The Wiskott-Aldrich The Wiskott-Aldrich Syndrome:Syndrome:

An X-linked Primary An X-linked Primary ImmunodeficiencyImmunodeficiency

Kristin GoffKristin Goff

WASWAS

Primary immune deficiency disorderPrimary immune deficiency disorder Entails part of the bodies immune system is Entails part of the bodies immune system is

missing or does not function properlymissing or does not function properly Caused by genetic defects in the immune Caused by genetic defects in the immune

systemsystem X-linked recessive traitX-linked recessive trait

Genetic defect causing deficiency is on the X-Genetic defect causing deficiency is on the X-chromosomechromosome

Only affects males and is passed to child from Only affects males and is passed to child from the mother, a healthy carrier of the disorderthe mother, a healthy carrier of the disorder

SymptomsSymptoms

Thrombocytopenia Thrombocytopenia (low platelet count (low platelet count and disturbed platelet and disturbed platelet function)function)

Recurrent infectionsRecurrent infections EczemaEczema Malignancies in the Malignancies in the

form of leukemia and form of leukemia and lymphoma occur in lymphoma occur in more severe casesmore severe cases

Normal platelets

Small Platelets

HistoryHistory

First described by German physician First described by German physician Alfred Wiskott in 1937 Alfred Wiskott in 1937

Robert Anderson Aldrich described Robert Anderson Aldrich described the disease as an X-linked recessive the disease as an X-linked recessive trait in 1954trait in 1954

Joined the list of Primary Immune Joined the list of Primary Immune Deficiency Diseases in the 1960’sDeficiency Diseases in the 1960’s

MutationsMutations

WAS is associated with the absence WAS is associated with the absence of the Wiskott-Aldrich Syndrome of the Wiskott-Aldrich Syndrome protein (WASP) which is caused by protein (WASP) which is caused by simple mutations in the WASP genesimple mutations in the WASP gene

Missense and frameshift mutations Missense and frameshift mutations are two known to cause WASare two known to cause WAS

A frameshift mutation deletes a DNA base, shifting the entire sequence and changing the amino acids from that point on. In this case, the Mutation turns an amino acid in the protein sequence into a stop codon and translation of the protein is prematurely ended.

A missense mutation has the ability to change one amino acid into a different amino acid, altering the protein and possibly causing it to be nonfunctional.

Actin ReorganizationActin Reorganization WASP is involved in the WASP is involved in the

reorganization of the actin skeleton. reorganization of the actin skeleton. When the WAS protein is altered, it When the WAS protein is altered, it does not properly bind and actin does not properly bind and actin reorganization is prohibited.reorganization is prohibited.

Affect on T LymphocytesAffect on T Lymphocytes

Cytoskeleton reorganization is Cytoskeleton reorganization is involved in the binding of T involved in the binding of T lymphocytes to antigen-presenting lymphocytes to antigen-presenting cells through CD3 crosslinking. cells through CD3 crosslinking.

Without actin reorganization, CD3 is Without actin reorganization, CD3 is not properly presented at the cells not properly presented at the cells surface and the T cell is not activated.surface and the T cell is not activated.

Causes recurrent viral and fungal Causes recurrent viral and fungal infections (as noted in symptoms).infections (as noted in symptoms).

Affect on B LymphocytesAffect on B Lymphocytes

Thymus dependent B lymphocytes need Thymus dependent B lymphocytes need T cells for activation and differentiation. T cells for activation and differentiation.

B cells only able to produce IgM through B cells only able to produce IgM through thymus independent B lymphocytes.thymus independent B lymphocytes.

Causes recurrent bacterial infections Causes recurrent bacterial infections because proper antibodies are not because proper antibodies are not produced against certain bacteria.produced against certain bacteria.

TreatmentTreatment

Intravenous immunoglobulin Intravenous immunoglobulin substitutionsubstitution

Specialized antibioticsSpecialized antibiotics SplenectomySplenectomy Hematopoietic stem cell Hematopoietic stem cell

transplantationtransplantation

WAS Discovered in FemalesWAS Discovered in Females

Skewed X-chromosome inactivation in a Skewed X-chromosome inactivation in a female carrier can cause the typically female carrier can cause the typically healthy female to exhibit clinical signs healthy female to exhibit clinical signs of the disorder.of the disorder.

Causes the X-chromosome carrying the Causes the X-chromosome carrying the normal WASP gene to become normal WASP gene to become inactivated so only the X-chromosome inactivated so only the X-chromosome with the mutant WASP gene is left with the mutant WASP gene is left active.active.

SummarySummary

WAS is caused by a mutation in the WASP WAS is caused by a mutation in the WASP gene.gene.

A mutation in the WASP gene inhibits actin A mutation in the WASP gene inhibits actin reorganization.reorganization.

Without actin reorganization, CD3 cannot Without actin reorganization, CD3 cannot be presented and T cells are not activated.be presented and T cells are not activated.

Thymus dependent B cells are not Thymus dependent B cells are not activated without production of T cells.activated without production of T cells.

B cell differentiation does not occur and B cell differentiation does not occur and only IgM antibodies are produced.only IgM antibodies are produced.