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Wiskott–Aldrich syndrome

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Wiskott–Aldrich syndrome
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Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). [1]It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954.[2] The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.

Signs and symptoms

The disease occurs only in males. The first signs of WAS are usually petechiae and bruising, resulting from a low platelet count. Spontaneous nose bleeds and bloody diarrhea are common. Eczema develops within the first month of life. Recurrent bacterial infections develop by three months. Enlargement of the spleen is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients.[3]Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated.[4]

Pathophysiology

In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.[citation needed] The immune deficiency is caused by decreased antibody production, and the inability of T cells to become polarized[5] (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T cells are unable to reorganize their actin cytoskeleton.

Genetics

Wiskott–Aldrich syndrome was linked in 1994[6] to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein gene (WASp). The disease X-linked thrombocytopenia was later discovered to be also due to WASp mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene.[citation needed]

The WASp gene codes for the protein WASp, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex. In T-cells, WASp is important because it is known to be activated via T-cell receptor signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse.[citation needed]

The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp.[7] Although autoimmune disease and malignancy may occur in both types of mutations, those patients with truncated WASp carry a higher risk. A defect in the CD43 molecule has been found in patients with Wiskott–Aldrich syndrome.[8]

Diagnosis

The diagnosis is made on the basis of clinical parameters, the peripheral blood smear, and low immunoglobulin levels. Typically, IgM levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed.[9] Skin immunologic testing (allergy testing) may reveal hyposensitivity. Not all patients have a positive family history of the disorder; new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of Wiskott-Aldrich syndrome protein and/or confirmation of a causative mutation provides the most definitive diagnosis.[citation needed]

Sequence analysis can detect the WAS-related disorders of Wiskott–Aldrich syndrome, XLT, and XLN. Sequence analysis of the WASp gene can detect about 98% of mutations in males and 97% of mutations in female carriers. Because XLT and XLN symptoms may be less severe than full WAS and because female carriers are usually asymptomatic, clinical diagnosis can be elusive. In these cases, genetic testing can be instrumental in diagnosis of WAS-related disorders.[citation needed]

Classification

Jin et al. (2004) employ a numerical grading of severity:[7]

  • 0.5: intermittent thrombocytopenia
  • 1.0: thrombocytopenia and small platelets (microthrombocytopenia)
  • 2.0: microthrombocytopenia plus normally responsive eczema or occasional upper respiratory tract infections
  • 2.5: microthrombocytopenia plus therapy-responsive but severe eczema or airway infections requiring antibiotics
  • 3.0: microthrombocytopenia plus both eczema and airway infections requiring antibiotics
  • 4.0: microthrombocytopenia plus eczema continuously requiring therapy and/or severe or life-threatening infections
  • 5.0: microthrombocytopenia plus autoimmune disease or malignancy

Treatment

Treatment of Wiskott–Aldrich syndrome is currently based on correcting symptoms. Aspirin and other nonsteroidal anti-inflammatory drugs should be avoided, since these may interfere with platelet function. A protective helmet can protect children from bleeding into the brain which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or removal of the spleen. For patients with frequent infections, intravenous immunoglobulins (IVIG) can be given to boost the immune system. Anemia from bleeding may require iron supplementation or blood transfusion.

As Wiskott–Aldrich syndrome is primarily a disorder of the blood-forming tissues, a hematopoietic stem cell transplant, accomplished through a umbilical cord blood or bone marrow transplant offers the only current hope of cure. This may be recommended for patients with HLA-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.

Studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus have begun.[10][11] Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome.[12] Currently, many investigators continue to develop optimized gene therapy vectors.[7][10][11][13] In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that three children with Wiskott–Aldrich syndrome showed significant improvement 20–30 months after being treated with a genetically modified lentivirus.[14] In April 2015 results from a follow-up British and French trial where six children with Wiskott–Aldrich syndrome were treated with gene therapy were described as promising.[15][16] Median follow-up time was 27 months.

Epidemiology

The estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births. No geographical factor is present.[17]

History

The syndrome is named after Dr. Robert Anderson Aldrich (1917–1998), an American pediatrician who described the disease in a family of Dutch-Americans in 1954,[2] and Dr. Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937.[18] Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006, a German research group analysed family members of Wiskott's three cases, and surmised they probably shared a novel frameshift mutation of the first exon of the WASp gene.[19]

References

  1. ^ Reference, Genetics Home. "Wiskott-Aldrich syndrome". Genetics Home Reference. Retrieved 2016-06-26.
  2. ^ a b Aldrich, R. A.; Steinberg, A. G.; Campbell, D. C. (1954). "Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea". Pediatrics. 13 (2): 133–139. PMID 13133561.
  3. ^ Wiskott-Aldrich Syndrome at eMedicine
  4. ^ Sande, Merle A.; Wilson, Walter P. (2001). Current diagnosis & treatment in infectious diseases. New York: Lange Medical Books/McGraw-Hill. p. 361. ISBN 0-8385-1494-4.[page needed]
  5. ^ "Wiskott-Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional". Retrieved 2008-03-01.
  6. ^ Derry JM, Ochs HD, Francke U (1994). "Isolation of a novel gene mutated in Wiskott-Aldrich syndrome". Cell. 78: 635–644, erratum on page 922. doi:10.1016/0092-8674(94)90528-2. PMID 8069912.
  7. ^ a b c Jin, Y.; Mazza, C.; Christie, J.; Giliani, S.; Fiorini, M.; Mella, P.; Gandellini, F.; Stewart, D.; Zhu, Q.; Nelson, D. L.; Notarangelo, L. D.; Ochs, H. D. (2004). "Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation". Blood. 104 (13): 4010–4019. doi:10.1182/blood-2003-05-1592. PMID 15284122.
  8. ^ Rosenstein, Y.; Park, J. K.; Hahn, W. C.; Rosen, F. S.; Bierer, B. E.; Burakoff, S. J. (1991). "CD43, a molecule defective in Wiskott-Aldrich syndrome, binds ICAM-1". Nature. 354 (6350): 233–235. Bibcode:1991Natur.354..233R. doi:10.1038/354233a0. PMID 1683685.
  9. ^ Radl, J.; Dooren, L. H.; Morell, A.; Skvaril, F.; Vossen, J. M.; Uittenbogaart, C. H. (1976). "Immunoglobulins and transient paraproteins in sera of patients with the Wiskott-Aldrich syndrome: a follow-up study". Clinical and experimental immunology. 25 (2): 256–263. PMC 1541349. PMID 954233.
  10. ^ a b Galy, A.; Roncarolo, M. G.; Thrasher, A. J. (2008). "Development of lentiviral gene therapy for Wiskott Aldrich syndrome". Expert Opinion on Biological Therapy. 8 (2): 181–190. doi:10.1517/14712598.8.2.181. PMC 2789278. PMID 18194074.
  11. ^ a b Frecha, C; M G Toscano; C Costa; M J Saez-Lara; F L Cosset; E Verhoeyen; F Martin (2008). "Improved lentiviral vectors for Wiskott Aldrich syndrome gene therapy mimic endogenous expression profiles throughout haematopoiesis". Gene Therapy. 15 (12): 930–41. doi:10.1038/gt.2008.20. PMID 18323794.
  12. ^ Boztug, K.; Schmidt, M.; Schwarzer, A.; Banerjee, P. P.; Díez, I. S. A.; Dewey, R. A.; Böhm, M.; Nowrouzi, A.; Ball, C. R.; Glimm, H.; Naundorf, S.; Kühlcke, K.; Blasczyk, R.; Kondratenko, I.; Maródi, L. S.; Orange, J. S.; Von Kalle, C.; Klein, C. (2010). "Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome". New England Journal of Medicine. 363 (20): 1918–1927. doi:10.1056/NEJMoa1003548. PMC 3064520. PMID 21067383.
  13. ^ Dewey, R.; Avedillo Díez, I.; Ballmaier, M.; Filipovich, A.; Greil, J.; Güngör, T.; Happel, C.; Maschan, A.; Noyan, F.; Pannicke, U.; Schwarz, K.; Snapper, S.; Welte, K.; Klein, C. (2006). "Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro". Experimental Hematology. 34 (9): 1161–1169. doi:10.1016/j.exphem.2006.04.021. PMID 16939809.
  14. ^ Aiuti, A.; Biasco, L.; Scaramuzza, S.; Ferrua, F.; Cicalese, M. P.; Baricordi, C.; Dionisio, F.; Calabria, A.; Giannelli, S.; Castiello, M. C.; Bosticardo, M.; Evangelio, C.; Assanelli, A.; Casiraghi, M.; Di Nunzio, S.; Callegaro, L.; Benati, C.; Rizzardi, P.; Pellin, D.; Di Serio, C.; Schmidt, M.; Von Kalle, C.; Gardner, J.; Mehta, N.; Neduva, V.; Dow, D. J.; Galy, A.; Miniero, R.; Finocchi, A.; Metin, A. (2013). "Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome". Science. 341 (6148): 1233151. doi:10.1126/science.1233151. PMID 23845947.
  15. ^ Gallagher, James (21 April 2015) Gene therapy: 'Tame HIV' used to cure disease BBC News, Health, Retrieved 21 April 2015
  16. ^ Malech, H. L.; Ochs, H. D. (2015). "An Emerging Era of Clinical Benefit from Gene Therapy". JAMA (Journal of the American Medical Association). 313 (15): 1522. doi:10.1001/jama.2015.2055.
  17. ^ Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD. Pediatric Wiskott-Aldrich Syndrome
  18. ^ Wiskott, A (1937). "Familiärer, angeborener Morbus Werlhofii? ("Familial congenital Werlhof's disease?")". Montsschr Kinderheilkd. 68: 212–16.
  19. ^ Binder, V.; Albert, M. H.; Kabus, M.; Bertone, M.; Meindl, A.; Belohradsky, B. H. (2006). "The Genotype of the Original Wiskott Phenotype". New England Journal of Medicine. 355 (17): 1790–3. doi:10.1056/NEJMoa062520. PMID 17065640.

Further reading

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