Clinical spectrum, pathophysiology and treatment of the Wiskott–Aldrich syndrome

@article{Albert2011ClinicalSP,
  title={Clinical spectrum, pathophysiology and treatment of the Wiskott–Aldrich syndrome},
  author={Michael H. Albert and Luigi Daniele Notarangelo and Hans D. Ochs},
  journal={Current Opinion in Hematology},
  year={2011},
  volume={18},
  pages={42–48}
}
Purpose of reviewThe Wiskott–Aldrich syndrome (WAS), caused by mutations in the WAS gene, is a complex and diverse disorder with X-linked inheritance. This review focuses on recent developments in the understanding of its basic pathophysiology, diverse clinical phenotypes and optimal patient management including novel therapies. Recent findingsThe protein encoded by the WAS gene is a multifunctional signaling element expressed in immune and hematopoietic cells that plays a critical role in… 
Wiskott‐Aldrich syndrome: a comprehensive review
TLDR
The absence of functional WASp leads to a severe clinical phenotype that can result in death if not diagnosed and treated early in life, and the treatment of choice with the best outcome is hematopoietic stem cell transplantation.
Gene therapy for Wiskott–Aldrich syndrome
TLDR
Risks and benefits of GT and allogeneic hematopoietic stem cell transplantation must be weighted considering remission, safety profiles, side effects, availability and cost effectiveness, despite long-term clinical benefits, uncontrolled clonal expansion remains a critical limitation.
Gene therapy for the Wiskott–Aldrich syndrome
TLDR
Preclinical efficacy and safety results using refined lentiviral vectors, and the development of robust clinical-grade manufacturing processes have supported the initiation of several phase I/II gene therapy trials for patients without HLA-compatible donors.
Wiskott–Aldrich syndrome in a child presenting with macrothrombocytopenia
TLDR
Molecular studies revealed a novel hemizygous 1-bp deletion in WAS gene, leading to a frameshift and stop codon at amino acid 308 (p.Arg268Glyfs*40), and next-generation sequencing of a total of 70 additional genes known to harbor variants implicated in inherited platelet disorders did not identify additional defects.
Hematopoietic Stem Cell Therapy for Wiskott–Aldrich Syndrome: Improved Outcome and Quality of Life
TLDR
After trials and errors, inactivating lentiviral vectors carrying the WAS gene were successfully evaluated in clinical trials, demonstrating cure of the disease except for insufficient resolution of the platelet defect.
Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.
TLDR
This study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome and demonstrated improvement in immunological and hematological characteristics and evidence of safety through vector integration analysis.
Report of clinical presentations and two novel mutations in patients with Wiskott-Aldrich syndrome/X-linked Thrombocytopenia
TLDR
Two patients with Wiskott-Aldrich syndrome/X-linked thrombocytopenia had severe clinical phenotypes compatible with classic WAS and developed lethal outcomes with intracranial hemorrhage and one patient with XLT developed pineoblastoma.
Wiskott-Aldrich Syndrome (WAS) and Dedicator of Cytokinesis 8- (DOCK8) Deficiency
Both Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8 (DOCK8) deficiency are primary immunodeficiency diseases caused by mutations in genes that result in defective organization of the
A case of familial X-linked thrombocytopenia with a novel WAS gene mutation
TLDR
The case of a 4-year-old boy with a history of marked thrombocytopenia since birth, who presented with recurrent herpes simplex infection and late onset of eczema is described, who found a new deletion mutation in the WAS gene: c.858delC (p.ser287Leufs*21) as a hemizygous form.
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References

SHOWING 1-10 OF 58 REFERENCES
Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome.
TLDR
A full understanding of the mechanisms leading to defects in T, B, and dendritic cells still remains poorly understood is still needed to further implement new therapeutic strategies for this peculiar immunodeficiency.
The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation.
TLDR
The results suggest that the platelet defect in WAS patients is not due to abnormal platelet production, but instead to cytoskeletal changes occuring in platelets during circulation.
Clinical course of patients with WASP gene mutations.
TLDR
It is demonstrated that WAS protein expression is a useful tool for predicting long-term prognosis for patients with WAS/XLT and hematopoietic stem cell transplantation should be considered, especially for WASP-negative patients, while the patients are young to improve prognosis.
Phenotypic perturbation of B cells in the Wiskott–Aldrich syndrome
TLDR
A deficit of total B‐cells is shown in WAS patients of various ages and phenotypic perturbations involving complement receptors and CD27 are identified, suggesting defects intrinsic to B‐ cells contribute to the impaired humoral immunity that characterizes this disease.
Systemic autoimmunity and defective Fas ligand secretion in the absence of the Wiskott-Aldrich syndrome protein.
TLDR
A novel role of WASp is described in regulating TCR-induced apoptosis and FasL secretion and it is suggested that WASp-deficient mice provide a good model for the study of autoimmune manifestations of WAS and the development of more specific therapies for these complications.
Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models.
TLDR
Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.
TLDR
By analyzing a large number of patients with WAS/XLT at the molecular level, 5 mutational hotspots in the WASP gene are identified and a strong association between genotype and phenotype is established.
Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia.
TLDR
In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of the neutropenia, suggesting a novel cause of myelodysplasia.
X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options.
TLDR
An analysis of the clinical outcome and molecular basis of patients with XLT shows excellent long-term survival but also a high probability of severe disease-related complications, which will allow better decision making when considering treatment options for individual patients withXLT.
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