Coping with WAS
History of WAS
In 1937, Dr. Alfred Wiskott described a family with three brothers who had eczema, hematorrhea and recurrent ear infections since early infancy. Dr. Wiskott noticed that while these three brothers died early due to bleeding and infection, their sisters were healthy. He proposed that this disease is due to a defect in the platelets and called it "hereditary thrombopathia". In 1954, Dr. Robert Aldrich, an American pediatrician studied six generations of a Dutch family affected by the disease and found that while several males had died due to the disease, no female was affected, and proposed that this disease had an X-linked recessive inheritance pattern. By the 1960's these patients were being increasingly recognized and they were referred to as patients with Wiskott-Aldrich Syndrome.
In 1968, the first bone marrow transplant using a matched unrelated donor was performed successfully on a patient with WAS. This disease spurred the earliest interest in bone marrow transplants as a potential cure for immunodeficiency diseases. It is heartwarming to know that one of the distant cousins of the original family described by Dr. Wiskott had a successful bone marrow transplant and is doing well.
In 1994, the gene causing the disease was identified on the X chromosome of these patients by Dr. Uta Francke1. Currently, at least 250 distinct mutations of the gene2 have been identified with a published database3 of 441 patients. Immunologists and transplant physicians have worked together and made great progress in the success of bone marrow transplant as a cure for the disease4 . Much remains to be done and research continues in major centers around the world.
Early diagnosis of WAS can be difficult as infants exhibit a variety of symptoms. Mutational analysis to find the defective gene is laborious and can take several weeks. In 1999,Yamada, M et al 5 discovered a simple and rapid screening tool for the diagnosis of WAS patients and carriers. They performed a flow-cytometric analysis of WASp-Wiskott-Aldrich Syndrome protein in the lymphocytes of patients and carriers. This test is now being used as a screening tool for early diagnosis of WAS followed by a genetic mutation analysis for confirmation and management of the disease.
Gene therapy has recently emerged as a possible alternative to bone marrow transplant. Christoph Klein et al reported their experience with gene therapy in 2007. Preparations are in progress for a Phase I/II trial6 in several centers in Europe in the spring of 2010.
Lessons from the Wiskott-Aldrich Syndrome
The genotype of the original Wiskott Phenotype
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1. Derry JM, Ochs HD, Francke U. Isolation of a Novel Gene mutated in Wiskott-Aldrich Syndrome. Cell 78:635-644,1994 2. Wiskott Aldrich Syndrome: www.ghr.nlm.nih.gov
4. Filipovich AH, Stone JV, Tomany SC, Ireland M, Kollman C, Pelz CJ, Casper JT, Cowan MJ, Edwards JR, Fasth A, Gale RP, Junker A, Kamani NR, Loechelt BJ, Pietryga DW, Ringdén O, Vowels M, Hegland J, Williams AV, Klein JP, Sobocinski KA, Rowlings PA, Horowitz MM. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001 Mar 15;97(6):1598-603.
5. Yamada M, Ohtsu M, Kobayashi I, Kawamura N, Kobayashi K, Ariga T, Sakiyama Y, Nelson DL, Tsuruta S, Anakura M, Ishikawa N. Flow Cytometric Analysis of Wiskott-Aldrich Syndrome (WAS) Protein in Lymphocytes From WAS Patients and Their Familial Carriers. Blood. 1999 Jan 15;93(2):756-76 Genethon, a non-profit organization for bio therapy www.genethon.fr