Wiskott Aldrich Syndrome Final Powerpoint
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My son had Wiskott Aldrich Syndrome (WAS). He had a bone marrow transplant in August 2006. His WAS is healed. This presentation was designed by some grad students. Some of the content is from my ...

My son had Wiskott Aldrich Syndrome (WAS). He had a bone marrow transplant in August 2006. His WAS is healed. This presentation was designed by some grad students. Some of the content is from my blog and it pictures my son, David. http://www.davidmcnally.blogspot.com

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  • Wiscott-Aldrich was first described by Alfred Wiskott in 1937. He Diagnosed three brothers who presented with thrombocytopenia, bloody diarrhea, eczema, and recurrent ear infection. These three brothers also died at an early age from intestinal bleeding and sepsis, associated with hemorrhagic disease and platelet dysfunction. Wiskott suggested hereditary thrombocytopenia, after describing three brothers who had the disease while their four sisters were not affected.
  • In 1957, Aldrich further described the disease as an X-linked inherited disorder. In a study of six generations, he found that 16 of the 40 males died of the disease but NONE of the females
  • Although rare, can occur in females. Happens only when one of the X-chromosome is inactive and the other carries the mutation.
  • The whole cell line is affected. This includes your neutrophils, monocytes, baso- and eosinophil, lymphocytes, and platelets.
  • High susceptibility to developing tumors and autoimmune manifestations. Immunodeficiency in newborns and toddlers are frequent. Recurrent bacterial infections such as ear infections are the most common.
  • Hemorrhage – petechiae/purpura/oral bleeding (Mild bleeding under skin) to intestinal/intercranial bleeding Eczema – Abnormal priming of antigen specific T-cells in the skin, caused by defective chemotaxis of dendritic cells. Dendritic cells in skin (Langherhans) are APC, processing antigenic material and presenting to lymphocytes.
  • Autoimmune disease associated with higher risk of developing tumors and increase risk of death. Usually have multiple autoimmune disorders simultaneously and can have a prognostic value. -i.e. AHA/autoimmune thrombocytopenia develops early (<5% survive 2 years after diagnosis, results in up to 25% of deaths. Immune deficiency plays a role in tumor synthesis. NK cell function is defective as well as other alternations in immune serveillance.
  • Early signs are directly related to the clinical triad. A study following 154 patients showed petechia/purpura in 78% of patience. Intercranial bleeding at birth or trauma.
  • Infant begins to have infection involving all classes of microorganisms. Viral infections are unusually severe. Most common: Ear infection and pneumonia More severe but less common: Sepsis and meningitis. Gram neg – Klebsiella pneumonia and E. coli cause sepsis and meningitis. Intense scratching can also lead to infection.
  • Due to wide spectrum of findings, it’s suspected in any boy presenting Unusual bleeding/bruising Thrombocytopenia Small platelets Characteristic WAS platelets can be seen in cord blood. This is the most useful for diagnosis >2 yr old immunologic abnormalities: Antibodies characterisiclly low or absent. Low level to blood group antigens (type A or B antigens) Vaccination: strep pneumonae
  • This mutation results in a wide range of phenotypes. The unique family mutation means that each family has a characteristic mutation of the WASP gene. The role of WASP is complex and is evident in the wide range of disorders that stem from a mutation in the gene. Clinical symptoms vary from mild X-linked thrombocytopenia to the classic Wiskott-aldrich syndrome. This is only different clinical forms of the same disease because the underlying cause is still a mutation in the same gene. X-linked thrombocytopenia (XLT) is considered an attenuated version of WAS. Both it and intermitten thrombocytopenia are milder forms of the disease.

Wiskott Aldrich Syndrome Final Powerpoint Presentation Transcript

  • 1. Wiskott-Aldrich Syndrome Briana Kittredge Annette Stewart Tiffany Yu
  • 2. History
    • First described in 1937 by Alfred Wiskott.
    • Diagnosed 3 brothers who presented with:
      • Thrombocytopenia
      • Bloody diarrhea
      • Eczema
      • Recurrent ear infections
    • Died at an early age from intestinal bleeding and sepsis.
      • Associated with hemorrhagic disease and platelet dysfunction.
    • Proposed hereditary thrombocytopenia.
  • 3. History
    • Further described by Aldrich in 1957
    • Demonstrated X-linked inheritance:
      • Observed six generations.
      • 16 of 40 males, but no females, died of the disease.
    • 1950’s & 1960’s Classified as a primary immunodeficiency disease involving T lymphs, B lymphs, and platelets.
  • 4. Present Day
    • Defined as:
      • X linked hereditary disorder
      • Eczema
      • Combined immunodeficiency
      • Thrombocyopenia with small platelets
      • increase risk of autoimmune disorders & cancers
  • 5. Statistics
    • Life expectancy of 15 years in a patient lacking WAS protein expression.
    • Affects 1 in 10 of every 1 million male newborns
        • can occur in females only when X-chromosome containing the functional allele is inactive
    • 90 % manifest thrombocytopenia at presentation
    • 20% only have hematopoietic abnormalities
    • 5% only have infectious manifestations
    • 0% only have eczema
  • 6. 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
  • 7.  
  • 8. Clinical Disorder
    • WAS is classified by a triad of symptoms:
      • Microthromobocytopenia
      • Eczema
      • Immunodeficiency
    • Classic triad appears only in 1/3 of patients.
  • 9. Clinical Manifestation
    • Hemorrhage
      • Result of severe thrombocytopenia with reduced size.
      • Ranges from non-life threatening to severe malfunction.
    • Eczema
      • Resistant to therapy and persist into adulthood.
      • Facilitates opportunistic skin infections.
      • Occurs less often in residual WASP expression.
      • Unknown cause, however elevated IgE with allergetic development suggest atopic origin.
  • 10. Clinical Manifestation
    • 3. Autoimmune manifestations & Tumors:
      • Most common
        • Autoimmune hemolytic anemia
        • Cutaneous vasculitis
        • Arthritis
        • Nephropathy
      • Less Common
        • Inflammatory bowl syndrome
        • Idiopathic thrombocytopenic purpura
        • Neutropenia
      • Mainly lymphoreticular malignancies with leukemia, myelodysplastic, and lymphoma.
  • 11. Clinical Manifestation
    • During first year bleeding, eczema, and recurrent infections are seen.
      • Petechia and purpura common.
      • Brusing of skin and oral mucosa.
    • Prolonged bleeding
      • Umbilical stump or following circumcision
      • Bloody diarrhea. Can progress to serious GI bleed
      • Intracranial bleeding
  • 12. Clinical Manifestation
    • Four to eight months: Loss of maternal IgG
      • Increase frequency of infection
        • Otitis Media
        • Pneumonia – upper and lower respiratory
        • Meningitis
        • Sepsis
    • Involves all classes of microorganisms.
      • Viral infections are unusually severe. Chicken pox can be life threatening.
      • Fungal infections are restricted to thrush.
  • 13. Diagnosis of WAS
    • 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.
      • Significantly smaller
      • Low count
    • 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.
  • 14. Underlying Defect
    • Mutation of WASP gene on the short arm of the X-chromosome produces Wiskott-Aldrich protein.
      • Mutations are “unique to family”
    • Severity of disease depends on mutation
      • Mutation of WASP gene produces a broad range of phenotypes
      • Different clinical forms of the same disease.
        • Classic WAS
        • XLT
        • Intermittent thrombocytopenia & neutropenia.
  • 15. Biochemistry - Wiskott-Aldrich Syndrome Protein (WASP)
    • Expressed exclusively in the cytoplasm of hematopoietic cells
    • Transducts signals from the cell membrane to the actin cytoskeleton
    • 502 aa long
    • 12 exons
  • 16. Biochemistry - Proposed interactions for WASP From G. Bouma et al. / Immunobiology 214 (2009) 778–790
    • EVH1 - stabilization
      • Common site of mutation
    • GBD – autoinhibition
      • Phosphorylation of Tyr291 and/or binding of Cdc42-GTP/Toca complex leads to activation
      • Cdc42 also important in filipodia formation, chemotaxis and cell polarity
    • VCA region binds actin monomers and activates polymerization
    • Proline rich region required for optimal actin polymerization
      • Required for immunologic synapse formation in Tcells
  • 17. Pathophysiology - Thrombocytopenia
    • Most common symptom and occurs irrespective of the mutation severity in WASP
    • Platelets are also often small in size
    • main cause still largely unknown
      • membrane/structural defects cause the spleen to overdo it in disposing of platelets
      • Antiplatelet antibodies
      • Megakaryocytes and platelets don’t migrate properly
    • Leads to bleeding problems
      • Petechiae, purpura, epistaxis, oral bleeding
      • Internal and intracranial bleeding in severe situations
      • Hemorrhage is the cause of death in WAS patients 21% of the time
  • 18. Pathophysiology - Tcell Defects
    • Immune Synapse
      • WASP is recruited to IS after TCR stimulation via WIP and Nck and activated by GTP-Cdc42
      • IS Stability and lipid raft dynamics are compromised in the absence of WASP
        • In cells lacking WASP the IS can only form via strong TCR stimulation
        • Leads to problems in signaling: cells with an impaired IS fail to proliferate or respond to Th1 cytokines
    From Nature Reviews Immunology 3, 973-983 (December 2003)
  • 19. Pathophysiology - Tcell Defects Cont.
    • Chemotaxis
    • Survival is decreased
    • Generation and function of T regulatory cells also show problems in WAS
      • Mediated via TCR
      • Tregs maintain immune homeostasis and suppress immune responses
        • Allergies, autoimmunity
  • 20. Pathophysiology - Bcell Defects
    • Largely unexplored until recent years since unlike Tcells, Bcells can still function normally in WASP patients
    • Do show problems with migration, adhesion, and protrusion
    • WASP patients often have abnormal immunoglobulin profiles
      • Elevated IgA and IgE – increased allergies
      • Normal IgG and IgM
    • Severe WASP cases show an inability to form antibodies against Tcell independent antigens like polysaccharides
      • do not form blood group antibodies
  • 21. Pathophysiology - Other Cell Defects
    • Macrophages, monocytes, dendritic cells
      • Antigen presentation
      • Unable to assemble podosomes
      • Adhesion and motility
  • 22. Exogenous Factors
    • Inheritance
      • Women are silent carriers
      • Some men are living long enough to have children
    • Spontaneous mutation
      • Carcinogens, mutagens, teratogens
      • Any source of DNA damage
  • 23. Exogenous Factors Cont.
    • Infections
      • Pneumocystis jiroveci
      • HSV, EBV
        • Leukemias and lymphomas
      • Chronic situations can lead to autoimmune problems
    • Splenectomy
    • Activities and drugs that cause bleeding
  • 24. Treatment
    • Only cure is hematopoeitic stem cell transplant
      • Matched sibling most successful
      • Unrelated donor much more risky
      • Greatest success when done <5yrs of age
    • Lentiviral gene therapy is in stage 1 and 2 clinical trials in Europe
  • 25. Treatment Cont.
    • Other therapy treats the symptoms
      • Prophylactic antibiotics
      • Platelet transfusions
        • Must be irradiated and CMV free
      • Splenectomy
        • Reverses the thrombocytopenia
        • Risk of septicemia
      • Intravenous immunoglobin for patients with antibody deficiency
  • 26. Morbidity and Mortality
    • Mortality reports are limited to information provided by hospitals and physicians, which may or may not include specific genetic defects and risk factors for that disease in the report.
    • The mortality and morbidity of a disease reports the rates of survival and the prevalence of the disease in a population.
    • These reports are extremely important in planning interventions, determining causes and evaluating treatments.
  • 27. Morbidity: The Prevalence
    • The estimated incidence of Wiskott-Aldrich syndrome in the United States is 1 in 250,000 live male births.
    • Several European countries had similar statistics with the prevalence of WAS in 2-8.8% of patients with PID.
    • Early diagnosis and treatments reduce morbidity and mortality.
  • 28. Mortality: Rates of Survival
    • Infection is the leading cause of death in WAS patients.
    • WASP expression is a useful tool for predicting long-term prognosis. Patients with a positive or negative expression react differently to treatments and have different risks involved. (i.e. negative WASP expression is at higher risk to bacterial, viral, and fungal infections.
    • Most WAS patients die of bleeding, infection, and malignancies. Lymphomas occur in 26% of patients aged 20 years and older, but can also occur in children.
    • The average lifespan for those who don’t have any immune response to treatment is life into their teens and twenties, but some are known to live into their forties.
    • There are discrepancies with the studies that I found. Two studies said that WASP negative patients are at higher risk of ICH, where one other said that it was at reduced risk.
  • 29. Bone Marrow Transplant (BMT):
    • WAS patients are good candidates for BMT because of the nature of the disease. However, BMT’s are risky and the results would be immediate if the patient were to reject the transplant.Since parents are making decisions about the life of their child, these decisions are very carefully considered.
    • Since BMT’s are very successful, experts suggest that it be considered for treatment for WAS patients. Also, with the younger patient, prognosis could be improved if the transplant was not delayed.
  • 30. Graft Versus Host Disease (GVHD):
    • This is a very serious side effect following a transplant of any kind. This is when the body starts to reject to the transplanted tissue. Some GVHD is good, showing that the immune system is working, but too much and ones body goes into full rejection. Patients that manage to avoid this side effect “usually have completely normal immune function,” and a positive prognosis.
  • 31. Splenectomy:
    • A splenectomy, like a BMT, is another successful treatment for WAS.
    • Successful splenectomies are related to the use prophylactic antibiotics.
    • In one study of 16 patients: 5 of the 7 patients that were not taking prophylatic antibiotics died. Of the 9 patients that took the antibiotics, all lived an average of 91.4 months after splenectomy. 6 of those 9 patients were still alive after 11 years.
    • Another study of 10 patients: 5 were WASP positive and 5 were WASP negative. Of the WASP positive patients: none had intracranial hemorrhage after surgery, 2/5 acquired and survived sepsis or meningitis. Of the WASP negative patients: 2/5 died of intracranial hemorrhage, the other 3 all acquired and survived sepsis and/or meningitis.
  • 32. David McNally
  • 33. Emotional Stresses:
    • Chronic underlying medical needs.
    • The unpredictable nature of the disease (i.e. infection, bleeds, malignancies, autoimmunity, and various emergencies).
    • The lack of consensus in the medical community on treatment.
    • Decision making regarding treatments (BMT’s, splenectomy, steroids, etc.).
    • They struggle with the potentiality that their child's symptoms may increase or worsen with age.
    • Dealing with a disease that is not well understood with the medical community, family members, friends and strangers.
    • Medications, doctor’s visits, insurance, copays and other financial issues.
  • 34. References
    • Bosticardo, M., F. Marangoni, et al. (2009). &quot;Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome.&quot; Blood 113 (25): 6288-6295.
    • Bouma, G., S. O. Burns, et al. (2009). &quot;Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation.&quot; Immunobiology 214 (9-10): 778-790.
    • Charrier, S., L. Dupre, et al. (2007). &quot;Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients.&quot; Gene Ther 14 (5): 415-428.
    • Huppa, J. B. and M. M. Davis (2003). &quot;T-cell-antigen recognition and the immunological synapse.&quot; Nat Rev Immunol 3 (12): 973-983.
    • Kurisu, S. and T. Takenawa (2009). &quot;The WASP and WAVE family proteins.&quot; Genome Biol 10 (6): 226.
  • 35. References
    • Ochs, H. D. (2009). &quot;Mutations of the Wiskott-Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes.&quot; Immunologic Research 44 (1-3): 84-88.
    • Ochs, H. D., A. H. Filipovich, et al. (2009). &quot;Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment.&quot; Biol Blood Marrow Transplant 15 (1 Suppl): 84-90.
    • Ramesh, N. and R. Geha (2009). &quot;Recent advances in the biology of WASP and WIP.&quot; Immunol Res 44 (1-3): 99-111.
    • Lum, L.G., Tbergen, D. G., Corash, L., Blaese, R. M. (1980, April 17). Splenectomy in the management of the thrombocytopenia of the Wiskott-Aldrich syndrome. New England Journal of Medicine , 302 (16), 892-896. Retrieved from http://content.nejm.org/cgi/content/abstract/302/16/892
  • 36. References
    • Aimee McNally. (2009, November 10). David McNally. Retrieved December 3, 2009: http:// davidmcnally.blogspot.com 1198 Vision and Learning.
    • Coping with WAS: Effects on the Family. (2009). Retrieved: December 3, 2009 from the Wiskott-Aldrich Syndrome support site: http:// sites.google.com/site/athreyi /
    • Chaudhry, B., & Harvey, D. (2001). Mosby’s Color Atlas and Text of Pediatrics and Child Health. London: Harcourt Publishers Limited.
    • Applying Public Health Strategies to Primary Immunodeficiency Diseases. (2004, January, 6). Retrieved December 3, 2009: From the CDC website: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5301a1.htm
    • Siperstein, R., Schwartz, R. A. (2009, February, 3). Wiskott-Aldrich Syndrome. Retrieved from the emedicine website: http://emedicine.medscape.com/article/888939-overview
    • Lee, T.L., Chan, G.C.F, Ha, S.Y., Lau, Y. L.(1999). A Single Center Experience of Primary Immunodeficiencies in Hong Kong. Hong Long Journal of Paediatrics, 4 (1), 16-20. Retrieved from http:// hkjpaed.org/details.asp?id =264&show=1234
  • 37. Refrences
    • Websites retrieved on December 5, 2009:
      • http:// davidmcnally.blogspot.com
      • http://en.wikipedia.org/wiki/Wiskott-Aldrich_syndrome
      • http://en.wikipedia.org/wiki/Wiskott-Aldrich_syndrome_protein
      • http:// ghr.nlm.nih.gov /condition= wiskottaldrichsyndrome
      • http://emedicine.medscape.com/article/888939-overview
      • http://www.primaryimmune.org/publications/book_pats/e_ch07.pdf
      • http://www.thaiclinic.com/boardimg/nihan-wiskott.jpg
      • http://www.thaiclinic.com/boardimg/nihan-aldrich.jpg