Related Diseases
Gaucher

Causes

Symptoms

Inheritance

Testing

Treatment/Management

Family Planning

Community Issues

Additional Information Links

In 1882, Phillipe Gaucher, A French physician, described the clinical disorder that now bears his name. Since his original description, many investigators have contributed to our understanding of Gaucher Disease. In the early 1900's, American physicians were the first to recognize its familial transmission and to characterize further the pathology of the disease. Although early investigations suggested that the disease was due to a metabolic disorder, it was not until 1965 that the specific metabolic defect, a deficiency in the enzyme glucocerebrosidase, was identified. We now recognize that the disease has three subtypes: Type I, II and III.

Causes

All three types of Gaucher disease are autosomal recessive inherited storage diseases, and all result from the deficiency of an enzyme called glucocerebrosidase, which is necessary for the breakdown of a particular fatty substance, glucocerebroside. This fatty substance is normally present in very small amounts in all body cells, but in patients with Gaucher disease, glucocerebroside is not broken down as it should be and becomes abnormally stored, primarily in unique cells called Gaucher cells.

Symptoms

The major disease manifestations are due to the progressive storage of glucocerebroside in Gaucher cells in the bone marrow, spleen and liver. Gaucher cells in the bone marrow can cause bone and joint pain, fractures and other orthopedic problems. Accumulation of Gaucher cells in the spleen and liver causes enlargement of these organs as well as blood abnormalities such as anemia, easy bruising and impaired blood clotting. In a small number of persons with Gaucher disease, glucocerebroside also accumulates in the central nervous system, leading to neurological damage.

The three types of Gaucher disease are distinguished by their clinical severity and course, and by the presence or absence of neurological complications. Type I is the most common form and does not have mental or neurological involvement. This disease primarily affects Jewish individuals of central and eastern European ancestry (Ashkenazi Jews), although it is also seen in people of other ethnic groups. Type II has its onset in infancy and is a fatal neuro-degenerative disorder with death occurring in the first or second year of life. It is an extremely rare type and does not occur with a higher frequency in any particular ethnic or demographic group. Type III begins in early childhood, has mild to severe neurological involvement, and is very rare, except in Sweden, where most patients have been found. Each of these three types of Gaucher disease is genetically distinct and "breeds true" in affected families - that is, no two types of Gaucher disease occur in the same family. This overview focuses on Type I Gaucher disease, the most common form of the disease.

Fact:
Unlike many more severe recessive disorders, most people with Type I Gaucher Disease can have children.

The clinical manifestations of Type I Gaucher disease usually become apparent in childhood or early adulthood, but some persons remain asymptomatic into their 50's and 60's. Common early symptoms include an enlarged spleen and hematologic or orthopedic problems. Since there is marked variability in the severity of Type 1 Gaucher disease even within a family, it is difficult to predict the future severity and extent of complications in individual patients. Although there is no classic, predictable disease course, prognosis generally depends on the severity at the time of diagnosis and the intervals between the onset of new disease complications in each affected individual.

Inheritance

Gaucher Disease, like Tay-Sachs, is an autosomal recessive disorder. Affected individuals have one copy of the altered gene. As in other recessive disorders, a couple where both people are carriers of the Gaucher Disease gene faces a 25% chance in each pregnancy that their child will inherit two copies of the altered gene and, in all probability, have the disease.

Unlike many more severe recessive disorders, most people with Type I Gaucher Disease (with two altered copies of the gene) will, of course, pass one of those nonfunctional genes on to each of his or her children. Therefore, all children of a person with Gaucher Disease will carry at least one altered copy of the Gaucher Disease gene. Thus, the children will be carriers, they will not have the disease unless the other parent is also a Gaucher carrier and passes his or her inactive gene on to the child.

The gene responsible for Gaucher Disease, called the glucocerebrosidase gene, is located on chromosome 1. Mutations in this gene cause Gaucher Disease symptoms in most individuals; however, some individuals with mutations in both copies of this gene show no symptoms whatsoever. Nine mutations are seen with some frequency in patients with Type I Gaucher Disease, and attempts have been made to correlate the mutations with the clinical presentation of the disease. Some correlations have been made between specific mutations and expression of clinical symptoms, but it is not possible to predict with certainty how severely an individual with a given pair of mutations will be affected.

Type I Gaucher Disease occurs primarily, but not exclusively, in individuals of Ashkenazi Jewish ancestry. It is estimated that about one in every 10 Jewish individuals of central and eastern European ancestry is a carrier of a Type I Gaucher Disease gene ant that one in every 450 Ashkenazi Jews has two altered copies of the gene. Although some of these people show no symptoms of Gaucher Disease, most do. Gaucher Disease is, therefore, one of the most common genetic diseases in the Ashkenazi Jewish population.

Testing

Concerned couples and individuals have options for carrier testing for Type I Gaucher Disease. DNA-based testing, which looks for mutations in the glucocerebrosidase gene, is the most reliable method, as measurements of the level of the enzyme glucocerebrosidase do not distinguish all carriers from non-carriers. DNA mutation analysis detects about 84% of all carriers, but the detection rate is higher (about 90%) for persons of Ashkenazi Jewish descent. Some affected but asymptomatic individuals learn that they have two copies of the Gaucher Disease gene when they undergo carrier testing.

Fact:
More recently, enzyme replacement therapy has become commercially available and has been successful in slowing and reversing the progression of many symptoms of Gaucher Disease.

Treatment/Management

Treatment for Type I Gaucher Disease has traditionally included periodic blood transfusions, partial or total spleen removal, and the use of pain relievers. More recently, enzyme replacement therapy has become commercially available and has been successful in slowing and reversing the progression of many symptoms of the disease. The treatment involves infusions of Cerezyme™, a chemically modified enzyme derived from glucocerebrosidase that has been specifically targeted to Gaucher cells. The disadvantages of this therapy are its high cost and the need for repeated infusions of the enzyme.To learn more about Cerezyme visit: www.cerezyme.com. ZavescaŽ is a substrate deprivation for affected individuals for whom infusions are not an option. To learn more about Zavesca visit www.actelion.com. In patients with severe clinical symptoms, bone marrow transplantation is sometimes performed; if successful, it provides a lifelong cure. It is possible that in the future, gene therapy using a patient's own bone marrow stem cells may be available to provide a permanent cure without the immunological complications of bone marrow transplantation from a donor.

Family Planning

The availability of treatment and the uncertainty of prognosis for individuals with two copies of the Gaucher disease gene make it especially difficult for at-risk couples to make decisions about whether they wish to undergo prenatal testing and to decide what to do with the information they may learn from test results. Carrier and prenatal testing for people with a family history of Gaucher disease should be offered in conjunction with genetic counseling so that people can be aware of their options and make informed decisions.

Prenatal testing methods for Gaucher disease include direct DNA analysis to identify mutations in the glucocerebrosidase gene, linkage analysis (another form of DNA testing which compares the DNA of the fetus to that of affected and unaffected relatives) and biochemical testing to measure the amount of glucocerebrosidase in the fetus. All types of testing can be done from samples obtained through amniocentesis or chorionic villus sampling (CVS); however, none of these types of testing can predict the degree to which the child will be affected clinically if it is determined that he or she has two copies of the altered glucocerebrosidase gene.

Community Issues

Despite the high carrier frequency of Gaucher Disease in the Ashkenazi Jews, population screening has not been recommended. Some arguments against population screening include:

  • the limitations of our ability to distinguish persons who will be asymptomatic from those who will be affected clinically with Gaucher Disease.
  • the highly variable course of the disease in affected individuals.
  • the availability of treatment for persons who are affected.

 

Additional Informational Links

The following online resources may be helpful in learning more about Gaucher disease: