Wiskott-Aldrich syndrome

Definitions & Key takeaways

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder that primarily affects males. The condition is caused by mutations in the WAS gene, which encodes for the Wiskott-Aldrich syndrome protein (WASP). The signs and symptoms of Wiskott-Aldrich syndrome can vary widely, but often include recurrent infections due to a weakened immune system, eczema, easy bruising or bleeding due to decreased platelets and abnormal clotting, autoimmune disorders such as rheumatoid arthritis or autoimmune hemolytic anemia, and increased risk of developing certain types of cancer, including lymphoma and leukemia.

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Introduction0:00–0:36

Wiskott-Aldrich syndrome is also called eczema-thrombocytopenia-immunodeficiency syndrome. So, one by one, there’s eczema, also called atopic dermatitis, which is characterized by dry red patches arising on the skin.
There’s a type of thrombocytopenia called microthrombocytopenia because not only are there very few platelets, but the platelets are also small in size.
And there’s a problem with the immune system that leads to repeated infections. All of the hematopoietic cells, which are cells in the bone marrow, produce Wiskott-Aldrich syndrome protein, or WASp for short.

Physiology0:36–3:58

There’s also a gene - called the WIPF1 gene, which encodes a protein called WAS/WASL-interacting protein family member 1, which helps stabilize Wiskott-Aldrich protein.
So WASp, aside from having a really long name that shortens down to the name of a scary flying insect - helps to reorganize the cell’s cytoskeleton, and therefore its overall shape.
The cytoskeleton can change by either adding to or removing actin proteins from the end of an actin chain. The chain grows longer in the direction that a cell wants to move and shortens on the side that a cell wants to move away from.
This helps with various cellular activities like phagocytosis and cellular division. Platelets specifically rely on this functionality, because they originate from large precursor cells called megakaryocytes.
This megakaryocyte has many long arms - like a squid - and the cytoskeleton changes shape so that these arms can detach to form cellular fragments called platelets.
The platelets then go off to form clots at damaged sites in the blood vessels, to stop bleeding. Another cell type are the T-cells, which are a type of immune cell, also rely on the cytoskeleton being able to change shape.
When they encounter a pathogen, T-cells form pseudopods or false legs that reach out and synapse or communicate with other cells.
Think of it like they’re shaking hands to exchange information. Helper T cells get activated when they form an immunological synapse with antigen presenting cells.
And once they’re activated, helper T-cells activate B-cells which generate antibodies which help destroy the pathogen. Next up are the cytotoxic T-cells and natural killer cells, which also reorganize their cytoskeleton to form an immunological synapse with various body cells to do surveillance, and find out if they’re healthy or if they’re infected or cancerous.
If an unhealthy cell is discovered, the immune cells make that unhealthy cell undergo apoptosis, or programmed cell death.
Together, the T-cells, B-cells, and natural killer cells protect the body from pathogens as well as cancer. There are also T-cells called regulatory T cells or T-regs, which downregulate the other T cells to limit the immune response and prevent autoimmune conditions from arising.
T-regs also rely on reorganizing their cytoskeleton to function normally. Finally, there are the phagocytic cells like monocytes, macrophages, and dendritic cells, which form small foot processes to make their way towards cytokines.
These phagocytic cells are like little bloodhounds and following a cytokine trail. These cells also perform phagocytosis, to swallow up debris, dead cells, and bacteria, so that it can be processed and destroyed.

Pathology3:58–6:00

In Wiskott-Aldrich syndrome, a mutation in the gene results in a Wiskott-Aldrich protein that can’t function normally. It’s an X-linked recessive disease, and as a result, males are affected more often than females.
Sometimes, however, the disease isn’t inherited and instead arises from a spontaneous DNA mutation in the Wiskott-Aldrich syndrome gene.
A small mutation in the gene might result in a mild disease, called X-linked thrombocytopenia, whereas a large mutation can result in a shortened protein, or no protein at all, and that causes Wiskott-Aldrich syndrome.
There’s also a condition called Wiskott-Aldrich syndrome type 2 which is caused by a mutation in the WIPF1 gene, which is very similar to Wiskott-Aldrich syndrome.
Since the Wiskott-Aldrich protein affects the cytoskeleton of hematopoietic cells, many cells are affected when a mutation occurs.
Megakaryocytes are less able to form platelets, and the platelets that are made are small and fragile - so it’s called microthrombocytopenia.
As a result, individuals can’t form normal clots and can have excessive bleeding. Helper T-cells and B-cells aren’t able to form an immunological synapse, resulting in an impaired immune response.
For unclear reasons, this leads to an increase in IgA and IgE antibodies, and normal or decreased levels of IgM and IgG antibodies.
T-cells and natural killer cells are also unable to form normal immunological synapses, which impairs their ability to defend against pathogens and cancers.
Regulatory T-cells are also prevented from doing their job, making autoimmune diseases more likely. Lastly, phagocytic cells like macrophages struggle to move around, making it harder for them to clean up debris.

Signs and symptoms6:00–6:45

The classic triad of symptoms in Wiskott-Aldrich syndrome includes easy bruising and bleeding, eczema, and recurrent infections.
The infections are classically due to encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis, fungi, such as Pneumocystis jirovecii and Candida albicans, and viruses, such as Molluscum contagiosum, Varicella zoster virus, and cytomegalovirus.
Individuals are also more prone to developing autoimmune conditions, such as idiopathic thrombocytopenic purpura, and cancers, like leukemia and lymphoma.

Diagnosis6:45–7:17

The diagnosis is usually suspected based on the triad of symptoms. The initial workup includes a peripheral smear which would show thrombocytopenia with small platelets.
Flow-cytometry can be used to determine whether a mutated Wiskott-Aldrich syndrome protein is being produced, though it might not identify a severely mutated protein.
The diagnosis is then confirmed by genetic sequence analysis of the Wiskott-Aldrich gene. Treatment is mainly aimed at the symptoms - and includes prophylactic antibiotics, regular intravenous immune globulin infusions, platelet transfusions in the case of severe bleeding, and potentially surgery to remove the spleen, which can help to maintain platelet counts within the blood.

Treatment7:17–7:50

Immunosuppressive treatment is sometimes needed to treat autoimmune conditions. Hematopoietic stem cell transplantation is a potentially curative treatment that is sometimes used.
All right, as a quick recap… Wiskott-Aldrich syndrome is a disease of the immune system that’s genetically inherited in an X-linked recessive manner, so it mostly affects males.

Review7:50–8:30

The classic triad of findings include microthrombocytopenia, repeated infections, and eczema. It’s caused by a mutation of Wiskott-Aldrich syndrome protein, which is produced by all of the hematopoietic cells.
Treatment is focused on controlling the symptoms and hematopoietic stem cell transplantation is currently the only potentially curative treatment.