Griscelli Syndrome: Rare Neonatal Syndrome of Recurrent Hemophagocytosis

Kumar, Manjusha; Sackey, Kwesi; Schmalstieg, Frank C.; Trizna, Zoltan; Elghetany, M. Tarek; Alter, Blanche P.

doi:10.1097/00043426-200110000-00015

Cited by 28 publications

(20 citation statements)

References 16 publications

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“…6,7 In the first few years of life, hemophagocytic lymphohistiocytosis (HLH) in these patients can be triggered by infections. 8 The prognosis is very poor unless early allogeneic hematopioetic SCT (aHSCT) is carried out, preferably before the development of the accelerated phase. To date, few cases of aHSCT in patients with GS have been reported.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic SCT in children with Griscelli syndrome: a single-center experience

Al-Ahmari

Al-Ghonaium

Al-mansoori

et al. 2010

Bone Marrow Transplant

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In total, 11 consecutive pediatric patients with Griscelli syndrome (GS) type 2, who received allogeneic hematopoietic SCT (aHSCT) at our center between 1993 and 2007, were reviewed. The median age at transplantation was 8.2 months (range, 4-36.3 months) and the median time from diagnosis to transplantation was 3.7 months (range, 1.4-19.5 months). Seven patients developed an accelerated phase and were treated with chemotherapy before transplantation. At the time of transplantation, all patients were in clinical remission. The source of grafts was matched-related marrows in eight patients and partially mismatched unrelated cords in three patients. All patients were engrafted at a median time of 15 days (range, 12-36 days). Grade I-II acute GVHD and venoocclusive disease occurred in three and one patient, respectively. A total of 10 patients are now alive and disease free at a median of 4.8 years post-HSCT. The post transplant course was complicated by CMV infection in four patients. One patient died in remission from septic shock, 6 months after transplantation. Chimerism studies at the last contact are available for nine patients: six patients have complete donor chimerism and three have stable mixed chimerism. Early aHSCT from matchedrelated donors or unrelated cord blood for children with GS is feasible.

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Section: Introductionmentioning

confidence: 99%

Hematopoietic SCT in children with Griscelli syndrome: a single-center experience

Al-Ahmari

Al-Ghonaium

Al-mansoori

et al. 2010

Bone Marrow Transplant

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“…The remaining, 'unconventional' myosins function in such processes as intracellular transport and tethering (e.g., regulation of exocytosis/secretion by myosins 1c/1e, Va/Vb, VI, VII and X), cell division, cell motility, actin cytoskeletal organization and cellular signaling [15]. Myosins have also been implicated in several human diseases, such as hypertrophic cardiomyopathy [16,17], Griscelli syndrome [18], deafness [19,20] and cancer [21,22]. Therefore, inhibitors of specific myosins could act as a valuable tool both in characterizing many intracellular processes and also in developing targeted treatments for diseases involving myosin overproduction/malfunction.…”

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confidence: 99%

Small-Molecule Inhibitors of Myosin Proteins

et al. 2012

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Advances in screening and computational methods have enhanced recent efforts to discover/ design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.The identification and characterization of pharmacological compounds that inhibit the functional activity of one or more specific proteins or processes has been the subject of much scientific investigation. On a basic science level, these membrane-permeable compounds provide the scientific community with a tool for the targeted and functional inhibition of a given protein in the cell; a potent means of evaluating the intracellular functions of that protein [1,2]. From a biomedical standpoint, the characterization of these small-molecule inhibitors affords an opportunity for the development of novel disease treatments centering on the repression of an offensive molecule or the reversal of its downstream effects [3][4][5].At present, several complementary methods for obtaining suitable small-molecule inhibitors of specific proteins exist. Traditional methods in inhibitor discovery involve the systematic testing of a series of chemically synthesized or naturally occurring compounds. Advances in robotics and data processing have made it possible to use high-throughput screens to test libraries of thousands or even millions of potential drugs for their ability to inhibit the function of a specific protein in a targeted biochemical or cellular assay [6][7][8]. These inhibitor discovery processes are complemented by more precise methods in small-molecule inhibitor design. Structure-based methods rely on the use of x-ray crystallographic or NMRbased structures of a protein of interest to design small molecules likely to bind and inhibit protein function [9,10]. Computer-aided inhibitor design uses computational methods to optimize potential inhibitors identified by screening or structure-based methods, to virtually © 2013 Folma Buss * Author for correspondence: Tel.: +44 1223 763348, Fax: +44 1223 762640, fb207@cam.ac.uk. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance w...

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“…Empiric antibiotic administration and steroid dose were discontinued, while cyclosporin was continued to alleviate the excessive lymphocyte activation and resultant excess of cytokines. Allogeneic bone marrow transplantation is the curative treatment for this otherwise fatal disease 8,12,14,16,19,20,32 ; no matched donor was found among immediate or extended family members and the search for matching unrelated donor is ongoing. …”

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NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome

Gazit

Aker

Elboim

et al. 2007

Blood

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Griscelli syndrome (GS) type 2 is an autosomal recessive disorder represented by pigment dilution and impaired cytotoxic T lymphocyte (CTL) activity. NK activity has been scarcely investigated in GS patients. Here, we describe a new patient, possessing a hemophagocytic syndrome with a homozygous Q118X nonsense RAB27A mutation. Single specific primerpolymerase chain reaction (SSP-PCR) was developed based on this mutation and is currently used in prenatal genetic analysis. As expected, CTLs in the patient are not functional and NK cytotoxicity against K562 or 721.221 cells is diminished. Surprisingly, however, we demonstrate that CD16-mediated killing is intact in this patient and is therefore RAB27A independent, whereas NKp30-mediated killing is impaired and is therefore RAB27A dependent. We further analyzed the signaling pathways of these 2 receptors and demonstrated phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. Thus, we identify a novel homozygous mutation in the RAB27A gene of a new GS patient, observe for the first time that some activating NK receptors function in GS patients, and demonstrate a functional dichotomy in the killing mediated by these human NK-activating receptors. ( IntroductionNatural killer (NK) cells are the lymphocytes of innate immunity, able to identify and eliminate virus-infected and tumor cells without prior antigen stimulation. 1,2 In addition, secretion of cytokines by NK cells recruits and activates additional immune cells and modulates the adaptive immune response. 3,4 Unlike other lymphocytes, NK cells do not express any single rearranged receptor such as the T-or B-cell receptors, but rather use a limited number of activating receptors. 5,6 The major human NK-activating receptors are NKp30, NKp44, NKp46, NKG2D, and the Fc␥RIIIA receptor CD16. 2,7 Engagement of NK lysis receptors leads to cytoskeleton reorganization, translocation of lytic granules, and directed exocytosis to facilitate the final step of killing. The precise understanding of signal transduction pathways of these receptors is therefore crucial for our basic understanding of how NK cells function.Griscelli syndrome (GS) was first described by Claude Griscelli et al, 8 who described 2 patients with a distinctive silver-gray hair color and impaired immune activity. Since the first description, heterogeneity in clinical manifestations of the syndrome has been recognized in about 100 patients reported so far. Genetic studies found mutations in MYO5A, RAB27A, or MLPH, and patients were thereafter categorized as GS type 1, 2, or 3, respectively. 9-11 The abnormal pigmentation is a common feature of all of these patients and immunologic impairments are associated with RAB27A mutations, whereas MYO5A and MLPH have redundant role in lymphoid cells. 12 Despite the apparent immunodeficiency, the major clinical difficulty is not an overwhelming infection, but rather a fatal hemophagocytic syndrome caused by inappropriate and excessive lymphoid-cell activation and cytokine release often triggered...

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Griscelli Syndrome: Rare Neonatal Syndrome of Recurrent Hemophagocytosis

Cited by 28 publications

References 16 publications

Hematopoietic SCT in children with Griscelli syndrome: a single-center experience

Hematopoietic SCT in children with Griscelli syndrome: a single-center experience

Small-Molecule Inhibitors of Myosin Proteins

NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome

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