NYU Comprehensive Gaucher Disease Program
Center of Excellence for the Diagnosis and Treatment of Gaucher Disease
NYU School of Medicine
403 East 34th Street, 2nd Floor
New York, NY 10016
Phone: (212) 263-8344
FAX: (212) 263-8310
Co-Directors: Edwin H. Kolodny, MD
Gregory M. Pastores, MD
- Nurse/Coordinator: Carol Fisher, RN
- Genetic Counselor: Pam Lenz, MS
- Office Manager: Michele Ford
Gaucher disease (GD) is an inborn error of the metabolism of a complex lipid (fatty material) called glucosylceramide (GC). The disease is characterized by the storage of this undegraded material in macrophages, as a result of the deficiency of the lysosomal enzyme, acid beta-glucosidase. GD is inherited as an autosomal recessive trait.
The disease is named after Dr. Philippe Charles Ernest Gaucher, a French medical student who provided a description of an affected young woman with an enlarged spleen in a doctoral thesis written in 1882. At that time he noted the hallmark cells (lipid-engorged macrophages, subsequently referred to as Gaucher cells) but he did not recognize it to be a storage disease and speculated that the condition may be a tumor of the spleen. In 1965, Dr. Roscoe O. Brady (at the NIH) recognized that the lipid build-up was not due to over-production but a block in the catabolic phase of its metabolism, when the complex lipid is not broken down or degraded completely into its more simple components.
Gaucher disease is characterized by a wide variety of clinical problems including low blood counts (anemia), enlarged liver and spleen and various bone problems including osteoporosis and fractures. The majority of the patients (about 97%) do not have primary central nervous system involvement and are said to have type I GD. The rest may have varying severity of nervous system involvement, associated with a reduced lifespan and significantly impaired quality of life.
Enzyme therapy for Gaucher disease was introduced into clinical practice in 1991 with FDA-approval of the placental-derived enzyme CeredaseR. Subsequently, a recombinant form of the enzyme CerezymeR was made available in 1994. The use of these therapies in symptomatic patients (that is, those who have developed complications of the disease) has been shown to be safe and effective.
Currently, clinical trials are taking place to determine whether gene therapy may be an effective option to treat Gaucher disease. The use of the substrate synthesis inhibitor OGT 918 is also being explored as a means to limit the buildup of the lipid.
The diagnosis of Gaucher disease can be established by a blood test that is available through specialized laboratories. The test used to confirm the diagnosis is based on determination of the residual enzyme activity; studies have shown that individuals with acid beta-glucosidase activity < 15% demonstrate lipid storage. The biochemical or enzyme diagnosis is often complemented by molecular (DNA) analysis. Individuals who have two Gaucher disease-causing gene defects, one copy inherited from each carrier parent, develop the enzyme deficiency (further discussed below).
As most GD patients are initially seen by a hematologist (specialist in diseases of the blood) because of concern relating to an abnormal blood count or enlarged spleen, a bone marrow biopsy has often been made before the patient is seen by a geneticist (specialist in inherited diseases). For these patients, we still recommend that the diagnosis be confirmed by biochemical testing prior to making any management decisions.
As an inherited disorder, individuals who are related to an affected person may also be at risk of being affected or carriers of the trait. Carriers are individuals who possess a single defective gene but do not develop the disease because their other normal gene is able to make up for the partial deficiency. However, carriers may be at risk of having affected children, if spouses also happen to be carriers. We recommend that affected individuals and their relatives receive genetic counseling.
Prenatal Diagnosis: Gaucher disease can be detected during pregnancy through chorionic villus sampling (placental biopsy) or amniocentesis.
There are three subtypes of Gaucher disease, delineated on the basis of the presence or absence of primary central nervous system involvement. The distinction is primarily based on clinical findings and disease course, as all GD subtypes involve the same gene and enzyme deficiency but differ in degree of severity.
Gaucher disease type I disease is the most common form. It is prevalent among individuals of Jewish ancestry from Central and Eastern Europe, but not restricted to this group. Approximately one in 18 Ashkenazi Jews carry the trait, that is, have one GD-gene defect, and about one in 1300 have the disease although a significant number of these individuals may not have any GD-related problems.
In the patients, clinical manifestations usually become apparent in childhood or early adulthood although a significant number can be without symptoms for most of their lives. Patients usually come to medical attention because of an enlarged spleen (splenomegaly), abnormal liver function, hematological problems (anemia and/or low platelet count [thrombocytopenia]) or orthopedic (bone) complications. It is rare for Gaucher disease to threaten the life of a patient, except under the following situations: severe bleeding complications, a fracture involving the spine, or the development of a rare complication (for example, pulmonary hypertension). For most, Gaucher disease if progressive can lead to a significant impairment in the quality of life (because of chronic pain and limitation in function).
This rare form of Gaucher disease is usually recognized in infancy and is a rapidly progressive disorder associated with degeneration of the nervous system. Death commonly occurs in the first or second year of life. Recently, it has been recognized that some of these patients can have skin findings at birth or shortly thereafter (edema, generalized swelling, collodion [wax-like] or ichthyosis [scaling] skin).
Patients with GD type III have varying severity of neurologic problems that may or may not be associated with systemic findings (like enlargement of the liver and spleen). Abnormalities of eye movements are detected in a majority of these individuals. A high incidence of this GD type have been identified in the northeastern part of Sweden (Norrbottnia), which has been attributed to a founder effect. Founder effect refers to the common ancestry of a population sharing a genetic disease because of geographic isolation as seen in the Norrbottnian with GD type III or marriage within the faith and the bond of a common language (Yiddish) as seen for the Ashkenazi Jews with GD type 1.
We recommend that patients diagnosed with Gaucher disease undergo testing to establish the pattern and severity of their condition. It should be noted that the wide variability or differences in presentation found between patients necessitates an individualized management approach.
At NYU, we perform blood tests to determine blood counts and liver function. Some patients who have received a blood transfusion or undergone surgery (for example, splenectomy or hip replacement) may have acquired hepatitis that we also screen for in patients with abnormal liver function. In addition, we obtain an MRI or CAT scan to measure liver and spleen volumes. Although an ultrasound may be useful it does not provide the anatomical details seen on an MRI or CT scan that may be important to consider in long-term management plans. A patient who is having an MRI can also be examined to assess the degree of bone marrow involvement in the spine and femurs at the same time.
To assess bone disease, we request x-rays of the thoracic and lumbar spine (lateral views only) and the femurs (frontal views only). X-rays of all problem areas are also done. In children, we obtain an x-ray of the left hand and wrist for bone age.
As a major referral center and because of our interest in lysosomal storage diseases and Gaucher disease in particular we also conduct studies on a research basis. Current research activities involve investigations of heart and lung involvement, bone disease, and alternative treatment options.
Prior to availability of enzyme therapy, treatment was primarily symptomatic. Symptomatic treatment meant prescribing medications for pain (analgesics), splenectomy for patients with massively enlarged spleens and/or dangerously low blood counts, or blood transfusions.
Since 1991, enzyme therapy for Gaucher disease has become available to treat symptomatic GD patients. It involves the regular intravenous administration of the enzyme (a protein) to make up for the deficiency, much like patients with diabetes require a regular injection of insulin. The use of alglucerase (CeredaseR) and imiglucerase (CerezymeR) in the treatment of GD patients has been demonstrated to be safe and effective. Lingering concerns include the high cost of treatment and the required commitment to regularly receiving the enzyme, potentially for the rest of the patients' life.
Enzyme therapy for the neurologic forms of Gaucher disease is also being explored. The treatment of a few patients with the acute, severe form (GD type II) does not lead to any meaningful response. Although enzyme therapy has been shown to reverse the extra-neurological manifestations of the disease, it does not have any significant impact on the long-term outcome. Enzyme therapy for the chronic neurologic form (GD type III) does appear to be beneficial. Whether the observed responses to therapy in the patients with neurologic involvement is equivalent or superior to the experience seen in patients subjected to bone marrow transplantation (BMT) is not established. Obviously, BMT is a procedure associated with a high morbidity and mortality rate. Thus, its application has been limited to severely affected patients who have a histocompatible (tissue-matched) donor. BMT also necessitates a commitment to medications to contain the recipient immune system and not reject the transplanted bone marrow.
Increased experience with the use of enzyme therapy suggests that GD patients who have developed disease complications may require the supportive care given when there was no means to specifically correct the lipid storage problem. Other medications are also being looked at to determine whether their use for GD patients may be beneficial. For example, GD patients with severe osteoporosis may benefit from treatment with a bisphosphonate (such as alendronate [FosamaxR]). Additional information regarding a trial to examine the role of Fosamax in GD may be obtained from the GD Center in Cincinnati (by calling 800-647-4805).
Several studies are currently being undertaken to improve the means of assessing disease severity and rate of progression. These efforts go hand-in-hand with investigations of new ways to treat symptomatic Gaucher disease. These include research on the safety and efficacy of substrate synthesis inhibitors such as OGT 918 and gene therapy.
With increased experience in the use of enzyme therapy, we will begin to understand the regimens that will be sufficient to achieve maintenance of good health and enhanced quality of life. We will also be able to address the issues related to the costs of on-going therapy.
Gene therapy as a therapeutic strategy involves the introduction of a normal gene for acid beta-glucosidase into the somatic (body) cells of a patient with Gaucher disease. This effort, also referred to as transduction, is intended to correct the enzyme deficiency, through endogenous (internal) production of the enzyme as opposed to its intravenous administration like a drug. To be effective, this strategy requires a sustained production of sufficient amounts of the enzyme. The current target for introduction of the normal acid beta-glucosidase gene is the stem cell. Stem cells are blood cells with the ability to propagate continuously and can be isolated from the bone marrow or peripheral blood. The successful transduction of these cells may provide a continual endogenous source of the enzyme.
Gaucher disease is an autosomal recessive disorder. This means that an affected individual has inherited two recessive GD-causing genes - one from each parent. All children born to an affected individual are carriers of the trait; these children would only be at risk for having the disease if their non-affected parent is either affected or a carrier. Individuals with only a single GD-causing gene are known as carriers. Carriers do not develop Gaucher disease; because the trait is recessive their one normal gene copy is able to make up for the partial deficiency. Carrier couples who may be concerned about having an affected child may consider prenatal diagnosis. The risk that carrier couples may have an affected child is 25% with each pregnancy. We recommend that affected and carrier individuals receive genetic counseling.
Additional information on Gaucher disease may be obtained from the National Gaucher Foundation (NGF) by calling 800-925-8885.
Last Update: 07 May, 2006
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