Wiskott-Aldrich Syndrome YASHWANT KUMAR DILLI BABU GROUP-8 3rd YEAR.
Introduction and epidemiology Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disease Presents with three main symptoms (immunodeficiency, thrombocytopenia and eczema) Caused by a mutation in the WAS protein (WASp) gene on short arm of x-chromosome. Frequency of 4 cases per million males worldwide and no geographical factor. Causes defects in both cellular and humoral immunity
HISTORY: First discovered by Dr. Alfred Wiskott in 1937 Dr. Robert Aldrich demonstrated the X- linked inheritance pattern in 1954 The WAS gene was discovered in 1994 Before 1937, life expectancy was only 8 months, but today the median life expectancy is 20 years, with a range of 1-35 years (Ochs, 2011)
Target Organ• WASP is a key regulator in hematopoietic cells. – All cells in the hematopoietic cell line are affected. – Primarily lymphocytes and platelets.• T cell defect in the activation and TCR engagement.• The spleen is a secondary target since it acts to remove the defective blood cells
Actin Reorganization• WASP is involved in the reorganization of the actin skeleton. When the WAS protein is altered, it does not properly bind and actin reorganization is prohibited.
Affect on T Lymphocytes• Cytoskeleton reorganization is involved in the binding of T lymphocytes to antigen- presenting cells through CD3 crosslinking.• Without actin reorganization, CD3 is not properly presented at the cells surface and the T cell is not activated.• Causes recurrent viral and fungal infections (as noted in symptoms).
Affect on B Lymphocytes• Thymus dependent B lymphocytes need T cells for activation and differentiation.• B cells only able to produce IgM through thymus independent B lymphocytes.• Causes recurrent bacterial infections because proper antibodies are not produced against certain bacteria.
Symptoms• Thrombocytopenia (low platelet count and disturbed platelet function)-causes bleeding.• Recurrent infections• Even brusing and petechia• Eczema• Malignancies in the form of leukemia and lymphoma occur in more severe cases
DIAGNOSIS• Genetic screening for mutation in the WASp gene after identification by symptoms• Immunologic abnormalities can be identified in children >2 years. – Used to support diagnosis. – Fail to produce anybodies to some vaccinations. – Skin Test to asses T cell function.• WAS is suspected in any boy with unusual bleeding or bruising with congenital or early onset thrombocytopenia.• Cord blood can be taken to observe platelets and the most useful diagnostically.• Prenatal diagnosis.
Treatment• Only cure is hematopoietic stem cell transplant – Matched sibling most successful – Unrelated donor much more risky – Greatest success when done <5yrs of age• Lentiviral gene therapy.• Bone marrow transplant.
Treatment for symptoms– Prophylactic antibiotics– Platelet transfusions(treat bleeding)– Splenectomy(no longer used) • Reverses the thrombocytopenia • Risk of septicemia– Intravenous immunoglobin for patients with antibody deficiency– MORTALITY:100%(SINCE MOST PATIENT DIE )