WASP and the phenotypic range associated with deficiency.
ABSTRACT This review reports on the range of clinical phenotypes that are caused by mutations in the Wiskott-Aldrich Syndrome Protein (WASP) gene. The basis of genotype-phenotype correlation in Wiskott-Aldrich syndrome (WAS) is discussed, with regard to expression of the WAS protein (WASp) and of the effects of WASP mutations on WASp function. Advances in preclinical models of gene therapy for WAS are presented.
Two recent studies have supported genotype-phenotype correlation in WAS and in related X-linked thrombocytopenia. Expression of the WASp was found to be the best predictor of clinical phenotype. Investigation of autoimmune manifestations associated with WAS has shown that autoimmune hemolytic anemia and elevated serum IgM associate with a more severe clinical course. Finally, while results of hematopoietic stem cell transplantation for WAS continue to improve, several studies have shown the potential benefit of novel therapeutic approaches based on gene transfer. In particular, use of lentiviral vector-driven expression of the WASP gene under autologous promoter sequences has been found to result in increased targeting of hematopoietic stem cells, higher levels of WASp expression, and improved reconstitution of immune function.
Availability of tools that allow analysis of WASp expression has provided evidence for a genotype-phenotype correlation in patients with WASP gene defects. Protein expression is an important prognostic indicator. The molecular and cellular abnormalities of WAS-associated defects are being identified, and significant advances in vector-mediated gene transfer have opened possibilities for the treatment of WAS based on gene therapy.
SourceAvailable from: Hiren Mehta[Show abstract] [Hide abstract]
ABSTRACT: The Wiskott–Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disease with a characteristic clinical phenotype that includes thrombocytopenia with small platelets, eczema, recurrent infections caused by immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies. We present a patient who was diagnosed with WAS in adulthood and was found to have bilateral bronchiectasis. Although recurrent infections are common with Wiskott–Aldrich syndrome the association with bronchiectasis has not been previously reported.Respiratory Medicine CME 01/2008; 1(1):54-58. DOI:10.1016/j.rmedc.2007.10.004
Article: Primäre Immundefekte[Show abstract] [Hide abstract]
ABSTRACT: Die Diagnose und Behandlung von Immundefekterkrankungen stellen eine Herausforderung dar. Zeitpunkt und Lokalisation der Symptome knnen wichtige Hinweise auf die tiologie des Immundefekts geben. Es werden primre B-Zell-Defekte, numerische und funktionelle T-Zell-Defekte, Phagozytendefekte und Komplementdefekte beschrieben. Die frhe Pneumocystis-jirovecii-Pneumonie, wiederholte Infektionen mit Herpesviren oder frh auftretende Ekzeme weisen auf T-Zell-Defekte hin. Dagegen knnen wiederholte bakterielle Pneumonien bei lteren Kindern auf einen Antikrpermangel hinweisen. Die Diagnostik sollte mit einem Differenzialblutbild und der Bestimmung der Immunglobulinspiegel beginnen, da diese Untersuchungen am kosteneffektivsten sind. Bei weiter bestehendem Verdacht sollten funktionelle zellulre Untersuchungen und die Messung spezifischer Antikrper folgen.The diagnosis and management of immunodeficiencies may present a significant challenge. Timing and location of symptoms can all provide important clues to the etiology of infection. Among those described are primary B-cell alterations, numerical and functional T-cell abnormalities, defects of phagocytes, or complement. Early Pneumocystis jiroveci pneumonia, recurrent viral infection of the herpes virus group, or eczematous dermatitis may indicate T-cell abnormalities whereas recurrent bacterial pneumonias in older children may be associated with antibody deficiency. The diagnostic work-up should start with a differential blood count and determination of immunoglobulin levels which are the most cost effective. In cases of high index of suspicion, further investigations including functional cellular assays and specific antibodies should follow.Der Pneumologe 08/2006; 3(5):349-363. DOI:10.1007/s10405-006-0108-x