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Rebecca H. Buckley - One of the best experts on this subject based on the ideXlab platform.
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the genetic landscape of Severe Combined Immunodeficiency in the united states and canada in the current era 2010 2018
The Journal of Allergy and Clinical Immunology, 2019Co-Authors: Christopher C Dvorak, Morton J. Cowan, Donald B Kohn, Luigi D. Notarangelo, Sung-yun Pai, Rebecca H. Buckley, Brent R Logan, Linda M Griffith, Elie Haddad, William T ShearerAbstract:In a 250 patient cohort from the US and Canada in the current era (2010–2018), we show that over 90% of patients with Severe Combined Immunodeficiency (SCID) can be genetically-characterized.
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comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of Severe Combined Immunodeficiency
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Christopher C Dvorak, Rebecca H. Buckley, A Hassan, Mary Slatter, Manfred Honig, Arjan C Lankester, Michael A Pulsipher, Jeffrey H Davis, Tayfun Gungor, Melissa GabrielAbstract:Background Patients with Severe Combined Immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs. Methods We performed a multicenter survey of Severe Combined Immunodeficiency transplantation centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT from either URDs (n = 37) or MSDs (n = 66). Results Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment compared with 97% for those with MSDs; however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively) compared with MSD recipients (92% and 89%, respectively; P P P Conclusion Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to that seen in MSD recipients, and reconstitution rates are adequate. However, only a minority will have myeloid and B-cell reconstitution, and attention must be paid to graft-versus-host disease prophylaxis. This approach might be safer in children ineligible for intense regimens to spare the potential complications of chemotherapy.
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transplantation outcomes for Severe Combined Immunodeficiency 2000 2009
The New England Journal of Medicine, 2014Co-Authors: Sung-yun Pai, Neena Kapoor, Roberta E Parrott, Rebecca H. Buckley, Christopher C Dvorak, Brent R Logan, Linda M Griffith, Imelda C Hanson, Alexandra H Filipovich, Soma JyonouchiAbstract:Background The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with Severe Combined Immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. Methods We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). Results Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infect...
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the long quest for neonatal screening for Severe Combined Immunodeficiency
The Journal of Allergy and Clinical Immunology, 2012Co-Authors: Rebecca H. BuckleyAbstract:Early recognition of Severe Combined Immunodeficiency (SCID) is a pediatric emergency because a diagnosis before live vaccines or nonirradiated blood products are given and before development of infections permits lifesaving unfractionated HLA-identical or T cell–depleted haploidentical hematopoietic stem cell transplantation, enzyme replacement therapy, or gene therapy. The need for newborn screening for this condition has been recognized for the past 15 years. However, implementation of screening required development of an assay for T-cell lymphopenia that could be performed on dried bloodspots routinely collected from newborn infants for the past 48 years. This was accomplished 6 years ago, and there have already been 7 successful pilot studies. A recommendation to add SCID to the routine newborn-screening panel was approved by the Secretary's Advisory Committee on Heritable Disorders of Newborns and Children in 2010 and was soon after approved by the Secretary of Health and Human Services. It is important for allergists, immunologists, and other health care providers to take an active role in promoting newborn screening for SCID and other T-lymphocyte abnormalities in their states. Even more important will be their roles in establishing accurate diagnoses for infants with positive screen results and in ensuring that they are given the best possible treatment.
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Transplantation of hematopoietic stem cells in human Severe Combined Immunodeficiency: longterm outcomes
Immunologic Research, 2011Co-Authors: Rebecca H. BuckleyAbstract:Severe Combined Immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T- and B-cell function and, in some types, also of NK cells and function. Mutations in thirteen different genes have been found to cause this condition, which is uniformly fatal in the first 2 years of life unless immune reconstitution can be accomplished. In the 42 years since the first bone marrow transplant was given in 1968, the standard treatment for all forms of SCID has been allogeneic bone marrow transplantation. Both HLA-identical unfractionated and T-cell-depleted HLA-haploidentical bone marrow transplants have been very successful in effecting immune reconstitution, especially if performed in the first 3.5 months of life and without pre-transplant chemotherapy. This paper summarizes the longterm outcome, according to molecular type, of 166 consecutive SCID infants given non-conditioned related donor bone marrow transplants at this institution over the past 28.3 years and reviews published reports of longterm outcomes of transplants in SCID performed at other centers.
Salima Haceinbeyabina - One of the best experts on this subject based on the ideXlab platform.
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gene therapy for x linked Severe Combined Immunodeficiency where do we stand
Human Gene Therapy, 2016Co-Authors: Marina Cavazzana, Emmanuelle Six, Chantal Lagreslepeyrou, Isabelle Andreschmutz, Salima HaceinbeyabinaAbstract:More than 20 years ago, X-linked Severe Combined Immunodeficiency (SCID-X1) appeared to be the best condition to test the feasibility of hematopoietic stem cell gene therapy. The seminal SCID-X1 clinical studies, based on first-generation gammaretroviral vectors, demonstrated good long-term immune reconstitution in most treated patients despite the occurrence of vector-related leukemia in a few of them. This gene therapy has successfully enabled correction of the T cell defect. Natural killer and B cell defects were only partially restored, most likely due to the absence of a conditioning regimen. The success of these pioneering trials paved the way for the extension of gene-based treatment to many other diseases of the hematopoietic system, but the unfortunate serious adverse events led to extensive investigations to define the retrovirus integration profiles. This review puts into perspective the clinical experience of gene therapy for SCID-X1, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge.
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a modified γ retrovirus vector for x linked Severe Combined Immunodeficiency
The New England Journal of Medicine, 2014Co-Authors: Salima Haceinbeyabina, Sung-yun Pai, Myriam Armant, Charles C. Berry, Stéphane Blanche, Jack J. Bleesing, Johanna Blondeau, Helen De Boer, Bobby H Gaspar, Karen F. BucklandAbstract:BACKGROUND In previous clinical trials involving children with X-linked Severe Combined Immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancermediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS All patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.)
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efficacy of gene therapy for x linked Severe Combined Immunodeficiency
The New England Journal of Medicine, 2010Co-Authors: Salima Haceinbeyabina, Charles C. Berry, Julia Hauer, Annick Lim, Capucine Picard, Gary P Wang, Chantal Martinache, Frederic Rieuxlaucat, Sylvain Latour, Bernd H BelohradskyAbstract:Background The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked Severe Combined Immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common γ chain. Methods The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of γ chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up. Results Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell−receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the Immunodeficiency improved the patients’ health. Conclusions After nearly 10 years of follow-up, gene therapy was shown to have corrected the Immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.)
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a serious adverse event after successful gene therapy for x linked Severe Combined Immunodeficiency
The New England Journal of Medicine, 2003Co-Authors: Salima Haceinbeyabina, Elisabeth Mcintyre, Jeanluc Villeval, Christopher C Fraser, Christof Von Kalle, Francoise Le Deist, Isabelle Radford, Manfred Schmidt, Nico M Wulffraat, Marina CavazzanacalvoAbstract:To the Editor: We recently reported (April 18 issue)1 the sustained correction of X-linked Severe Combined Immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease. These results have since been confirmed in four additional patients with typical X-linked Severe Combined Immunodeficiency. Of the first four successfully treated patients, three continue to do well up to 3.6 years after gene therapy, whereas a serious adverse event occurred in the fourth patient. At a routine checkup 30 months after gene therapy, lymphocytosis consisting of a monoclonal population . . .
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sustained correction of x linked Severe Combined Immunodeficiency by ex vivo gene therapy
The New England Journal of Medicine, 2002Co-Authors: Salima Haceinbeyabina, Francoise Le Deist, Nico M Wulffraat, Frederique Carlier, Cecile Bouneaud, Christophe Hue, Jeanpierre De Villartay, Adrian J Thrasher, Ricardo U Sorensen, Sophie DupuisgirodAbstract:Background X-linked Severe Combined Immunodeficiency due to a mutation in the gene encoding the common γ (γc) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the γc gene can restore the immune system in patients with Severe Combined Immunodeficiency. Methods CD34+ bone marrow cells from five boys with X-linked Severe Combined Immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the γc transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer. Results No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro pro...
Warren J Leonard - One of the best experts on this subject based on the ideXlab platform.
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defective il7r expression in t b nk Severe Combined Immunodeficiency
Nature Genetics, 1998Co-Authors: Anne Puel, Rebecca H. Buckley, Steven F Ziegler, Warren J LeonardAbstract:Severe Combined Immunodeficiency (SCID) is caused by multiple genetic defects1,2,3. The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor γ chain (γc) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors1,5,6,7,8,9,10. In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to γc (Refs 9,12) and is required for γc-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal1,2,3,13,14 (T-B+NK- SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in Il7- or Il7r-deficient mice15,16 and that Il7r-deficient mice have NK cells17, we hypothesized that T–B+NK+ SCID might result from defective IL-7 signalling, although apparent differences in the role of the IL-7/IL-7R pathway in humans and mice in T-cell and B-cell development have been suggested1,18. We now demonstrate that defective IL7R expression causes T–B+NK+ SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Rα signalling.
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the defective gene in x linked Severe Combined Immunodeficiency encodes a shared interleukin receptor subunit implications for cytokine pleiotropy and redundancy
Current Opinion in Immunology, 1994Co-Authors: Warren J LeonardAbstract:Abstract The interleukin-2 receptor plays a pivotal role in the regulation of the normal T cell immune response to foreign antigen. The IL-2 receptor γ-chain is one component of this receptor, and is encoded by the gene that is defective in X-linked Severe Combined Immunodeficiency. The clinical manifestations of this disease led to the hypothesis and subsequent confirmation that the γ-chain was in fact a subunit shared by multiple cytokine receptors, including those for IL-2, IL-4, and IL-7.
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interleukin 2 receptor γ chain mutation results in x linked Severe Combined Immunodeficiency in humans
Cell, 1993Co-Authors: Masayuki Noguchi, Huafang Yi, Howard M Rosenblatt, A H Filipovich, S Adelstein, William S Modi, Wesley O Mcbride, Warren J LeonardAbstract:Abstract The interieukin-2 (IL-2) receptor γ chain (IL-2Rγ) is a component of high and intermediate affinity IL-2 receptors that is required to achieve full ligand binding affinity and internalization. We have localized the IL-2Rγ gene to human chromosome Xq13. Genetic linkage analysis indicates that the IL-2Rγ gene and the locus for X-linked Severe Combined Immunodeficiency (XSCID) appear to be at the same position. Moreover, we demonstrate that each of three unrelated patients with XSCID has a different mutation in his IL-2Rγ gene resulting in a different premature stop codon and predicted C-terminal truncation. These data establish that XSCID is associated with mutations of the IL-2Rγ gene product. Since XSCID is characterized by absent or markedly reduced numbers of T cells, our findings imply that IL-2Rγ plays a vital role in thymic maturation of T cells. These results also have important implications for prenatal and postnatal diagnosis, carrier female detection, and gene therapy for XSCID.
Bobby H Gaspar - One of the best experts on this subject based on the ideXlab platform.
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a modified γ retrovirus vector for x linked Severe Combined Immunodeficiency
The New England Journal of Medicine, 2014Co-Authors: Salima Haceinbeyabina, Sung-yun Pai, Myriam Armant, Charles C. Berry, Stéphane Blanche, Jack J. Bleesing, Johanna Blondeau, Helen De Boer, Bobby H Gaspar, Karen F. BucklandAbstract:BACKGROUND In previous clinical trials involving children with X-linked Severe Combined Immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancermediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS All patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.)
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how i treat Severe Combined Immunodeficiency
Blood, 2013Co-Authors: Bobby H Gaspar, Persios J Amrolia, Graham E Davies, Waseem Qasim, Kanchan Rao, Paul VeysAbstract:Severe Combined Immunodeficiency (SCID) arises from different genetic defects associated with lymphocyte development and function and presents with Severe infections. Allogeneic hematopoietic stem cell transplantation is an extremely effective way of restoring immunity in these individuals. Numerous multicenter studies have identified the factors determining successful outcome, and survival for SCID has shown great improvement. Advances in understanding the genetic basis of disease also mean that we increasingly tailor transplant protocols to the specific SCID form. Wherever possible, we attempt to transplant SCID patients without the use of cytoreductive conditioning, but it is clear that this is only successful for specific SCID forms and, although survival is good, in specific patients there are ongoing humoral defects. We aim to use matched related and unrelated donors (including cord blood) whenever possible and have limited the use of mismatched haploidentical donors. The development of autologous hematopoietic stem cell gene therapy provides another treatment of the X-linked and adenosine deaminase-deficient forms of SCID, and we discuss how we have integrated gene therapy into our treatment strategy. These developments together with the advent of universal newborn screening for SCID should allow for a highly favorable outcome for this otherwise lethal condition.
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gene therapy for Severe Combined Immunodeficiency due to adenosine deaminase deficiency
Current Gene Therapy, 2012Co-Authors: Claudia A Montielequihua, Adrian J Thrasher, Bobby H GasparAbstract:The Severe Combined Immunodeficiency caused by the absence of adenosine deaminase (SCID-ADA) was the first monogenic disorder for which gene therapy was developed. Over 30 patients have been treated worldwide using the current protocols, and most of them have experienced clinical benefit; importantly, in the absence of any vector-related complications. In this document, we review the progress made so far in the development and establishment of gene therapy as an alternative form of treatment for ADA-SCID patients.
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neonatal diagnosis of Severe Combined Immunodeficiency leads to significantly improved survival outcome the case for newborn screening
Blood, 2011Co-Authors: Lucinda Brown, Graham E Davies, Paul Veys, Bobby H Gaspar, Andrew J Cant, Mary Slatter, Jinhua Xubayford, Zoe Allwood, Andrew R GenneryAbstract:Severe Combined Immunodeficiency (SCID) carries a poor prognosis without definitive treatment by hematopoietic stem cell transplantation. The outcome for transplantation varies and is dependent on donor status and the condition of the child at the time of transplantation. Diagnosis at birth may allow for better protection of SCID babies from infection and improve transplantation outcome. In this comparative study conducted at the 2 designated SCID transplantation centers in the United Kingdom, we show that SCID babies diagnosed at birth because of a positive family history have a significantly improved outcome compared with the first presenting family member. The overall improved survival of more than 90% is related to a reduced rate of infection and significantly improved transplantation outcome irrespective of donor choice, conditioning regimen used, and underlying genetic diagnosis. Neonatal screening for SCID would significantly improve the outcome in this otherwise potentially devastating condition.
Chaim M. Roifman - One of the best experts on this subject based on the ideXlab platform.
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a novel mutation in lig4 in an infant presenting with Severe Combined Immunodeficiency with thymic medullary dysplasia
LymphoSign Journal, 2017Co-Authors: Willa Liao, Boyee Ngan, Harjit Dadi, Daniele Merico, Chaim M. RoifmanAbstract:Background: DNA ligase IV deficiency is a rare autosomal recessive condition resulting from mutations in LIG4, an essential component of the non-homologous end-joining pathway that prevents mutagenesis and apoptosis. Patients with LIG4 deficiency present with varying degrees of Combined Immunodeficiency, or less commonly, Severe Combined Immunodeficiency (SCID). Assessment of thymus pathology has been instrumental in defining a growing number of T cell deficiencies. In this case report, we present thymic histopathology of a LIG4 deficient patient who presented with SCID.Methods: Whole exome sequencing and Sanger confirmation were used to identify a novel mutation in LIG4. Standard immune work up and histopathology were completed to characterize deficits in immune function and dysplastic thymic architecture in our patient.Results: Next generation sequencing techniques identified a homozygous c.1102G>T, resulting in amino acid change D368Y in the adenylation domain of LIG4. Histopathology revealed a distinc...
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increased resting energy expenditure is associated with failure to thrive in infants with Severe Combined Immunodeficiency
The Journal of Pediatrics, 2011Co-Authors: Mary A Barron, Paul B Pencharz, Melanie M Makhija, Lorrie E M Hagen, Eyal Grunebaum, Chaim M. RoifmanAbstract:Objectives To measure resting energy expenditure (REE) and determine whether increased REE (hypermetabolism) is associated with failure to thrive (FTT) in patients with Severe Combined Immunodeficiency (SCID) at diagnosis. Study design REE was measured in 26 patients with SCID in a single transplant center. Predicted REE was determined with World Health Organization standards. Measured REE >110% of predicted REE was classified as hypermetabolism. Other data collected included FTT status, infections, genotype, phenotype, and the feeding methods used. Results Fifteen of 26 patients (57.7%) had FTT, and 18 of 26 patients (69.2%) were hypermetabolic. Hypermetabolism occured in 14 of 15 patients (93%) with FTT, and only 4 of 11 patients (36%) without FTT had hypermetabolism (P = .003). There was a significant difference between the measured REE (71.75 ± 16.6 kcal/kg) and the predicted REE (52.85 ± 2.8 kcal/kg; P Conclusions Hypermetabolism is common in patients with SCID and may contribute to the development of FTT. The hypermetabolism in these patients may necessitate intensive nutrition support.
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Omenn syndrome: inflammation in leaky Severe Combined Immunodeficiency.
Journal of Allergy and Clinical Immunology, 2008Co-Authors: Anna Villa, Luigi D. Notarangelo, Chaim M. RoifmanAbstract:Omenn syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of Severe Combined Immunodeficiency (SCID). Similar to other patients with SCID, patients with OS present early in infancy with viral or fungal pneumonitis, chronic diarrhea, and failure to thrive. Unlike typical SCID, patients with OS have enlarged lymphoid tissue, Severe erythroderma, increased IgE levels, and eosinophilia. The inflammation observed in these patients is believed to be triggered by clonally expanded T cells, which are predominantly of the T H 2 type. These abnormal T cells, in the absence of proper regulation by other components of the immune system, secrete a host of cytokines that promote autoimmune as well as allergic inflammation. The emergence of these T-cell clones occurs in patients with hypomorphic mutations in recombination activating gene 1 or 2, but not in patients with deleterious mutations in these enzymes which render them inactive. Recently, OS was also identified in a growing list of other leaky SCIDs with mutations in RNA component of mitochondrial RNA processing endoribonuclease , adenosine deaminase , IL-2 receptor γ , IL-7 receptor α , ARTEMIS , and DNA ligase 4 . This new information revealed OS is a distinct inflammatory process that can be associated with genetically diverse leaky SCIDS.
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burkitt s lymphoma in a patient with adenosine deaminase deficiency Severe Combined Immunodeficiency treated with polyethylene glycol adenosine deaminase
The Journal of Pediatrics, 2007Co-Authors: Maitham Husain, Eyal Grunebaum, Ahmed Naqvi, Adelle Atkinson, Boyee Ngan, Alessandro Aiuti, Chaim M. RoifmanAbstract:We describe a patient with Severe Combined Immunodeficiency because of aberrations in adenosine deaminase (ADA) who despite adequate replacement with polyethylene glycol-linked ADA (PEG-ADA) for 13 years developed Burkitt's lymphoma. Although treatment corrected the metabolic abnormalities caused by ADA deficiency, it failed to fully restore cellular immunity.
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effect of cd3δ deficiency on maturation of α β and γ δ t cell lineages in Severe Combined Immunodeficiency
The New England Journal of Medicine, 2003Co-Authors: Harjit Dadi, Amos J Simon, Chaim M. RoifmanAbstract:Three closely related infants with a form of Severe Combined Immunodeficiency characterized by the absence of T cells but normal numbers of B cells were found to have an identical germ-line mutation in the CD3δ gene. The mutation prevented synthesis of the CD3δ protein and was associated with a block early in the development of thymocytes into mature T cells.
