The Wiskott-Aldrich Syndrome: An X-linked Primary Immunodeficiency

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The Wiskott-Aldrich SyndromeAn X-linked Primary
Immunodeficiency

• Kristin Goff

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WAS

• Primary immune deficiency disorder
• Entails part of the bodies immune system is
  missing or does not function properly
• Caused by genetic defects in the immune system
• X-linked recessive trait
• Genetic defect causing deficiency is on the
  X-chromosome
• Only affects males and is passed to child from
  the mother, a healthy carrier of the disorder

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Symptoms

• Thrombocytopenia (low platelet count and
  disturbed platelet function)
• Recurrent infections
• Eczema
• Malignancies in the form of leukemia and lymphoma
  occur in more severe cases

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Normal platelets
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Small Platelets
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History

• First described by German physician Alfred
  Wiskott in 1937
• Robert Anderson Aldrich described the disease as
  an X-linked recessive trait in 1954
• Joined the list of Primary Immune Deficiency
  Diseases in the 1960s

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Mutations

• WAS is associated with the absence of the
  Wiskott-Aldrich Syndrome protein (WASP) which is
  caused by simple mutations in the WASP gene
• Missense and frameshift mutations are two known
  to cause WAS

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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.
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.
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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.

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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).

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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.

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Treatment

• Intravenous immunoglobulin substitution
• Specialized antibiotics
• Splenectomy
• Hematopoietic stem cell transplantation

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WAS Discovered in Females

• Skewed X-chromosome inactivation in a female
  carrier can cause the typically healthy female to
  exhibit clinical signs of the disorder.
• Causes the X-chromosome carrying the normal WASP
  gene to become inactivated so only the
  X-chromosome with the mutant WASP gene is left
  active.

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Summary

• WAS is caused by a mutation in the WASP gene.
• A mutation in the WASP gene inhibits actin
  reorganization.
• Without actin reorganization, CD3 cannot be
  presented and T cells are not activated.
• Thymus dependent B cells are not activated
  without production of T cells.
• B cell differentiation does not occur and only
  IgM antibodies are produced.