosher. There is some anecdotal evidence that a vegetarian diet could help improve symptoms. One person who had an enlarged spleen and low blood counts went on a strictly vegan diet and her numbers improved. However, a single case report does not constitute evidence, and vegan diets can sometimes cause deficiencies in certain important vitamins and minerals.

Sometimes a patient follows a certain diet, and the symptoms improve—but we can’t necessarily prove that the results were due to the diet. There are patients who spontaneously improve. To definitively answer the question of the impact of diet and exercise, we need a large-scale study, and that has not yet been done.

Diet as part of overall care for Gaucher disease

What we can say with certainty: It’s important for people with Gaucher disease to eat a healthy diet, as part of the big picture of care. People with GD may be at higher risk for certain medical issues, and a nutritious diet can keep them on a healthy path.

  • Weight gain: People often gain weight after starting ERT, which can lead to an increase in fatty liver and a risk of developing fatty liver disease. The risk for becoming pre-diabetic or overtly diabetic also may increase after beginning ERT.
  • Bone health: ERT replaces the deficient enzyme, but people also need to replenish the building blocks of the bones. Bone health is especially important for people during puberty and pregnancy.
  • Iron deficiency: Women with Gaucher disease who menstruate can become iron deficient and anemic.
  • Vitamin B12 deficiency: Some patients with GD develop vitamin B12 deficiency, which can lead to blood problems, low energy, and even neurological problems.

We don’t want to add diabetes, fatty liver disease, obesity, bone loss, or other related conditions on top of GD symptoms. So while there isn’t a specific diet that can help improve symptoms, making smart choices can help optimize a person’s health. A Gaucher disease specialist should take a holistic approach to care, which includes counseling and recommendations for diet and exercise.

Advances in Gaucher Disease Treatments for Children

Clinical trials are starting to study oral medications for the pediatric population. For younger patients, this option could give them the freedom they need. Many are heading off to college and don’t want to deal with regular enzyme infusions, usually given every two weeks.

We’re getting a glimpse into this treatment option for older adolescents, as patients from the original phase 2 eliglustat trial are reaching 10 years of follow up. Some of these patients started eliglustat when they were 16 to 18 years old.

We can also glean insights from some younger children who are currently taking Cerdelga®, the oral capsule, on a case-by-case basis because they are intolerant of ERT. And so far, these children have tolerated it well.

Factors that affect GD treatment for children

We need to consider certain pediatric-specific treatment factors. For example, if we’re treating children under age 10, we need to think about growth issues and ensure that they can grow and develop normally. Drugs such as eliglustat might have effects on growth and development in children that are not concerns in adults.

And there are technical issues as well: Cerdelga, or eliglustat, is a capsule. Many children can’t swallow capsules. We don’t currently have a liquid formulation of the medication that is absorbed properly. These are some just some of the factors and complications to consider when we’re talking about transitioning from adult treatment to treating children.

Do People With Gaucher Disease Have Biological Advantages?

Are there biological advantages to being a Gaucher carrier or even having Gaucher disease? The most common genetic mutation in people with GD who live in the U.S., Israel, and Western Europe is the N370S mutation.

N370S mutation in Ashkenazi Jews

We have traced this one genetic alteration to the 10th century CE somewhere in Europe. Although the N370S mutation is found in non-Jews, the carrier rate in Ashkenazi Jews is 1 in 10 to 1 in 15—which is much higher than in any other population in the world. Why has this mutation persisted, despite its association with a disease than can cause severe symptoms in people who have two copies of N370S?

Is it high just because of the historical tendency in the Ashkenazi Jewish community to marry other Ashkenazi Jews, a social phenomenon that has allowed the N370S gene to remain relatively prevalent and undiluted in the Jewish population?

Or is there some biological advantage to the mutation: Is the high rate because people with this genetic alteration can more easily adapt to changing environments? Perhaps the mutation changes metabolism in a way that has led to biological advantages, an example of what Darwin called “survival of the fittest.”

Lessons from sickle cell disease

To better understand this concept, we can look at another genetic disease: sickle cell disease. This condition is prevalent in Africa and in African-Americans. The carrier state, which rarely causes any bad effects, actually protects people from developing and dying from malaria, a life-threatening infectious disease that to this day is not controlled in Africa and in parts of Asia.

GD mutation N370S: Could something similar be happening with N370S? It’s possible that having a single N370S gene might change cellular metabolism in a way that provides protection against serious infectious diseases such as tuberculosis or typhus. So far, however, there is no evidence that is the case.

Interestingly, the N370S mutation is what differentiates type 1 from types 2 and 3. So this specific genetic mutation might protect people from having babies with neuronopathic Gaucher disease, variants of GD that are usually associated with severe symptoms and even death early in life.

GD mutation 844GG: A more chronologically recent Gaucher disease mutation is 844GG, which probably arose in the 16th century in Eastern Europe, at a time when Jews were forced to live apart from the non-Jewish population. This genetic isolation allowed the gene to spread among Ashkenazi Jews, even though having it in conjunction with another Gaucher mutation often caused severe manifestations of GD. (This mutation does not protect the carrier from having children with neuronopathic disease).

Because 84GG is chronologically a very recent mutation, it is largely confined to people of Ashkenazi Jewish ancestry. However, in modern times, with increasing rates of intermarriage between Ashkenazi Jews and Sephardi Jews as well as with non-Jews, 84GG is found in families who have no knowledge or memory of any Jewish relatives.

Conclusion: Most GD mutations are very recent in terms of the long history of modern humans (homo sapiens). 1,000 years is a drop in the evolutionary bucket. The sickle cell disease mutation goes back 100,000 years, a sufficient time for a biological survival advantage to become evident in a population that generally remained in the same geographical place.

Thus, we just do not know whether GD mutation results in a biological advantage, especially as our environment changes so rapidly due to industrialization, new technologies, advances in healthcare, and the ability for people to move rapidly over long distances.

Discussing a Gaucher Disease Diagnosis With Family Members

Doctors respect and understand that a person’s genetic information is private. Moreover, this privacy is also legally protected.

But we do encourage people who are diagnosed with GD to talk about it with family members, so relatives can understand their risk for being affected, either as carriers or with GD. They can use the knowledge to make informed personal and reproductive healthcare decisions.

Gaucher disease is a recessive disorder—which means the people most at risk are the siblings of the “proband,” the person who’s been diagnosed. In the Ashkenazi community, we encourage reaching out to cousins as well, because there’s such a high carrier rate.

With some other genetic diseases, if the siblings don’t have current symptoms, doctors may not check their genetic status. If there’s no treatment for the condition, then knowing often leads to anxiety and may affect insurability.

Sharing information can lead to earlier treatment

But the situation is different with Gaucher disease—because there is an effective treatment for type 1. Doctors may want to start the therapy early, before irreversible bone damage and long-term complications occur. We can reverse damage to the spleen and liver and improve anemia and platelet count, but we can’t undo bone damage. And bone disease, unless it is far advanced, is not something you can suspect just by looking at a person.

A Gaucher specialist, who is qualified and experienced in managing care for GD, knows the appropriate tests to use to monitor a person’s symptoms. He or she can advise when to watch symptoms closely and when to begin treatment. If a person needs treatment, the earlier the better, to prevent bone damage and other symptoms.

If you’ve been diagnosed, reach out and discuss the diagnosis with family members. The screening and testing processes are relatively simple:

  • Screening for carrier status (to find out if you’re a carrier) can be done from the comfort of your home with a saliva DNA test.
  • Testing for Gaucher disease (to test your enzyme level and see if you are affected) is done through a blood test at your doctor’s office.

Parents may want to decide to test their other children. Each child has a one in four chance of developing GD if both their parents are carriers. But there is hope for people diagnosed with type 1 Gaucher disease. There is treatment. So know your status, talk to your family and find a Gaucher specialist who can help you navigate the process.

Does Gaucher Disease Increase the Risk of Cancer?

A study in the 1980s and 1990s—before enzyme replacement therapy was available—found that compared to the general population, patients with Gaucher disease had a significantly higher risk of developing multiple myeloma, certain blood cancers, liver cancer, and kidney cancer.

However, the actual risk is still small—for example, perhaps one to three people out of 100 are at higher risk. But now there is testing that makes it possible to detect many of these cancers when they are at an early stage and easier to treat with surgery or drug therapy.

A Gaucher specialist helps ensure that a person gets regular screening for cancer as part of their comprehensive Gaucher disease care. This preventive care includes cancer screening that is recommended for everyone at certain ages, such as mammography for breast cancer and colon cancer screening.

The Link Between Gaucher Disease and Parkinson’s Disease

When researchers first noticed that some patients with GD were developing Parkinson’s disease, they thought it was a coincidence. Just because people have a rare disease doesn’t mean they’re protected from other diseases, especially relatively common conditions like Parkinson’s.

But then scientists looked closer at family histories. It turned out that many patients with GD had relatives that had Parkinson’s. So there did seem to be a Gaucher-Parkinson’s connection—the risk for middle aged or elderly patients with GD was higher if a family member had Parkinson’s.

More decisive evidence emerged from studies of people with Parkinson’s looking for Gaucher gene mutations:

  • About 5% of patients with Parkinson’s did have at least a single mutation of the Gaucher gene.
  • In the Ashkenazi population, about a quarter of the patients with Parkinson’s have a single Gaucher mutation (meaning they are Gaucher carriers).

Many investigators from both the Gaucher and Parkinson “worlds” are studying the GD-PD connection to identify the involved chemical pathways, so that they can be targeted for new treatments. This work is already at the stage of clinical trials in patients.

From the statistical analyses, we know that most patients with GD will not develop Parkinsonism, even when they live to a ripe old age. However, the risk of getting Parkinson’s is a little higher than in the general population. Examinations that monitor for signs of Parkinson’s disease should be part of a holistic care plan for all Gaucher patients over 40 years old

Care for Gaucher Disease: Looking Ahead

The field of Gaucher disease continues to evolve. Scientists and organizations such as NGF are working tirelessly to advance research initiatives. We are looking toward an exciting future with more effective (and less strenuous) treatments, opportunities to help people better manage symptoms and lower their risk of related conditions, and promising research that may one day lead to a cure.

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