Wiskott-Aldrich Syndrome

Briana Kittredge

Annette Stewart

Tiffany Yu

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.

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.

Present Day• Defined as:

– X linked hereditary disorder– Eczema– Combined immunodeficiency– Thrombocyopenia with small platelets– increase risk of autoimmune disorders & cancers

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

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

Clinical Disorder

• WAS is classified by a triad of symptoms:1) Microthromobocytopenia

2) Eczema

3) Immunodeficiency

• Classic triad appears only in 1/3 of patients.

Clinical Manifestation1. Hemorrhage

– Result of severe thrombocytopenia with reduced size.– Ranges from non-life threatening to severe malfunction.

2. 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.

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.

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

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.

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.

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.

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

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

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

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)

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

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

Pathophysiology - Other Cell Defects

• Macrophages, monocytes, dendritic cells– Antigen presentation

– Unable to assemble podosomes

– Adhesion and motility

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

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

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

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

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.

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.

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.

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.

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.

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.

David McNally

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.

References

• Bosticardo, M., F. Marangoni, et al. (2009). "Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome." Blood 113(25): 6288-6295.

• Bouma, G., S. O. Burns, et al. (2009). "Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation." Immunobiology 214(9-10): 778-790.

• Charrier, S., L. Dupre, et al. (2007). "Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients." Gene Ther 14(5): 415-428.

• Huppa, J. B. and M. M. Davis (2003). "T-cell-antigen recognition and the immunological synapse." Nat Rev Immunol 3(12): 973-983.

• Kurisu, S. and T. Takenawa (2009). "The WASP and WAVE family proteins." Genome Biol 10(6): 226.

References

• Ochs, H. D. (2009). "Mutations of the Wiskott-Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes." Immunologic Research 44(1-3): 84-88.

• Ochs, H. D., A. H. Filipovich, et al. (2009). "Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment." Biol Blood Marrow Transplant 15(1 Suppl): 84-90.

• Ramesh, N. and R. Geha (2009). "Recent advances in the biology of WASP and WIP." 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

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

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