Gaucher Disease

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.
 
All three types of Gaucher Disease are 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.
 
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.
 
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 I 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.
 
Gaucher Disease 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.
 
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 and 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.