What is Gaucher Disease?

Gaucher disease in its three forms—Type I, Type II, and Type III—is an inherited storage disease that results from the deficiency of an enzyme, acid beta-glucosidase, that is necessary for the breakdown of a particular fatty substance, glucosyl ceramide. Normally, glucosyl ceramide is present in very small amounts in all body cells where it is produced, broken down, and then re-synthesized daily, allowing for the normal growth of cells.

Metabolic Defect

Gaucher patients cannot break down glucosyl ceramide properly. Therefore cells that normally metabolize this substance, abnormally store it. These enlarged, abnormal cells are Gaucher cells.

Gaucher disease manifests when there is an abnormal accumulation of Gaucher cells, primarily in the bone marrow, spleen, and liver. Only Types II and III Gaucher disease does the accumulation of enlarged, abnormal Gaucher cells also occur in the central nervous system.

Genetics

Since it was identified and characterized in 1989—the gene for acid beta-glucosidase, the defective protein/enzyme responsible for the deficiency in Gaucher disease—our analysis of this gene has led to the recognition of more than 60 gene alterations or mutations that cause Gaucher disease. Four of these mutations account for approximately 90 to 95 percent of disease-causing changes among Jewish patients, while 50 to 75 percent of the mutations occur among non-Jewish people. The Center uses molecular genetic analysis to determine the patient’s genotype that identifies the exact error in the acid beta-glucosidase gene that we can use as an aid in predicting the severity of involvement in determining the patient's phenotype.

Familial Transmission

Gaucher disease is a genetic disorder transmitted in an autosomal recessive mode. An affected individual must inherit two recessive Gaucher genes—one from each parent—in order to have Gaucher disease. Individuals with only a single Gaucher gene are carriers. Carriers are completely normal with respect to Gaucher disease. Carrying only one recessive gene for Gaucher disease has no bearing on an individual’s health, though it may have reproductive implications. With prenatal diagnosis, we can now ascertain early in a pregnancy if Gaucher disease affects the fetus in the instance of having two carrier biological parents.

If two carrier individuals have children, there is a 25 percent chance with each pregnancy producing a child with Gaucher disease. If a carrier and a non-carrier have children, none of their offspring will have Gaucher disease, but each pregnancy bears a 50 percent chance of producing a carrier of the disease. None of the children of a patient with Gaucher disease and a non-carrier will be affected carriers. If a patient with Gaucher disease and a carrier have children, on average, 50 percent will have the disease and 50 percent will be carriers.

Parent 1		Parent 2		Probability of Each Child Not Being a Carrier or Affected	Risk of Each Child Being a Carrier	Risk of Each Child Being Affected
carrier	+	carrier	=	25 percent	50 percent	25%
carrier	+	non-carrier	=	50 percent	50 percent	0%
affected	+	carrier	=	0 percent	50 percent	50%
affected	+	non-carrier	=	0 percent	100 percent	0

Clinical Manifestations

There are three subtypes of Gaucher disease, and there is a wide variability in the pattern and severity of disease involvement between and within each subtype. All three variants of Gaucher disease are inherited storage diseases, with each distinguished by the presence or absence of neurologic complications. Each of the three types of Gaucher disease is genetically distinct and breeds true in affected families: the type of Gaucher disease occurring in a specific family remains the same through successive generations.

Clinical Features	Type I	Type II	Type III
Clinical Onset	Childhood/ Adulthood	Infancy	Childhood
Hepatosplenomegaly	+	+	+
Hematologic Complications	+	+	+
Skeletal Involvement	+	-	+
Neurologic Involvement	-	+	+
Survival	Variable	< 2 years	2nd - 4th decade
Ethnic Predilection	Ashkenazic Jewish	Panethnic	Northern Swedish

Type I Gaucher Disease

Type I disease is the most common form of Gaucher disease and does not directly involve the nervous system. In the United States, there are an estimated 20,000 or more patients with Type I Gaucher disease. This disease is the most common genetic disorder in Jewish individuals of Central and Eastern European ancestry (Ashkenazic Jews). Approximately 1 in 18 Ashkenazi carry the gene for this disease. However, Gaucher disease has been found in all ethnic groups; it is not restricted by geographic or cultural boundaries.

The clinical manifestations usually become apparent in childhood or early adulthood, when patients initially show an enlarged spleen or develop hematologic problems, such as anemia and/or low platelet count, or orthopedic bone complications. Gaucher cells in the bone marrow may lead to symptoms of bone and joint pain, fractures, and other orthopedic problems. Accumulation of Gaucher cells in the spleen and liver leads to enlargement of these organs as well as blood abnormalities such as anemia and thrombocytopenia, low platelet count, with subsequent easy bruising and impaired blood clotting.

Since there is marked variability in the severity of Type I Gaucher disease, even among family members, it is difficult to predict the future severity and extent of complications in individual patients. Some patients in their teens are affected severely; others are relatively asymptomatic when diagnosed in their fifties or sixties. Although there is no classic, predictable disease course, prognosis in each patient generally depends on the severity at diagnosis and the occurrence interval between disease complications.

Type II Gaucher Disease

Type II disease has its onset in infancy and is a fatal neuro-degenerative disorder with death occurring in the first or second year of life. Extensive liver and spleen enlargement is present, but oculomotor eye movement abnormalities may be the first noted findings. Other findings may include rapid head thrusts, bilateral fixed strabismus, and/or neck muscle hypertonia, limb rigidity, and seizures. Type II Gaucher disease is very rare and does not have a predilection for any particular ethnic or demographic group.

Type III Gaucher Disease

Type III disease is intermediate in severity between Type I and Type II Gaucher disease. In Type II Gaucher disease, neurologic symptoms occur but present later and in a milder form than in Type II. The first symptoms are usually the enlargement of the liver and spleen with eventual eye movement disorders. Some patients progress to have further neurologic involvement including dementia, ataxia, and spasticity. The prototype form of this disease has been found in population isolates in northern Sweden, but this form of the disease can occur in all ethnic and demographic groups.

Diagnosis

We can test concerned couples and individuals for Gaucher disease. We testing and analyze blood samples wherein the level of enzyme responsible for Gaucher disease is measured, and the Gaucher gene itself is analyzed at the molecular level.

Testing individuals. Individuals who are carriers have an enzyme level that is intermediate between that of affected patients and that of non-carrier individuals. Affected individuals have two Gaucher genes and therefore have very low enzyme levels. An overlap exists in the range of enzyme activity values between non-carriers and Gaucher disease carriers, therefore enzyme testing alone as a means of carrier identification is only about 90 percent accurate. Use of direct genetic testing or molecular DNA analysis has provided increased reliability of greater than 98 percent accuracy.

Prenatal diagnosis. We use amniocentesis, or chorionic villus sampling (CVS) to diagnose all types of Gaucher disease during pregnancy. Prenatal diagnosis is available for couples who are at risk for having a child with Gaucher disease. By measuring the level of acid beta-glucosidase in the fetal cells removed during amniocentesis or chorionic villus sampling, we can determine if the fetus has Gaucher disease.

Amniocentesis involves the insertion of a needle through the abdominal wall and uterus into the amniotic sac surrounding the fetus to remove a small amount of amniotic fluid. This fluid of fetal origin contains fetal cells that grow in the laboratory.
Chorionic villus sampling (CVS) involves a sample of the developing placenta obtained and grown in the laboratory or studied directly. When sufficient numbers of cells have grown after approximately two to four weeks, they are studied biochemically and by DNA techniques.

Treatment

The goal for management of Gaucher disease has been supportive and aimed at minimizing future clinical complications. Management initially involves careful monitoring of blood-cell values and orthopedic problems, and appropriate medical intervention when problems develop. The laboratory and radiologic findings must correlate with the patient's general well-being, as assessed by a comprehensive physical examination.

Enzyme replacement therapy is available to combat and treat the underlying problem in Gaucher disease directly. Originally, the enzyme derived from the placenta was Ceredase®. Since 1994, Cerezyme®, a recombinant form of acid beta-glucosidose approved by the FDA, also treats symptomatic Gaucher disease. Several clinical studies have demonstrated the safety and efficacy of both enzyme preparations in reversing the clinical manifestations of Gaucher disease.

Enzyme replacement therapy entails the regular intravenous infusion of the enzyme, which has been biochemically modified to target the Gaucher cell specifically. In conjunction with coordinated management of Gaucher disease manifestations and complications, this therapy can lead to a greater improved quality of life for affected patients and families.

Decisions regarding enzyme replacement therapy are complicated not only by the fact that the minimal effective dose and optimal frequency of enzyme administration have not been established but also by the extreme variability of clinical manifestations among patients, the expense of therapy, and the required commitment on the part of the patient to regular intravenous administration of the enzyme. Therefore, careful and coordinated management by physicians with special expertise in Gaucher disease is required to tailor each individual's treatment program in order to maximize benefit and well-being.