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Wiskott-aldrich Syndrome

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Description: Wiskott-Aldrich syndrome is a rare, X-linked recessive genetic disorder characterized by eczema, thrombocytopenia, immune deficiency, and an increased risk of autoimmune diseases and malignancies.
Type: Wiskott-Aldrich Syndrome is a primary immunodeficiency disorder characterized by eczema, thrombocytopenia (low platelet count), and increased susceptibility to infections. It is inherited in an X-linked recessive pattern, which means the faulty gene responsible for the condition is located on the X chromosome. Because males have only one X chromosome, a single defective gene is sufficient to cause the disease in males. Females, having two X chromosomes, are typically carriers of the condition and usually do not show severe symptoms, although some may exhibit mild symptoms.
Signs And Symptoms: WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 and 10 males per million. The first signs are usually petechiae and bruising, resulting from a low platelet count (i.e. thrombocytopenia). Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections typically develop by three months of age. The majority of children with WAS develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to thrombocytopenia, WAS patients have abnormally small platelets (i.e. microthrombocytes) and ~30% also have elevated eosinophil counts (i.e. eosinophilia).
Prognosis: Outcomes from Wiskott–Aldrich syndrome are variable and depend on how severely an individual is affected (the WAS score may be used to assess disease severity). The milder end of the disease spectrum associated with the WAS gene is referred to as X-linked neutropenia or X-linked thrombocytopenia, and the latter is thought to have a normal life expectancy with reports of minimally affected males surviving into their seventh decade without treatment. Traditionally however Wiskott–Aldrich syndrome has been associated with premature death from causes including bleeding, infections, or malignancy. Wiskott–Aldrich syndrome is a condition with variable expressivity, meaning that even within the same family some may exhibit only chronic thrombocytopenia while others experience severe, life-threatening complications of Wiskott–Aldrich syndrome in infancy or childhood. Given symptoms often progress with age, it is challenging to predict how affected a newly diagnosed infant will eventually be. There is some genotype-phenotype correlation, with most individuals with X-linked thrombocytopenia having missense variants in the WAS gene versus 86.5% of those that make no WAS protein having the classic Wiskott–Aldrich syndrome phenotype. Overall the prognosis for individuals with Wiskott–Aldrich syndrome has improved considerably over the past decades due to earlier diagnoses and more access to treatments.
Onset: Wiskott-Aldrich Syndrome (WAS) typically has an onset in infancy or early childhood. The symptoms can include easy bruising or bleeding, recurrent infections, and eczema. The condition is rare and primarily affects males.
Prevalence: Wiskott-Aldrich syndrome (WAS) is a rare genetic disorder. Its prevalence is estimated to be approximately 1 to 10 cases per million male live births.
Epidemiology: The estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births. While still a rare disease, this makes it more common than many genetic immunodeficiency syndromes such as hyper-IgM syndrome or SCID, which have an estimated incidence of about one in 1,000,000 live births, and Wiskott–Aldrich syndrome is thought to account for 1.2% of all inherited immunodeficiencies in the United States. WAS occurs worldwide and is not known to be more common in any particular ethnic group.
Intractability: Wiskott-Aldrich Syndrome (WAS) is generally considered intractable if left untreated, as it involves complex issues related to the immune system and blood clotting. However, advances in medical treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy have improved outcomes significantly. Early diagnosis and appropriate treatment can manage symptoms and improve quality of life, making the disease more manageable.
Disease Severity: Wiskott-Aldrich syndrome (WAS) typically presents with severe disease manifestations. These can include recurring infections, eczema, and a predisposition to autoimmune disorders and malignancies such as lymphoma. The severity of symptoms can vary, but the condition is generally considered serious and potentially life-threatening.
Healthcare Professionals: Disease Ontology ID - DOID:9169
Pathophysiology: The microthrombocytes seen in WAS patients have only been observed in one other condition, ARPC1B deficiency. In both conditions the defective platelets are thought to be removed from circulation by the spleen and/or liver, leading to low platelet counts. WAS patients have increased susceptibility to infections, particularly of the ears and sinuses, and this immune deficiency has been linked to decreased antibody production and the inability of immune T cells to effectively combat infection.
Carrier Status: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive condition. Carrier status typically applies to females who have one mutated copy of the WAS gene on one of their X chromosomes. These carriers usually do not exhibit severe symptoms but can have mild manifestations or none at all. Carrier females have a 50% chance of passing the mutated gene to their offspring, which would result in sons being affected and daughters being carriers.
Mechanism: Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disorder characterized by immunodeficiency, eczema, and thrombocytopenia. The primary mechanism involves mutations in the WAS gene, which encodes the Wiskott-Aldrich syndrome protein (WASP).

**Mechanism:**

1. **Genetic Mutation:** Mutations in the WAS gene lead to defective or absent WASP.
2. **Protein Deficiency:** Lack of functional WASP impacts cells of the hematopoietic system, particularly affecting the signaling pathways and cytoskeletal reorganization necessary for cell functions.

**Molecular Mechanisms:**

1. **Actin Cytoskeleton Reorganization:** WASP plays a crucial role in the organization of the actin cytoskeleton. Its deficiency impairs this process, affecting cell shape, movement, and interaction.
2. **Signal Transduction:** WASP is involved in transmitting signals from the cell surface to the interior. Mutations disrupt these signaling pathways, hampering immune cell activation, proliferation, and function.
3. **Immune Cell Function:** WASP is essential for the normal functioning of various immune cells, including T cells, B cells, macrophages, and platelets. Defective WASP leads to compromised immune responses, faulty cell-cell communication, and impaired ability to form immune synapses.

Overall, these disruptions contribute to the clinical manifestations of Wiskott-Aldrich syndrome, including increased susceptibility to infections, autoimmune manifestations, and bleeding tendencies.
Treatment: Hematopoietic stem cell transplant
Treatment of Wiskott–Aldrich syndrome depends on the severity of the disease. WAS is primarily a disorder of the blood-forming tissues, so in cases of severe disease (WAS score 3–5) the only widely available curative treatment currently available is a hematopoietic stem cell transplant (HCT). In this procedure stem cells are harvested from umbilical cord blood, bone marrow, or peripheral blood following treatment with medications that cause stem cells to leave the bone marrow and circulate systemically. The best outcomes are with HLA-identical or similar donors (often siblings). In cases of milder disease the potential benefits of HCT (>90% probability of cure if transplant occurs before age two) must be considered in the context of non-trivial risks presented by the procedure itself and the potential need for lifelong immunosuppression to prevent graft-versus-host disease. Generally outcomes are better if HCT occurs prior to the development of autoimmune disease or malignancy, however there are risks associated with chemotherapy (needed to make room for the new stem cells) especially in young infants (risk of a second cancer, or infertility).Bleeding complications
Otherwise WAS treatment is focused on managing symptoms and preventing complications. The greatest mortality risk in WAS before age 30 is from bleeding so aspirin and other nonsteroidal anti-inflammatory drugs that may interfere with already compromised platelet function should generally be avoided. Circumcision, as well as elective surgeries, should generally be deferred in males with thrombocytopenia until after HCT if possible. Protective helmets can help protect children from life-threatening intracranial hemorrhage (brain bleed) which could result from head injuries. Patients may require platelet transfusions when there is extreme bloodloss (such as during surgery) or for very low platelets splenectomy (removal of the spleen) may also be lifesaving. However, splenectomy is generally considered palliative and is not universally recommended in WAS because it can increase the risk of life-threatening infections. Post-splenectomy patients will require lifelong antibiotic prophyllaxis to prevent infections. Study of eltrombopag, a thrombopoietic agent used to increase platelets in immune thrombocytopenic purpura (ITP), in WAS concluded that although it increased platelet numbers it failed to increase platelet activation in most patients. It has since been proposed the eltrombopag may be used to bridge to HCT in patients with severe thrombocytopenia to normalize platelet numbers without transfusions and decrease bleeding events.Anemia from bleeding may require iron supplementation or blood transfusion. Regular surveillance of blood counts is recommended.
Infections and autoimmune disease
For patients with frequent infections, intravenous immunoglobulins (IVIG) or subcutaneous immunoglobulins can be regularly scheduled to boost the immune system. Adequacy of IVIG replacement can be assessed via periodic lab draws. WAS patients with immune system compromise may benefit from antibiotic prophylaxis, for example by taking trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii-related pneumonia. Similarly, prophylactic antibiotic use may also be considered in patients with recurrent bacterial sinus or lung infections. When there are signs or symptoms of an infection, prompt and thorough evaluation is important including blood cultures to guide therapy (often IV antibiotics). Live vaccines (such as MMR or rotavirus) should be avoided during routine childhood vaccination. Inactivated vaccines may be given safely but may not provide protective levels of immunity. Eczema is generally treated with topical steroids, and if chronic skin infections exacerbate eczema an antibiotic may also be given. Autoimmune disease is managed with judicious use of appropriate immunosuppressants.Gene therapy
For severely affected males without an HLA-matched donor, studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus are underway. Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome. In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that three children with Wiskott–Aldrich syndrome showed significant improvement (improved platelet counts, immune functiona, and clinical symptoms) 20–30 months after being treated with a genetically modified lentivirus. In April 2015 results from a follow-up British and French trial six out of seven individuals showed improvement of immune function and clinical symptoms an average of 27 months after treatment with gene therapy. Importantly, neither study showed evidence of leukemic proliferation following treatment, a complication of early attempts at gene therapy using a retroviral vector. It is unknown why these gene therapies did not restore normal platelet numbers, but gene therapy treatment was still associated with transfusion-independence and a significant reduction in bleeding events. A version of this treatment, OTL-103, is being developed by Orchard Therapeutics and (as of 28 June 2021) is undergoing Phase I/II clinical trials.
Compassionate Use Treatment: Wiskott-Aldrich Syndrome (WAS) is a rare X-linked recessive disorder characterized by eczema, thrombocytopenia, immune deficiency, and an increased risk of autoimmune diseases and malignancies. For compassionate use treatment, off-label, or experimental treatments:

1. **Hematopoietic Stem Cell Transplantation (HSCT):** This is the most definitive treatment for WAS and may be pursued on a compassionate use basis when a suitable donor is available.

2. **Gene Therapy:** Experimental gene therapy has been explored to correct the genetic defect in WAS. Clinical trials have shown promise, with some patients achieving improved immune function and platelet counts.

3. **Immunoglobulin Replacement Therapy:** Off-label use of intravenous or subcutaneous immunoglobulin can help manage infections due to immune deficiency.

4. **Splenectomy:** This surgical procedure may be considered off-label to manage severe thrombocytopenia, though it is less common due to the risk of infection.

5. **Eltrombopag:** This is a thrombopoietin receptor agonist that has been used off-label to increase platelet counts in thrombocytopenic patients.

It is important to discuss these options with a healthcare provider specializing in WAS to determine the appropriateness and potential risks of these treatments.
Lifestyle Recommendations: For individuals with Wiskott-Aldrich syndrome, specific lifestyle recommendations can help manage the condition and improve quality of life:

1. **Infection Prevention**: Maintain good hygiene, avoid contact with sick individuals, and stay up to date with vaccinations as recommended by healthcare providers.
2. **Bleeding Precautions**: Avoid activities that carry a high risk of bruising or bleeding. Use protective gear during physical activities and ensure prompt treatment of any injuries.
3. **Regular Medical Care**: Regular follow-up with healthcare providers, including immunologists and hematologists, to monitor health and address any issues promptly.
4. **Healthy Diet**: Maintain a balanced diet to support the immune system and overall health.
5. **Stress Management**: Implement stress-reduction techniques such as meditation, yoga, or counseling to cope with the emotional and psychological aspects of the condition.
6. **Education and Support**: Educate family, friends, and school personnel about the condition to ensure a supportive environment. Join support groups for additional emotional and practical support.

Always consult with healthcare professionals for personalized advice tailored to the individual's specific medical condition.
Medication: Wiskott-Aldrich Syndrome (WAS) primarily requires management through various treatments rather than a specific medication. The treatment strategy generally includes:

1. **Hematopoietic Stem Cell Transplantation (HSCT)**: This is the definitive treatment and can cure the disease by replacing the defective immune system with a healthy one.

2. **Gene Therapy**: Experimental and still under investigation, gene therapy aims to correct the genetic defect causing WAS.

3. **Prophylactic Antibiotics**: Used to prevent infections due to the immune system's compromised state.

4. **Immunoglobulin Replacement Therapy**: Administered to boost the immune system and help fight infections.

Medication specifics like "nan" don’t correlate directly to Wiskott-Aldrich Syndrome treatment. If "nan" was intended to reference a particular aspect of treatment, more context would be needed to provide precise information.
Repurposable Drugs: Wiskott-Aldrich syndrome (WAS) is a rare, X-linked recessive immunodeficiency disorder. Repurposable drugs for WAS are not well-established due to the specific genetic nature of the disease; however, some treatments and management strategies may involve:

1. **Immunoglobulin Replacement Therapy:** To help boost the immune system.
2. **Antibiotics:** To prevent or treat infections.
3. **Thrombopoietic Agents:** To increase platelet counts.

Hematopoietic stem cell transplantation (HSCT) remains the most effective treatment for WAS. Research into gene therapy is ongoing and showing promise.

"Nan" is not applicable in this context.
Metabolites: Wiskott-Aldrich Syndrome (WAS) is an X-linked recessive immunodeficiency disorder primarily affecting males, characterized by eczema, thrombocytopenia (low platelet count), and immune deficiency. The syndrome is associated with mutations in the WAS gene, which encodes the Wiskott-Aldrich Syndrome protein (WASP) crucial for cytoskeletal organization in blood cells.

Regarding metabolites, Wiskott-Aldrich Syndrome primarily impacts immune function rather than metabolic pathways. However, since the disorder can lead to chronic infections, there might be secondary impacts on metabolism due to the body's response to infection and inflammation. Elevated or imbalanced levels of inflammatory cytokines may alter metabolic processes indirectly. Specific research on metabolites directly influenced by WAS may not be extensively documented.
Nutraceuticals: Wiskott-Aldrich Syndrome (WAS) is a rare genetic immunodeficiency disorder. Nutritional support for individuals with WAS typically involves managing symptoms and preventing complications through a well-balanced diet. However, there are no specific nutraceuticals proven to treat or significantly alter the course of WAS. Treatment primarily focuses on immunoglobulin replacement therapy, antibiotics for infections, and hematopoietic stem cell transplantation as the only curative option. Always consult healthcare professionals before using any supplements. Regarding "nan," there are no relevant applications of nanotechnology specific to the treatment of WAS documented in current medical literature.
Peptides: Wiskott-Aldrich Syndrome (WAS) is an X-linked recessive immunodeficiency disorder primarily affecting males. It is characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and an increased risk of autoimmune diseases and certain malignancies. WAS is caused by mutations in the WAS gene, which encodes the WAS protein (WASP) essential for normal immune cell function.

Regarding peptides and nanoparticles (nan):

1. **Peptides**: Researchers are investigating the therapeutic potential of synthetic peptides to restore or mimic WASP function. Peptides designed to interact with cellular pathways disrupted in WAS can potentially correct immune cell defects.

2. **Nanoparticles (nan)**: Nanoparticles are being explored for gene therapy and drug delivery systems in WAS. Nanoparticle-based approaches might be used to deliver functional copies of the WAS gene or specific drugs directly to affected cells, aiming to improve immune function and reduce disease symptoms.

These advanced strategies are still under research and clinical trials to evaluate their efficacy and safety.