Type 1 Gaucher Disease: Growing Awareness of a Rare Disorder

In March, we published data from the Lysosomal Disease Network WORLD Symposium on new treatment options being studied for type 1 Gaucher disease. Gaucher disease is a lysosomal storage disorder (LSD) that occurs in approximately 1 of every 20,000 births. This inherited genetic condition is rare; fewer than 10,000 people in the world have Gaucher disease. People of Ashkenazi Jewish descent have a higher risk of being born with Gaucher than non-Jewish individuals, but the disease arises in people of all backgrounds.

Patients with Gaucher disease make an insufficient amount of β-glucosidase (glucocerebrosidase), an enzyme stored in the lysosomes of macrophages that is vital to breaking down glucocerebroside. These lipids begin to accumulate in the spleen, liver, kidneys, lungs, brain, and bone marrow. Type 1 Gaucher disease, which accounts for the majority of cases, does not affect the brain or central nervous system. It does, however, cause bone disease and bleeding problems. If left untreated, it can cause mild to severe morbidity or death.

There are probably few people who know more about Gaucher disease than Neal Weinreb, MD, a senior physician with Northwest Oncology Hematology Associates PA in Coral Springs, Florida, where he treats many patients with Gaucher disease. Weinreb is also director of the University Research Foundation for Lysosomal Storage Diseases and is involved in clinical research to improve treatment options for Gaucher disease patients.

Weinreb first became involved in Gaucher research more than 30 years ago, working alongside Roscoe Brady, MD, as a research assistant at the National Institutes of Health. Brady is credited with discovering the enzyme deficiency that causes Gaucher disease and conceiving of enzyme replacement therapy (ERT) as a treatment. Weinreb contributed to some of the processes integral to the development of Cerezyme (imiglucerase for injection), an ERT by Genzyme Corporation that has remained the gold standard for treating type 1 Gaucher disease for more than a decade.

Today, in addition to running his practice and conducting research, Weinreb chairs the International Collaborative Gaucher Group (ICGG) North American section and is co-chair of the ICGG International Board of Scientific Advisors. The ICGG stewards the Gaucher Registry, established in 1991 to track clinical outcomes for patients with Gaucher disease treated at the community level. The Registry receives financial and logistic support from Genyzyme and currently includes data for more than 6000 patients from all over the world. Its data has been used as the foundation for more than 25 peer-reviewed scientific articles and various presentations at scientific symposia.

In addition to improving care for patients with Gaucher disease, one of Weinreb’s long-term goals has been to increase awareness of this disorder in the medical community and among the population at large. “A survey indicated that in the United States and other developed countries, 70% of patients with type 1 Gaucher disease are cared for by hematologists,” Weinreb said, emphasizing why hematologists need to be aware of this disorder. Like anyone else, patients with Gaucher disease sometimes develop cancer and may require care from an oncologist, and these clinicians also need to know about Gaucher.

American Journal of Hematology.

Weinreb also recommended an editorial by Derralyn Hughes, MD, which appeared in the same issue.

Multiple myeloma (MM) may be of particular concern for patients with type 1 Gaucher disease. “Depending on which study is cited,” said Weinreb, “older type 1 Gaucher disease patients have an increased risk for developing myeloma, ranging from 6- to 50-fold over that expected in the general population.” Weinreb said these studies are epidemiological in nature and typically compare the rates of myeloma in select Gaucher populations (eg, all patients in the Gaucher Registry, Gaucher patients in Western Europe, or patients at a large Gaucher center) to the rates in a reference population matched for age and sex. “There are also many anecdotal case reports,” said Weinreb. Researchers have yet to determine why patients with type 1 Gaucher disease appear to have an increased risk of MM, but Weinreb said Taddei et al have published articles examining possible causes, including one in the April 2009 issue of

In addition to MM, Weinreb said Gaucher patients might have an increased risk of other hematological malignancies, such as lymphoma and, to a lesser extent, myelodysplasia and leukemia, as well as hepatocellular carcinoma. “I am not convinced that the incidence of solid tumors is significantly higher in Gaucher patients nor that the risk of dying from these other cancers is increased,” Weinreb said. Although data suggests that people with Ashkenazi Jewish descent have an increased risk of BRCA-linked cancers, Weinreb said, “I am not aware that there is any interaction between Gaucher disease and BRCA mutation—cancers, other than that both are more common among Ashkenazi Jews.”

While Weinreb knows of no studies on treating cancer in patients with Gaucher disease, he noted a few areas of possible concern. “In terms of Gaucher disease and its bone complications—especially decreased bone mineral density and potential for fractures—it is conceivable that lytic metastatic bone disease may increase the risk.” He said theoretically this might also be the case when using treatments known to cause bone mineral loss. Myelosuppression from using cytotoxic chemotherapy or radiation therapy might be a concern for patients with untreated Gaucher disease whose bone marrow demonstrates extensive Gaucher cell infiltration. Weinreb recommends assessing the skeletal status of patients with Gaucher disease prior to initiating treatment for cancer. “Follow-up monitoring would be dictated by the pretreatment status and nature of the malignancy,” he said, and anticancer treatment would obviously need to be individualized.

While most patients with type 1 Gaucher disease typically receive a diagnosis in their early to mid-twenties, greater awareness of the disorder is contributing to earlier discovery of the disease and intervention. “Currently more than half of the patients in the ICGG Gaucher Registry have been diagnosed either as children or adolescents,” Weinreb said. Although increasingly less common, there continue to be some patients who do not receive a diagnosis until they are much older. “It is certainly possible that a cancer patient with not-yet diagnosed Gaucher disease could be referred to an oncologist for treatment,” he noted.

In some cases, patients with Gaucher disease are first thought to have some type of malignancy, typically lymphoma or leukemia. This is because patients with Gaucher disease often present with nonspecific signs and symptoms, such as abnormal blood counts, enlarged spleens and livers, and/or bone complaints. “Because of the rarity of Gaucher disease,” Weinreb explained, “unless there is a family history or possibly identification of Ashkenazi Jewish descent, it is usually not thought of as first in a list of potential diagnoses.”

Historical analysis indicates that patients with type 1 Gaucher disease in the United States have a life expectancy of approximately 68 years compared to 77 years for the reference US population. Weinreb noted that most of the underlying data for these calculations, however, do not reflect the positive effect ERT might have on life expectancy. “It is certainly conceivable that life expectancy might be longer—possibly even normal—in a baby with type 1 Gaucher disease who is born in 2010,” he said. The risk of cancer increases with age, and as people with Gaucher disease continue to live longer lives due to improved care, oncologists and hematologists may encounter more patients with this condition in practice.

Weinreb recommends that oncologists, hematologists, and all physicians treating patients with Gaucher disease consider enrolling patients in the Gaucher Registry after obtaining informed consent. “The Registry offers individualized graphic reports that can be shared and reviewed with patients for education and counseling, processes data requests on a large number of topics related to Gaucher disease, and prepares country-specific and regional data analyses as well as an annual report,” Weinreb said. The Gaucher Registry accomplishes so much, added Weinreb, that it would take another article to discuss it. Physicians can learn more about the Gaucher Registry at www.gaucherregistry.com.