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 |