Gaucher disease and genetics
Gaucher disease is a rare genetic disorder characterized by the abnormal accumulation of fatty substances in the body due to mutations in the GBA gene, which is responsible for producing the enzyme beta-glucocerebrosidase. There are three main types of the disease, with Type I being the most prevalent, particularly among individuals of Ashkenazi Jewish descent. Type II presents with rapid neurological degeneration and is often fatal in early childhood, while Type III is marked by a slowly progressive neurological decline, with symptoms potentially appearing in early childhood.
Gaucher disease follows an autosomal recessive inheritance pattern, meaning that both parents must carry the mutated gene for a child to be affected. Symptoms vary widely depending on the type, and may include organ enlargement, anemia, skeletal deformities, and developmental issues. Although there is no cure for the more severe forms, treatment options such as enzyme replacement therapy and substrate reduction therapy are available for Type I, aiming to alleviate symptoms and improve quality of life. Genetic counseling is recommended for families with a history of Gaucher disease to discuss reproductive options and risk factors.
Gaucher disease and genetics
DEFINITION Gaucher disease is a rare, inherited disease that causes the abnormal storage of fatty substances. There are three types of Gaucher disease. Type I is the most common form, found widely in people of Ashkenazi Jewish descent. Type II is a very rare, rapidly progressive form of Gaucher disease. Type III is a very rare form, with most cases found in Japan and Sweden and other parts of Scandinavia.
Risk Factors
The primary risk factor for Gaucher disease is a family history of the disease.
Etiology and Genetics
Mutations in the GBA gene, located on the long arm of chromosome 1 at position 1q21, cause Gaucher disease. The normal protein product of this gene is an known as beta-glucocerebrosidase, which acts in cells to catalyze the breakdown of large fatty molecules called glucocerebrosides into smaller fats (ceramides) and simple sugars (glucose). In patients with Gaucher disease, the levels of this enzyme are profoundly reduced or absent altogether. As a result, glucocerebrosides and related complex fats accumulate to toxic levels in the liver, spleen, bone marrow, lungs, and occasionally in the brain.
Gaucher disease is inherited as a classic autosomal recessive trait. Both copies of the gene must be deficient in order for the disease to be expressed. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has Gaucher disease and the other is a carrier, there is a 50 percent probability that each child will be affected.
Gaucher disease is one of the most common of a class of conditions known as lysosomal storage disorders. The beta-glucocerebrosidase enzyme is generally located in lysozomes, which are small organelles in cells that contain a number of different digestive enzymes that function to break down toxic substances and recycle used cellular components. Both a simple blood test to check for carriers of the gene and a specific enzyme replacement therapy for patients with the disease are now available.
Symptoms
The three types of Gaucher disease vary in onset and severity of symptoms. In general, the later the onset of symptoms, the less likely that symptoms will be severe.
Type I symptoms may include enlargement of the spleen or liver, fatigue due to anemia, deformity of the thigh bones known as “Erlenmeyer flask deformity,” compression of the lungs, slow or stunted growth in children, and bone and joint problems. Other symptoms may include blood abnormalities, intestinal problems, poor lung and brain function, seizures, eye problems, and developmental delay. In type II, neurologic symptoms appear within the first few months of life and are fatal by the age of three. In type III, the primary symptom is a slowly progressive neurologic disease. Other symptoms are similar to type I and may appear in early childhood. People with type III Gaucher who survive through adolescence may survive until their thirties or forties.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. Diagnosis of Gaucher disease is confirmed with tests or tests that measure glucocerebrosidase activity, including blood, tissue, or urine tests.
Treatment and Therapy
There is no treatment for the severe neurologic symptoms that may occur with type II and type III Gaucher. However, new treatment options for type I Gaucher include enzyme replacement therapy, which consists of a regular infusion of cerezyme, a chemically modified enzyme. This treatment can help reduce skeletal abnormalities and liver and spleen size, and it can also reverse some abnormal blood counts.
Substrate reduction therapy is another treatment option. Zavesca (miglustat) has been approved by the U.S. Food and Drug Administration for treatment of type I Gaucher disease in adults who cannot receive hormone replacement therapy.
Another form of treatment for type I Gaucher is a bone marrow transplant. A transplant is used only in patients with severe clinical symptoms and bone abnormalities. If it is successful, it provides a lifelong cure. A splenectomy, the surgical removal of the spleen, may be done if enzyme replacement therapy is not available.
Prevention and Outcomes
There is no known way to prevent Gaucher disease. Individuals who have Gaucher disease or have a family history of the disorder can talk to a genetic counselor when deciding whether to have children.
Bibliography
Chen, Harold. “Gaucher Disease.” In Atlas of Genetic Diagnosis and Counseling. Humana Press, 2006.
Dursun, Huseyin, Esra Yildzhan, and Fahri Bayram. "Overall Assessment of Patients with Type 1 Gaucher Disease: A Single Centre's Experience." Journal of Rare Diseases, vol. 2, no. 14, 2 Oct. 2023, doi.org/10.1007/s44162-023-00019-6. Accessed 9 Sept. 2024.
Futerman, Anthony H., and Ari Zimran, eds. Gaucher Disease. CRC/Taylor & Francis, 2007.
"Gaucher Disease." MedlinePlus, NIH National Library of Medicine, 1 Nov. 2022, medlineplus.gov/genetics/condition/gaucher-disease/. Accessed 20 Sept. 2024
Stone, William, et al. Gaucher Disease. StatPearls, National Library of Medicine, 9 Sept. 2024, www.ncbi.nlm.nih.gov/books/NBK448080/. Accessed 9 Sept. 2024.