Wiskott-Aldrich syndrome and genetics
Wiskott-Aldrich syndrome (WAS) is a rare inherited disorder primarily affecting males, characterized by a triad of symptoms: eczema, thrombocytopenia (low platelet count), and immunodeficiency. This condition arises from mutations in the WAS gene located on the X chromosome, which encodes for a protein that is crucial for the proper function of blood cells. The resulting dysfunction leads to issues with blood clotting, heightened susceptibility to infections, autoimmune diseases, and an increased risk of certain cancers, particularly those of the immune system.
Diagnosis typically involves analyzing platelet size and number, along with antibody levels, and is confirmed through genetic testing for mutations in the WAS gene. Treatment options depend on the severity of the symptoms and may include blood transfusions, splenectomy, immunoglobulin replacement therapy, and, in some cases, bone marrow transplantation, which can offer a potential cure. Gene therapy is also showing promise, as recent studies have demonstrated success in enhancing patients' immune systems through genetic modifications.
Genetic counseling is recommended for families affected by WAS, particularly for understanding carrier status and the risks of transmission to offspring. The overall prognosis has improved significantly with advances in treatment, although outcomes vary based on individual circumstances and the severity of the disease.
Wiskott-Aldrich syndrome and genetics
ALSO KNOWN AS: Eczema-thrombocytopenia-immunodeficiency syndrome; Aldrich syndrome
DEFINITION Wiskott-Aldrich syndrome is an inherited disorder in which cells of the blood function improperly. The disease is caused by mutation of the gene encoding for Wiskott-Aldrich syndrome protein (WASP), which controls the shape, attachment, division, and movement of blood cells. Patients with Wiskott-Aldrich syndrome have problems with blood clotting and increased rates of infection, autoimmune disease, and cancers of the immune system.
Risk Factors
Wiskott-Aldrich syndrome is caused by a rare, recessive, sex-linked allele. The disease is seen almost exclusively in males. Cases in females are exceedingly rare. The global incidence of Wiskott-Aldrich syndrome is estimated at 1 to 10 in 1,000,000 males. There are no environmental risk factors.
Etiology and Genetics
The WAS gene encoding for WASP is found on the X chromosome (Xp11.22-23). Wiskott-Aldrich syndrome is caused by a rare recessive allele that causes disease predominantly in males because they have only one copy of the X chromosome. Although most cases of Wiskott-Aldrich syndrome are inherited from the mother, as many as one-third arise from spontaneous mutation. WASP is expressed predominantly in blood cells where its cellular function is to transmit signals to the cytoskeleton, thereby controlling the shape, attachment, division, and movement of these cells. Expression of nonfunctional WASP results in defects in platelets and cells of the immune system.
Many mutations in WASP have been found to cause Wiskott-Aldrich syndrome, and the severity of disease corresponds to the specific mutation that is present. Some patients with mild mutations may exhibit only low platelet counts, small platelet size, and bleeding, while others with more severe phenotypes may exhibit eczema, infections, autoimmune disease, and/or cancers of the immune system.
A specific activating mutation in the WAS gene is associated with a distinct disease, X-linked neutropenia.
Symptoms
All patients with Wiskott-Aldrich syndrome exhibit platelets that are reduced in number and in size. Platelets play important roles in blood clotting, and bruising and bleeding may be present from birth. The spleen, which is responsible for removing damaged platelets, is sometimes enlarged. Eczema is also common in Wiskott-Aldrich patients. Many patients are immunodeficient, and at increased risk for bacterial, viral, and fungal infections due to defects in the activity of T cells and B cells. Patients may also exhibit autoimmune disease that can affect a variety of tissues. Patients are also at a higher risk for leukemia and lymphoma.
Screening and Diagnosis
Because patients with Wiskott-Aldrich syndrome invariably have platelets that are small and reduced in number, careful analysis of platelet number and size can be useful in determining diagnosis. Antibody levels are also abnormal in patients due to improper immune cell function and can be analyzed to aid diagnosis. Levels of IgG are low and levels of IgA and sometimes IgE are elevated. Genetic testing that confirms the presence of a mutation in the WAS gene provides the most definitive diagnosis.
Treatment and Therapy
Treatments vary depending on the severity of the disease. Patients with severe bleeding may require transfusions of red blood cells or platelets. Splenectomy results in increased platelet numbers and reduced bleeding but may make patients more susceptible to infection. Young boys may wear helmets to protect from head injuries that might result in bleeding in the brain. Susceptibility to various infectious agents may be a major problem in Wiskott-Aldrich syndrome patients, and proper antimicrobial therapy is essential. Patients may also benefit from immunoglobulin replacement therapy, in which antibodies from many donors are administered intravenously to provide some protection against infection, raise platelet levels, and reduce autoimmune disease. Patients should not receive live virus vaccines because they may cause infection.
Bone marrow transplantation or cord blood stem cell transplantation is the only cure for Wiskott-Aldrich syndrome. Because this technology has the potential to eliminate disease, a search for a matched donor usually occurs immediately following confirmation of diagnosis. In transplantation, the blood-producing cells of the patient are destroyed and replaced with those from a nondiseased individual. The new cells make normal platelets and immune cells, thereby eliminating symptoms. Although success rates of transplantation are high and improving, not all patients are good candidates for transplantation and significant risks are associated with transplantation.
A 2023 study reports success with gene therapy in five young patients in a clinical trial. Researchers used a lentivirus to carry the missing gene into blood stem cells from the boys. The children then underwent chemotherapy. Once the blood stem cells had been genetically modified, they were infused into the patients. All the genetically altered blood cells gained at least one copy of the missing gene. Follow-up exams over several years showed the patients' immune systems had improved. The degree of improvement correlated with the number of genes added to the blood stem cells. Boys whose cells had gained at least two copies of the gene had platelet counts close to normal.
Prevention and Outcomes
There is no means to prevent Wiskott-Aldrich syndrome. One-half of the brothers of patients with Wiskott-Aldrich syndrome also have the disease, and one-half of sisters are unaffected carriers of the disease-causing allele. Genetic counseling should be made available for parents of an affected child. Genetic testing can detect the presence of the disease in the fetus and determine if unaffected females are carriers. Outcome depends on the severity of disease and the response to treatment. Before modern treatment, the life expectancy of Wiskott-Aldrich patients was between two and three years. Nearly 90 percent of patients that receive tissue-matched bone marrow from unaffected siblings can be cured. The overall cure rate is lower because patients with infection or cancer may not be good candidates for transplantation.
Bibliography
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