In early February, more than 1,600 participants from around the world gathered at the annual research conference WORLDSymposium™. WORLD stands for “We’re Organizing Research on Lysosomal Diseases.”

Why WORLD?

If two heads are better than one, imagine what 1,600+ heads can do? The WORLDSymposium focuses on lysosomal storage diseases, including Gaucher disease. The goal of this yearly conference is to gather lysosomal disease experts in one place. These specialists from around the globe have an opportunity to meet and discuss all aspects of lysosomal diseases.

Participants present about the latest research, new treatment options, ways to improve diagnosis, and how to raise awareness in the medical community and among the general population.

Dr. Heather Lau, a neurologist and director of the NYU Lysosomal Storage Disorders Program at NYU Langone Health, attended and presented at this year’s symposium. Dr. Lau is actively engaged in clinical research evaluating enzyme replacement therapies, small molecules, and gene therapy. She is a member of the NGF Medical Advisory Board.

Dr. Lau talks about some of the findings presented at this year’s WORLDSymposium and what this conference means for the Gaucher community.

Raising Awareness of Gaucher Disease

If people—and doctors—don’t know what to look for and aren’t aware of the signs of Gaucher disease (GD), then people are misdiagnosed. A misdiagnosis means that in addition to not receiving the proper treatment, people often receive incorrect treatments. They lose valuable time in preventing lasting damage, especially bone problems.

Gaucher disease is tricky—like many rare diseases, it’s all too easy to chalk up the symptoms to a more common condition. That’s why Gaucher awareness, both among high-risk populations such as Ashkenazi Jews as well as among the medical community, is one of the highest priorities of people involved in the field of Gaucher disease.

Misdiagnosis of GD: Study #1

Dr. Lau presented about a group of patients in their late teens and early 20s. These patients were misdiagnosed for years. Among their symptoms were gastrointestinal symptoms. GI problems have many possible causes, and they are also not considered traditional Gaucher disease symptoms. So the doctors didn’t think of Gaucher as a possible cause of this group’s illness.

And even though members of the cohort did have Gaucher-like symptoms—spleen enlargement, low platelets, fatigue—and they were Ashkenazi Jews (a high-risk population), doctors most likely were not informed enough about GD to consider it a possible diagnosis. Lacking the proper awareness and information, the doctors did not advise the patients to get tested for Gaucher disease. Many patients were instead incorrectly diagnosed with irritable bowel syndrome.

After an extended period, these young people finally received the correct diagnosis. They were properly diagnosed either because they did carrier screening or, unfortunately, their symptoms increased, and their health deteriorated. They were at last able to get the proper treatment and start to feel better.

Misdiagnosis of GD: Study #2

In one study, researchers reported on the misdiagnosis of GD at a French referral center. They found:

• 84 of the 131 patients, a staggering 64%, did not receive a correct diagnosis within the 1st year of the onset of their symptoms.
• The median diagnostic delay was 5 years!
• 14 of those patients (17%), had a number of misdiagnoses. These included arthritic disorders in children, gestational and immunologic thrombocytopenia in young women, infectious mononucleosis, and hemochromatosis.

Even more troublesome is the incorrect treatment some of these people received.

• One person received an unnecessary splenectomy.
• Another person was inappropriately treated with corticosteroids.

Once again, it seems that doctors were focusing on traditional GD symptoms. Patients who presented with the classic swollen liver and spleen were more likely to receive the correct diagnosis. Patients who did not have enlarged liver and spleen were less likely to be diagnosed correctly.

With more awareness of the disease, these patients could have received the proper treatment much sooner. One lesson for doctors is not to narrowly focus just on the classic symptoms. Even if a patient presents with an out-of-the-ordinary symptom like GI trouble, it’s important to look at the whole picture. Consider the person’s history, risk factors, overall well-being, and all of their symptoms to paint the big picture of what’s happening with their health.

Getting GD on the diagnostic radar: How to make an appropriate and timely diagnosis

How can we improve the accuracy of diagnosis? There have been several algorithms designed to improve doctors’ ability to correctly diagnose GD.

These tools are aimed not at Gaucher specialists, but at primary care physicians, in an effort to help them determine if a patient should be tested for Gaucher disease. Making it easier and more efficient for doctors to arrive at an accurate diagnosis can lead to improved treatment and outcomes for patients.

One algorithm was proposed by the Gaucher Earlier Diagnosis Consensus (GED-C). The GED-C is an initiative whose goal is to improve diagnosis for people who are at risk for developing GD. The GED-C has identified certain signs and symptoms that can help non-GD specialists identify high-risk patients so these patients are diagnosed earlier.

The GED-C’s proposal includes identifying major and minor early indicators of GD, using a point-scoring system (PSS). The PSS works by assigning points to certain symptoms and using the result to determine whether the patient should undergo GD testing or not.

For example, an enlarged spleen receives three points (the highest amount); bone pain or having Jewish ancestry each receive two; anemia gets one; and other minor symptoms, like gallstones and fatigue, receive half a point.

A preliminary test of this algorithm applied the PSS to 25 patient groups, which included patients with GD, liver disease, blood cancers, and immune thrombocytopenic purpura (ITP, a condition where a person has decreased platelets, leading to bruising easily).

Researchers distinguished GD from the other illnesses based on certain Gaucher-specific signs such as Ashkenazi Jewish ancestry, enlarged spleen and liver, bone pain, and elevated levels of serum ferritin (a blood protein). The preliminary results of using this PSS were encouraging, suggesting that continuing to develop this algorithm could result in earlier and more accurate diagnoses for patients.

This information, along with studies in other countries, including the U.S., may better define just how extensive the under-diagnosis of GD is. The results may help justify including GD in newborn screening test panels.

Biomarkers for Gaucher Disease

Biomarkers can help doctors and researchers see how a disease is progressing and if treatment is working. A biomarker is a measurable substance in the body, so by measuring the levels of certain biomarkers, doctors can track the progress of a disease. It is also helpful in identifying if something else other than the disease is causing a person’s symptoms.

As Dr. Lau points out, when someone has a rare disease, they may blame all their symptoms and discomfort on the disease. However, using biomarkers, doctors can get to the bottom of what’s causing the symptoms.

“If a recognized biomarker for GD such as chitotriosidase or glucosylsphingosine (Lyso-GB3) is low, it means the person should be feeling better and less fatigued, with fewer symptoms. So if a patient with low biomarkers is still complaining of fatigue or has persistent anemia or spleen enlargement, I know to dig deeper. I may discover that the person also has sleep apnea, which is leading to fatigue, and the fatigue is not actually due to GD. Then I can get that person the sleep apnea treatment they need.”

Two biomarkers of interest:

Chitotriosidase (ChT): This is the classic Gaucher disease biomarker that scientists have been using for many years. While it correlates well with a person’s response to treatment, results are often not consistent from lab to lab. This inconsistency is due to different techniques for analysis, including use of different test substrates.

There is another wrinkle with using ChT: Anywhere from 6-15% of the general as well as the Gaucher population have a double mutation of the chitotriosidase gene. The double mutation prevents them from making any chitotriosidase to measure.

People with one copy of this mutation have roughly half the level as patients without any mutation. These limitations result in difficulties using ChT as a primary universal biomarker and highlight the need for a better one.

Glucosylphingosine (Lyso-GB1): Enter the recently discovered glucosylphingosine (Lyso-GL1 or Lyso-GB1), a substrate of glucocerebrosidase that accumulates in patients with GD. Lyso-GB1 appears to be pathogenic, or disease-causing, in its own right, affecting a person’s immune system. The good news is that testing for Lyso-GB1 is commercially available in the U.S. from a number of companies. Tracking Lyso-GB1 can help doctors provide better, more effective treatment for patients.

Lyso-GB1 as a clinical biomarker in GD was discussed in many presentations. One study screened a large population with classic GD symptoms for the presence of GD. They studied 3,500 people, and the results affirmed the accuracy of using Lyso-GB1 for the diagnosis and screening of GD:

• 23 were found to have Lyso-GB1 levels above the normal level.
• Among 153 patients with known GD, all had much higher levels of Lyso-GB1 compared to the control group.

Lyso-GB1 for Gaucher disease type 2 and 3: Scientists found the highest levels of Lyso-GB1 in patients with Gaucher disease types 2 and 3. People who had persistently high Lyso-GB1 levels typically had poor disease control, which continues to confirm the accuracy of Lyso-GB1 and its ability to predict how a person’s disease will progress.

Lyso-GB1 levels before and after treatment: Another study confirmed a strong correlation between Lyso-GB1 and pre-treatment Gaucher signs, as measured by spleen and liver measurements and hemoglobin concentrations. But once treatment started, levels decreased. Lyso-GB1 levels decreased by approximately 90% after patients started eliglustat (Cerdelga®), improving organ and blood symptoms.

Similar results have been found in other studies—for example, increases in Lyso-GB1 were found in patients who were either not treated or were receiving ERT but not following the treatment protocol carefully.

And only Lyso-GB1 correlated with the bone symptoms, including bone disease and bone lesions. All of this data points to using Lyso-GB1 as the primary biomarker for diagnosis and follow-up care of GD patients.

Gaucher Disease Type 3

Gaucher disease type 3 (GD3), which involves the central nervous system (the brain and spinal cord, CNS), has remained frustrating for doctors and patients. People with GD3, known as neuronopathic Gaucher disease, often receive ERT to manage the non-neurological symptoms.

But because current treatments do not cross the blood-brain barrier, there are currently no effective treatments for the neurological effects of GD3. What’s the future for Gaucher disease type 3?

A recent study looked at 42 patients with GD3. In patients who had the L444P mutation, the disease progressed slowly and consistently over time. Certain non-neurological symptoms that might have responded to ERT or substrate reduction therapy (SRT) contributed significantly to morbidity. This finding seems to confirm that people with type 3 should continue to undergo ERT or SRT.

In patients who had other mutations, progression was more rapid. Researchers found that the genotype-phenotype correlations were reliable regarding prognosis of the disease. The genotype-phenotype correlation is the relationship that predicts certain traits or symptoms a person will exhibit (phenotype) if they have a certain mutation or group of mutations (genotype). So scientists were accurately able to predict symptoms based on a person’s genetic mutations.

L444P mutation: One study described three siblings, each one with the L444P mutation, but with different neurological symptoms. One brother had severe autism. When doctors did whole exome sequencing, analyzing the boy’s genes, they discovered that he had an additional unique mutation in a gene that may be involved in protein trafficking to lysosomes.

Researchers believe autism is a complex diagnosis, and not a single disease. It almost certainly has multiple causes. In the case of this brother, scientists don’t know whether:

• The autism was part of the manifestations of type 3 GD.
• The second mutation was the contributory cause.
• Both mutations worked in tandem to result in autism.
• None of the above is true, and there may be no connection at all.

This family case study illustrates how cautiously genetic and genomic data must be interpreted and rigorously tested before reaching conclusions about any individual patient.

Other genes that are essential for neurological development were also expressed differently among the siblings. Scientists need to understand and assess the genome and transcriptome (the RNAs) to understand how and why people experience different symptoms and how the disease manifests itself in different people.

Does geo-location matter? Could geographic locale impact disease progression and symptoms as well? Two Turkish patients had cardiac, ocular, neurologic, and visceral (internal organs) symptoms of Gaucher disease type 3. These have been found to be more common in the Middle East than in Europe and the U.S. Four more Turkish patients were found to have the D409H mutation (another GD mutation) and 11 had the L444P mutation. They received ERT and had visceral improvement but no neurological improvement.

Of course, a person’s geographic location does not cause them to develop GD. And scientists have found that environment is not a likely factor in GD phenotypes. The development in the Turkish patients may be related instead to the commonalities in the gene pool of people originating from a certain area. (In the same way that GD is more common and presents in a specific way in Ashkenazi Jews.)

But the case of these Turkish patients raises an interesting point:

Patients, families, and physicians in other parts of the world may experience different challenges with GD. Symptoms and signs may present differently than the “classic” symptoms that manifest in patients in Europe and the United States.

It’s important for the GD community to recognize those differences. The rapid shift in global demographics only increases the importance of acknowledging and raising awareness of different GD challenges around the world.

Cognitive symptoms: Another study looked at the history of cognition in GD3 in a group of 36 patients. They all received neuropsychological evaluations at the National Institutes of Health between 1982 and 2017, repeated anywhere from one to 18 times. Most patients received ERT. That means the cognitive test results were not as affected by systemic Gaucher disease symptoms, which should have been mostly controlled by the treatment.

The mean IQs were 80-85, which is below average. Behavioral issues, ataxia (degenerative nerve disease), myoclonus (involuntary muscle spasms), and ADD affected performance IQ. Total IQ was negatively affected by splenectomy, which may be because patients who needed a splenectomy had more severe symptoms despite undergoing ERT.

IQ varied over time, but not in a linear way. This means that in order to use cognitive function as an endpoint in clinical trials, it’s necessary to perform repeated evaluations before and after treatment to establish an accurate trajectory.

Eye symptoms: Researchers studied people who had GD3 and experienced abnormal saccadic eye movements—a quick movement of both eyes at the same time. Researchers reported that this area still requires development. They noted that there is a lack of standardized measurements as well as clear thresholds to determine improvement and deterioration.

There is also a lack of agreement among experts as to what constitutes the minimal clinically significant change. So this eye symptom, the most common hallmark of neuronopathic GD, is difficult to use as a clinical study endpoint.

Medication for GD3: Currently, there is a medication for GD3 going through clinical trials. This medicine, called Venglustat, is showing promise. A recent study reported preliminary safety, pharmacology, and efficacy data from a phase 2 trial of this medication. It can penetrate the central nervous system (CNS), so it can enter the blood-brain barrier and deliver needed medications to the brain and spinal fluid.

Venglustat is a glycosylceramide synthase oral inhibitor used along with imiglucerase ERT. Patients who are eligible are adults with GD3 who:

• Have used ERT for more than three years
• Achieved certain therapeutic goals
• Have abnormal horizontal saccadic eye movements

Unlike eliglustat, which does not enter the CNS, measurable levels of Venlgustat were found in the central spinal fluid after 26 weeks of therapy. Lyso-GB1 was reduced and there were no serious adverse effects. This study is ongoing.

These topics represent just a few of the issues discussed at this year’s symposium. There is a huge breadth and depth of research happening in the field of lysosomal storage diseases, to better understand these diseases and the challenges people face. Researchers from all over the world are working tirelessly to make diagnosis more accurate, treatments more effective, and ultimately, to find a cure for Gaucher disease.