Gaucher Disease

Gaucher disease is an inherited lysosomal storage disorder in which a deficiency of the enzyme glucocerebrosidase leads to the accumulation of the lipid glucocerebroside within the lysosomes of the monocyte-macrophage system.1

Gaucher cells

Lipid-engorged cells with eccentric nuclei, known as Gaucher cells, accumulate and displace healthy normal cells in bone marrow and visceral organs, causing a range of manifestations, including skeletal deterioration, anemia, hepatosplenomegaly, and thrombocytopenia. In rare cases Gaucher cells affect the brain and nervous system.2

Gaucher disease is a panethnic disorder. It has been divided into three types based on the presence and severity of neurological involvement:

Type 1 (non-neuronopathic)

The most common type, it afflicts both children and adults. Incidence is 1 in 45,000-60,000 in the general population and 1 in 850 among people of Ashkenazi Jewish ancestry, with a carrier rate of 1 in 15 Ashkenazi Jews.3

Cerezyme is only indicated for treatment of Type 1 Gaucher disease. It is not indicated for treatment of Type 2 or Type 3 Gaucher disease.

Type 2 (acute neuronopathic) and Type 3 (chronic neuronopathic)

These less common forms of the disease are characterized by central nervous system involvement. Type 2 patients rarely survive to age 2. Type 3 is characterized by a variable course and is marked by slowly progressive neurological involvement. Prevalence of each type is <1 in 100,000.4,5,6

Cerezyme is only indicated for treatment of Type 1 Gaucher disease. It is not indicated for treatment of Type 2 or Type 3 Gaucher disease.

Inheritance

Gaucher disease is an autosomal recessive disorder defined by the presence of two mutant alleles for the glucocerebrosidase gene.

With each pregnancy, each carrier of the mutated gene has a 50% chance of passing it on. When both parents are carriers, there is a 25% chance with each pregnancy that the child will develop Gaucher disease.

The diagrams below show how the Gaucher gene can be passed from one generation to the next.

Genetic counseling and testing

People at risk of being carriers may want to consider genetic counseling and family DNA testing. Individuals at risk include: relatives of Gaucher disease patients, people of Ashkenazi Jewish descent, and those with symptoms. 

Signs and Symptoms

Type 1 Gaucher disease is heterogeneous, presenting with a wide array of signs and symptoms throughout the body and progressing at variable rates. Signs and symptoms may be classified by four key anatomical compartments: visceral, hematologic, skeletal, and metabolic. These groupings may be useful in narrowing the diagnostic investigation and ordering appropriate tests.

Cerezyme is indicated for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or splenomegaly. These signs and symptoms are described below.

The skeletal pathologies associated with bone marrow infiltration can be particularly painful and debilitating, and are common. Up to 83% of patients have clinical or radiologic evidence of bone pain,7 and 34% are experiencing bone disease at the time of diagnosis.7 Among children, 72% are diagnosed with bone disease by age 6, and 92% are diagnosed with bone disease at ages 12 to 18.8

Since these signs and symptoms also appear with many other conditions, they may not be immediately recognized as Gaucher disease6, often creating an interval between symptom onset and diagnosis.9 To learn more, visit Diagnosing Gaucher disease.

Below are some specific signs and symptoms of Gaucher Disease6:

1. Hepatosplenomegaly

Gaucher patients may have protruding abdomens from enlarged liver and/or spleen, due to accumulation of Gaucher cells. The spleen can swell to 5-75 times its normal size, and the liver can swell to 1.25-2.5 times. The involvement of these organs can have other effects on patients, including appetite suppression (because the swelled organs press on the stomach, creating a full feeling), cytopenias related to an overactive spleen.

2. Thrombocytopenia

A build-up of Gaucher cells in bone marrow may cause fewer blood platelets to be produced. In addition, an enlarged, overactive spleen (caused by accumulated Gaucher cells) may break down blood cells faster than they are produced, contributing to an overall lower platelet count. As a result, Gaucher patients may experience excessive bruising and bleeding, including after minor trauma due to abnormalities in clotting and fibrinolytic factors.

3. Anemia

When the spleen is enlarged from accumulated Gaucher cells, it may become overactive and break down red blood cells faster than they are produced, contributing to anemia. The resulting fatigue may be exacerbated by the low stamina caused by a higher-than-normal metabolism found in many Gaucher patients.

4. Leukopenia

When the spleen is enlarged from accumulated Gaucher cells, it may become overactive and filter white blood cells faster than usual. As a result, Gaucher patients may be susceptible to infection.

5. Bone crisis

Gaucher patients may experience severe bone pain, or “bone crisis,” as a result of bone infarction (with insufficient blood flow and delivery of oxygen and nutrients to the bone) due to infiltration of Gaucher cells in the intramedullary space and local release of chemical factors. The pain is intense, often accompanied by fever, and can last from a few hours to a few days or even weeks, usually rendering patients bedridden during this time.

6. Osteopenia

Adult patients with Gaucher disease may have lower bone mass than expected for age and sex due to generalized demineralization, loss of trabecular bone and cortical thinning. This reduced bone density causes weakening and thus greater susceptibility to fractures.

7. Pathological fracture

Weakened bones due to osteopenia are susceptible to pathological fractures from normal activity.

8. Erlenmeyer flask deformity

Gaucher disease includes osteoclastic dysfunction and bone remodeling abnormalities. The most common among Gaucher patients is the Erlenmeyer flask deformity, in which the ends of the bone (most commonly the femur and tibia) develop a flared, flattened shape rather than the normal rounded form.

Indication & Usage

Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions:

  1. anemia
  2. thrombocytopenia
  3. bone disease
  4. hepatomegaly or splenomegaly

Important Safety Information

Approximately 15% of patients have developed IgG antibodies to Cerezyme during the first year of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity, and these patients have a higher risk of hypersensitivity. It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment.

Hypersensitivity has also been observed in patients without detectable IgG antibodies. Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of all patients, and anaphylactoid reactions in less than 1%. Treatment with Cerezyme should be approached with caution in patients who have exhibited hypersensitivity symptoms such as pruritus, flushing, urticarial, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Pre-treatment with antihistamines and/or corticosteroids and a reduced rate of infusion may allow continued treatment in most patients.

In less than 1% of patients, pulmonary hypertension and pneumonia have been observed during treatment with Cerezyme. These are known complications of Gaucher disease regardless of treatment. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension.

Approximately 13.8% of patients have experienced adverse events related to treatment with Cerezyme. Some of these are injection site reactions such as discomfort, pruritus, burning, swelling or sterile abscess at the site at the site of venipuncture. Additional adverse reactions that have been reported include nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Transient peripheral edema has also been reported for this therapeutic class of drug.

To report suspected adverse reactions, contact Genzyme at 800-745-4447, option 2 or FDA at 800-FDA-1088 or http://www.fda.gov/Safety/MedWatch

Please see Full Prescribing Information (PDF).

References

  1. Charrow J, Andersson HC, Kaplan P, et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med. 2000;160:2835-2843.
  2. Brady RO, Barton NW, Grabowski GA. The role of neurogenetics in Gaucher disease. Arch Neurol. 1993;50:1212-1224.
  3. Taddei T, Kacena K, et al. The underrecognized progressive nature of N37OS Gaucher disease and assessment of cancer risk in 403 patients. Am J Hematol. 2009; 208-214.
  4. Morales LE. Gaucher’s disease: a review. Ann Pharmacother. 1996;30:381-388.
  5. Zimran A, Gelbart T, Westwood B, et al. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991;49:855-859.
  6. Beutler E, Grabowski G. Gaucher disease. In:Scriber CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995; 2:2641-2661.
  7. Weinreb N, vom Dahl, S, A Report from the International Collaborative Gaucher Group (ICGG) Gaucher Registry ASH, 2008, 1, 2.
  8. Kaplan, Paige, et al. The Clinical and Demographic Characteristics on Nonneuronopathic GD in 887 Children at Diagnosis. Archives of Pediatrics and Adolescent Medicine. 2006;160:603-608.
  9. Data on file at Genzyme
Cerezyme has been demonstrated for over 17 years to be an effective treatment for Type 1 Gaucher disease in adults and children.