Epidemiology and Disease Mechanism
Wiskott-Aldrich Syndrome occurs almost exclusively in boys with an incidence of 4 in 1 million live male births in the U.S. with a few girls being affected. There are approximately 500 WAS patients in the U.S. The disease has a similar incidence in countries around the world. Although the reporting data are probably incomplete, the incidence has remained stable over the last several decades.
Wiskott-Aldrich Syndrome (WAS) is caused by a defect in the WAS gene on the short arm of the X chromosome. This gene enables the cells to produce Wiskott-Aldrich Syndrome Protein (WASp). This protein is only present in white blood cells, platelets in the blood and their parent cells in the bone marrow. The exact function of WASp has not yet been fully understood. The WAS protein regulates and helps organize the scaffolding (cytoskeleton) of the cell which is made up of filaments of the protein called actin. The actin cytoskeleton regulates many functions within the cell such as growth, cell movement, signaling within the cell etc. The mutation of the gene in WAS patients causes the cells to have little or no WASp. In the absence of this protein the T and the B lymphocytes which are the two major kinds of white blood cells cannot grow and divide properly, nor can they respond effectively to outside invaders such as bacteria, fungi or viruses. This makes the patient prone to infections, especially in the ears and sinuses.
In the absence of WASp the T lymphocytes do not function effectively and are unable to weed out cancer causing cells resulting in a higher incidence of leukemia and lymphoma in these patients. Often the white cells turn against the patients own body, destroying its own cells and organs causing autoimmune disorders such as hemolytic anemia where red cells are destroyed, idiopathic thrombocytopenia where the patients body destroys its own platelets, nephropathy, where the kidneys are affected, arthritis etc.
The platelets in these patients have no WASp and are smaller than normal. They function less effectively and have a shorter life span because they break down more rapidly. These patients can bleed with minor injuries or spontaneously. They have increased bruising, bloody diarrhea, frequent bloody noses and can have serious bleeding in the brain.
The amount and quality of WASp present in the white blood cell determines the severity of the disease. If the protein is completely absent or truncated into pieces (WASp negative), it results in a more severe form of WAS. When a lesser amount or defective protein is present (WASp positive) it causes a milder form of the disease. Different defects in the WAS gene cause different diseases, such as Classic WAS, XLT, intermittent thrombocytopenia and XLN, all of which are classified together as WAS Related Disorders. Considerable overlap has been observed between patients with XLT and Classic WAS, where the same gene defect causes XLT in some patients and Classic WAS in others. The differing manifestations of these disorders underscores the complex nature of the WASP Gene and the difficulties in determining the exact function of WASp.
Genotype and Phenotype
Genotype is the location and exact nature of the mutation (defect) of the gene on the X-chromosome in the patient. Phenotype is the various ways in which the disease manifests itself in the patient. In most cases there is a good correlation between the genotype and the phenotype i.e. the type of defective gene the patient has correlates with the symptoms they show. The genotype of patients with Classic WAS causes the patients blood cells to be WASp negative and this results in a severe phenotype that is, the patient will have severe manifestations of the disease. The genotype of XLT patients causes the cells to be WASp positive resulting in milder disease. This has been observed in large studies1 that have listed the mutations and the disease patterns and their relationship studied. The relationship is not always perfectly true and there are exceptions to this. Doctors determine the genotype of each patient and try to predict the severity of the disease in order to decide the best possible treatment option for each child.
1. Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, Gandellini F, Stewart DM, Zhu Q, Nelson DL, Notarangelo LD, Ochs HD. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004 Dec 15;104(13):4010-9.