Title: The Wiskott-Aldrich Syndrome: An X-linked Primary Immunodeficiency
1The Wiskott-Aldrich SyndromeAn X-linked Primary
Immunodeficiency
2WAS
- 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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5Symptoms
- Thrombocytopenia (low platelet count and
disturbed platelet function) - Recurrent infections
- Eczema
- Malignancies in the form of leukemia and lymphoma
occur in more severe cases
6Normal platelets
7Small Platelets
8History
- 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
9Mutations
- 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
10A 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.
11Actin 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.
12Affect 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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14Affect 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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17Treatment
- Intravenous immunoglobulin substitution
- Specialized antibiotics
- Splenectomy
- Hematopoietic stem cell transplantation
18WAS 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.
19Summary
- 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.