24 results on '"Hershfield, Ms"'
Search Results
2. Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency.
- Author
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Hicks ED, Hall G, Hershfield MS, Tarrant TK, Bali P, Sleasman JW, Buckley RH, and Mousallem T
- Subjects
- Animals, Female, Humans, Infant, Infant, Newborn, Male, Immune Reconstitution, Recombinant Proteins therapeutic use, Treatment Outcome, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Agammaglobulinemia therapy, Enzyme Replacement Therapy, Severe Combined Immunodeficiency therapy
- Abstract
Purpose: Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi., Methods: We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data., Results: Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred., Conclusion: Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data., (© 2024. The Author(s).)
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- 2024
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3. Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency.
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Barzaghi F, Cicalese MP, Zoccolillo M, Brigida I, Barcella M, Merelli I, Sartirana C, Zanussi M, Calbi V, Bernardo ME, Tucci F, Migliavacca M, Giglio F, Doglio M, Canarutto D, Ferrua F, Consiglieri G, Prunotto G, Saettini F, Bonanomi S, Rovere-Querini P, Di Colo G, Jofra T, Fousteri G, Penco F, Gattorno M, Hershfield MS, Bongiovanni L, Ponzoni M, Marktel S, Milani R, Peccatori J, Ciceri F, Mortellaro A, and Aiuti A
- Subjects
- Adenosine Deaminase genetics, Granulocyte Colony-Stimulating Factor, Humans, Intercellular Signaling Peptides and Proteins, Severe Combined Immunodeficiency, Tumor Necrosis Factor Inhibitors, Twins, Monozygotic genetics, Agammaglobulinemia diagnosis, Agammaglobulinemia genetics, Neutropenia, Polyarteritis Nodosa
- Abstract
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic manifestations, potentially progressing over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of plasmatic adenosine deaminase 2 (ADA2) activity in both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense (p.Leu188Pro) mutation on the paternal ADA2 allele. While, whole genome sequencing identified an unreported deletion (IVS6_IVS7del*) on the maternal allele predicted to produce a transcript missing exon 7. The patients experienced the disease onset during childhood with early strokes (Patient 1 at two years, Patient 2 at eight years of age), subsequently followed by other shared DADA2-associated features, including neutropenia, hypogammaglobulinemia, reduced switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, the almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed: clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 successfully underwent an urgent hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, disease evolution and is currently on anti-TNF therapy and anti-infectious prophylaxis. The unique cases confirmed that heterozygous patients with null ADA2 activity deserve deep investigation for possible structural variants on a single allele. Moreover, this report emphasizes the importance of timely recognizing DADA2 at the onset to allow adequate follow-up and detection of disease progression. Finally, the therapeutic management in these identical twins raises significant concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like elective allogeneic HSCT. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barzaghi, Cicalese, Zoccolillo, Brigida, Barcella, Merelli, Sartirana, Zanussi, Calbi, Bernardo, Tucci, Migliavacca, Giglio, Doglio, Canarutto, Ferrua, Consiglieri, Prunotto, Saettini, Bonanomi, Rovere-Querini, Di Colo, Jofra, Fousteri, Penco, Gattorno, Hershfield, Bongiovanni, Ponzoni, Marktel, Milani, Peccatori, Ciceri, Mortellaro and Aiuti.)
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- 2022
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4. Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC.
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Cuvelier GDE, Logan BR, Prockop SE, Buckley RH, Kuo CY, Griffith LM, Liu X, Yip A, Hershfield MS, Ayoub PG, Moore TB, Dorsey MJ, O'Reilly RJ, Kapoor N, Pai SY, Kapadia M, Ebens CL, Forbes Satter LR, Burroughs LM, Petrovic A, Chellapandian D, Heimall J, Shyr DC, Rayes A, Bednarski JJ, Chandra S, Chandrakasan S, Gillio AP, Madden L, Quigg TC, Caywood EH, Dávila Saldaña BJ, DeSantes K, Eissa H, Goldman FD, Rozmus J, Shah AJ, Vander Lugt MT, Thakar MS, Parrott RE, Martinez C, Leiding JW, Torgerson TR, Pulsipher MA, Notarangelo LD, Cowan MJ, Dvorak CC, Haddad E, Puck JM, and Kohn DB
- Subjects
- Adenosine Deaminase, Child, Preschool, Humans, Infant, Infant, Newborn, Agammaglobulinemia genetics, Hematopoietic Stem Cell Transplantation, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy
- Abstract
Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.
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- 2022
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5. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.
- Author
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Reinhardt B, Habib O, Shaw KL, Garabedian E, Carbonaro-Sarracino DA, Terrazas D, Fernandez BC, De Oliveira S, Moore TB, Ikeda AK, Engel BC, Podsakoff GM, Hollis RP, Fernandes A, Jackson C, Shupien S, Mishra S, Davila A, Mottahedeh J, Vitomirov A, Meng W, Rosenfeld AM, Roche AM, Hokama P, Reddy S, Everett J, Wang X, Luning Prak ET, Cornetta K, Hershfield MS, Sokolic R, De Ravin SS, Malech HL, Bushman FD, Candotti F, and Kohn DB
- Subjects
- Adenosine Deaminase genetics, Adolescent, Agammaglobulinemia genetics, Child, Child, Preschool, Follow-Up Studies, Hematopoietic Stem Cell Transplantation methods, Humans, Infant, Severe Combined Immunodeficiency genetics, Transplantation, Autologous methods, Treatment Outcome, Agammaglobulinemia therapy, Genetic Therapy methods, Severe Combined Immunodeficiency therapy
- Abstract
Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)-ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.gov as #NCT00794508., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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6. Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy.
- Author
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Baloh CH, Borkar SA, Chang KF, Yao J, Hershfield MS, Parikh SH, Kohn DB, Goodenow MM, Sleasman JW, and Yin L
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- Adenosine Deaminase deficiency, Adenosine Deaminase therapeutic use, Agammaglobulinemia therapy, Enzyme Replacement Therapy, Female, Genetic Therapy, Humans, Infant, Lymphocyte Count, Severe Combined Immunodeficiency therapy, Agammaglobulinemia immunology, Immunoglobulin Heavy Chains immunology, Severe Combined Immunodeficiency immunology
- Abstract
Purpose: Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) through an accumulation of toxic metabolites within lymphocytes. Recently, ADA deficiency has been successfully treated using lentiviral-transduced autologous CD34+ cells carrying the ADA gene. T and B cell function appears to be fully restored, but in many patients' B cell numbers remain low, and assessments of the immunoglobulin heavy (IgHV) repertoire following gene therapy are lacking., Methods: We performed deep sequencing of IgHV repertoire in peripheral blood lymphocytes from a child following lentivirus-based gene therapy for ADA deficiency and compared to the IgHV repertoire in healthy infants and adults., Results: After gene therapy, Ig diversity increased over time as evidenced by V, D, and J gene usage, N-additions, CDR3 length, extent of somatic hypermutation, and Ig class switching. There was the emergence of predominant IgHM, IgHG, and IgHA CDR3 lengths after gene therapy indicating successful oligoclonal expansion in response to antigens. This provides proof of concept for the feasibility and utility of molecular monitoring in following B cell reconstitution following gene therapy for ADA deficiency., Conclusion: Based on deep sequencing, gene therapy resulted in an IgHV repertoire with molecular diversity similar to healthy infants., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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7. ADA2 deficiency (DADA2) associated with Evans syndrome and a severe ADA2 genotype.
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Ferriani MPL, Valera ET, de Sousa GR, Sandrin-Garcia P, de Moura RR, Hershfield MS, and de Carvalho LM
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- Agammaglobulinemia complications, Agammaglobulinemia drug therapy, Anemia, Hemolytic, Autoimmune complications, Anemia, Hemolytic, Autoimmune drug therapy, Antirheumatic Agents therapeutic use, Child, Etanercept therapeutic use, Female, Glucocorticoids therapeutic use, Humans, Immunoglobulins, Intravenous therapeutic use, Immunologic Factors therapeutic use, Mutation, Missense, Pedigree, Sequence Deletion, Severe Combined Immunodeficiency complications, Severe Combined Immunodeficiency drug therapy, Thrombocytopenia complications, Thrombocytopenia drug therapy, Adenosine Deaminase genetics, Agammaglobulinemia genetics, Anemia, Hemolytic, Autoimmune genetics, Intercellular Signaling Peptides and Proteins genetics, Severe Combined Immunodeficiency genetics, Thrombocytopenia genetics
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- 2021
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8. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.
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Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, Bhatia P, Sharma V, Bhattad S, Chengappa KG, Gupta V, Misra DP, Chavan PP, Malaviya S, Dudam R, Sharma B, Kumar S, Bhojwani R, Gupta P, Agarwal V, Sharma K, Singhal M, Rathi M, Nada R, Minz RW, Chaturvedi V, Aggarwal A, Handa R, Grossi A, Gattorno M, Huang Z, Wang J, Jois R, Negi VS, Khubchandani R, Jain S, Arostegui JI, Chambers EP, Hershfield MS, Aksentijevich I, Zhou Q, and Lee PY
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- Adenosine Deaminase genetics, Adenosine Deaminase metabolism, Adolescent, Adult, Agammaglobulinemia diagnosis, Agammaglobulinemia drug therapy, Agammaglobulinemia genetics, Age of Onset, Anemia physiopathology, Child, Child, Preschool, Delayed Diagnosis, Female, Glucocorticoids therapeutic use, Hemorrhage physiopathology, Humans, India, Infant, Infarction physiopathology, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Leukopenia physiopathology, Lung Diseases physiopathology, Male, Myocarditis physiopathology, Pancreatic Diseases physiopathology, Retrospective Studies, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency drug therapy, Severe Combined Immunodeficiency genetics, Stroke physiopathology, Treatment Outcome, Tumor Necrosis Factor Inhibitors therapeutic use, Vasculitis physiopathology, Young Adult, Agammaglobulinemia physiopathology, Gastrointestinal Diseases physiopathology, Hematologic Diseases physiopathology, Kidney Diseases physiopathology, Nervous System Diseases physiopathology, Severe Combined Immunodeficiency physiopathology
- Abstract
Objective: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India., Methods: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects., Results: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported., Conclusion: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults., (© 2020, American College of Rheumatology.)
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- 2021
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9. Morbidity in an adenosine deaminase-deficient patient during 27 years of enzyme replacement therapy.
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Grunebaum E, Reid B, Naqvi A, Hershfield MS, Kim VH, Muller MP, Hicks LK, Lee E, Betschel S, and Roifman CM
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- Adenosine Deaminase therapeutic use, Adult, Agammaglobulinemia epidemiology, Female, Humans, Morbidity, Severe Combined Immunodeficiency epidemiology, Adenosine Deaminase deficiency, Agammaglobulinemia drug therapy, Enzyme Replacement Therapy, Severe Combined Immunodeficiency drug therapy
- Abstract
Introduction: Adenosine deaminase (ADA) deficiency causes severe immunodeficiency that is lethal in infancy. Enzyme replacement therapy (ERT) can improve the metabolic, immune and non-immune abnormalities in patients prior to transplantation, however, its benefits over extended periods are not well characterized. We describe a 28-year-old female who received ERT for 27 years. She suffered from EBV negative B cell lymphoma of the hip at 14 years of age and Guillian-Barre Syndrome 2 years later. At 22 years of age, she experienced a gastrointestinal infection with Mycobacterium genavense. At 26 years of age, lymphoma reoccurred with multiple liver lesions followed by Mycobacterium genavense infection with dissemination to the brain. Throughout this period, ADA activity in the plasma was within the therapeutic range. Repeated evaluations demonstrated very low lymphocyte counts and impaired T cell function., Conclusions: ERT might be insufficient to maintain normal immunity over extended periods in some ADA-deficient patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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10. Homozygous Splice ADA2 Gene Mutation Causing ADA-2 Deficiency.
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Chong-Neto HJ, Segundo GRS, Bandeira M, Chong-Silva DC, Rosário CS, Riedi CA, Hershfield MS, Ochs H, Torgerson T, and Rosário NA
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- Adenosine Deaminase genetics, Adenosine Deaminase immunology, Agammaglobulinemia diagnosis, Agammaglobulinemia immunology, Child, Female, Homozygote, Humans, Intercellular Signaling Peptides and Proteins deficiency, Loss of Function Mutation, Mutation, RNA Splicing genetics, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency immunology, Adenosine Deaminase deficiency, Agammaglobulinemia genetics, Intercellular Signaling Peptides and Proteins genetics, RNA Splice Sites genetics, RNA Splicing immunology, Severe Combined Immunodeficiency genetics
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- 2019
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11. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency.
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Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, and Grunebaum E
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- Adenosine Deaminase therapeutic use, Animals, Consensus, Enzyme Replacement Therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Adenosine Deaminase deficiency, Agammaglobulinemia therapy, Severe Combined Immunodeficiency therapy
- Abstract
Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
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- 2019
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12. Disrupted N-linked glycosylation as a disease mechanism in deficiency of ADA2.
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Lee PY, Huang Y, Zhou Q, Schnappauf O, Hershfield MS, Li Y, Ganson NJ, Sampaio Moura N, Delmonte OM, Stone SS, Rivkin MJ, Pai SY, Lyons T, Sundel RP, Hsu VW, Notarangelo LD, Aksentijevich I, and Nigrovic PA
- Subjects
- Adenosine Deaminase blood, Adenosine Deaminase genetics, Agammaglobulinemia blood, Child, Preschool, Female, Glycosylation, Humans, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins genetics, Mutation, Severe Combined Immunodeficiency blood, Adenosine Deaminase deficiency, Agammaglobulinemia genetics, Intercellular Signaling Peptides and Proteins deficiency, Severe Combined Immunodeficiency genetics
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- 2018
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13. Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation.
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Hsu AP, West RR, Calvo KR, Cuellar-Rodriguez J, Parta M, Kelly SJ, Ganson NJ, Hershfield MS, Holland SM, and Hickstein DD
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- Adenosine Deaminase genetics, Adolescent, Adult, Agammaglobulinemia genetics, Child, Child, Preschool, Codon, Nonsense, Diagnostic Errors, Female, Humans, Intercellular Signaling Peptides and Proteins genetics, Male, Severe Combined Immunodeficiency genetics, Transplantation, Haploidentical, Exome Sequencing, Young Adult, Adenosine Deaminase deficiency, Agammaglobulinemia diagnosis, Agammaglobulinemia therapy, GATA2 Transcription Factor deficiency, Hematopoietic Stem Cell Transplantation, Intercellular Signaling Peptides and Proteins deficiency, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency therapy
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- 2016
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14. A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient.
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Tartibi HM, Hershfield MS, and Bahna SL
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- Follow-Up Studies, Humans, Infant, Male, Young Adult, Adenosine Deaminase deficiency, Adenosine Deaminase therapeutic use, Agammaglobulinemia drug therapy, Enzyme Replacement Therapy, Severe Combined Immunodeficiency drug therapy
- Abstract
Severe combined immunodeficiency (SCID) is a fatal childhood disease unless immune reconstitution is performed early in life, with either hematopoietic stem cell transplantation or gene therapy. One of its subtypes is caused by adenosine deaminase (ADA) enzyme deficiency, which leads to the accumulation of toxic metabolites that impair lymphocyte development and function. With the development of polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme replacement therapy, many ADA-deficient children with SCID who could not receive a hematopoietic stem cell transplantation or gene therapy survived and had longer and healthier lives. We report a 24-year course of treatment in a patient who was diagnosed with ADA deficiency at 4 months of age. The patient was treated with PEG-ADA, which was the only therapy available for him. The patient's plasma ADA level was regularly monitored and the PEG-ADA dose adjusted accordingly. This treatment has resulted in near-normalization of lymphocyte counts, and his clinical course has been associated with only minor to moderate infections. Thus far, he has had no manifestations of autoimmune or lymphoproliferative disorders. This patient is among the longest to be maintained on PEG-ADA enzyme replacement therapy., (Copyright © 2016 by the American Academy of Pediatrics.)
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- 2016
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15. Impulse oscillometry identifies peripheral airway dysfunction in children with adenosine deaminase deficiency.
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Komarow HD, Sokolic R, Hershfield MS, Kohn DB, Young M, Metcalfe DD, and Candotti F
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- Adolescent, Child, Child, Preschool, Female, Humans, Male, Prospective Studies, Spirometry, Adenosine Deaminase deficiency, Agammaglobulinemia diagnosis, Lung physiology, Lung Diseases diagnosis, Oscillometry methods, Severe Combined Immunodeficiency diagnosis
- Abstract
Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is characterized by impaired T-, B- and NK-cell function. Affected children, in addition to early onset of infections, manifest non-immunologic symptoms including pulmonary dysfunction likely attributable to elevated systemic adenosine levels. Lung disease assessment has primarily employed repetitive radiography and effort-dependent functional studies. Through impulse oscillometry (IOS), which is effort-independent, we prospectively obtained objective measures of lung dysfunction in 10 children with ADA-SCID. These results support the use of IOS in the identification and monitoring of lung function abnormalities in children with primary immunodeficiencies.
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- 2015
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16. Effects of enzyme replacement therapy on immune function in ADA deficiency patient.
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Nakazawa Y, Kawai T, Uchiyama T, Goto F, Watanabe N, Maekawa T, Ishiguro A, Okuyama T, Otsu M, Yamada M, Hershfield MS, Ariga T, and Onodera M
- Subjects
- Adenosine Deaminase blood, Adenosine Deaminase immunology, Adenosine Deaminase metabolism, Adenosine Deaminase therapeutic use, Adolescent, Agammaglobulinemia enzymology, Agammaglobulinemia immunology, B-Lymphocytes drug effects, B-Lymphocytes immunology, B-Lymphocytes metabolism, Female, Flow Cytometry, Humans, Lymphocyte Count, Severe Combined Immunodeficiency enzymology, Severe Combined Immunodeficiency immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Treatment Outcome, Adenosine Deaminase deficiency, Agammaglobulinemia drug therapy, Enzyme Replacement Therapy methods, Severe Combined Immunodeficiency drug therapy
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- 2015
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17. Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience.
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Baffelli R, Notarangelo LD, Imberti L, Hershfield MS, Serana F, Santisteban I, Bolda F, Porta F, and Lanfranchi A
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- Adenosine Deaminase genetics, Agammaglobulinemia epidemiology, Agammaglobulinemia therapy, Child, Preschool, Consanguinity, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Infant, Italy, Male, Mutation genetics, Retrospective Studies, Roma, Severe Combined Immunodeficiency epidemiology, Severe Combined Immunodeficiency therapy, Treatment Outcome, Adenosine Deaminase deficiency, Adenosine Deaminase metabolism, Agammaglobulinemia diagnosis, Enzyme Replacement Therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Severe Combined Immunodeficiency diagnosis
- Abstract
Purpose: We carried out a retrospective analysis of 27 patients with Adenosine Deaminase (ADA) deficiency diagnosed in a single center from 1997 to the 2013, for evaluating whether data regarding types of disease-inducing mutations, biochemical and immunological features as well as clinical outcomes of patients treated with enzyme replacement or transplantation, were comparable to those obtained in multicenter studies., Methods: The ADA deficiency diagnosis was performed with biochemical, immunological and molecular techniques. Ten patients treated with hematopoietic stem cell transplantation and three in treatment with enzyme replacement were followed up in our center., Results: Twenty-four different mutations were identified and five were not previously reported. Identical mutations were found among patients from the same Romani ethnic group or from the same geographical region. A more rapid recovery was observed in enzyme replacement treated patients in comparison with those transplanted that, however, showed a continuous and long-lasting improvement both in terms of immune and metabolic recovery., Conclusion: The data obtained in our single center are comparable with those that have been reported in multicenter surveys.
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- 2015
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18. Outcomes in two Japanese adenosine deaminase-deficiency patients treated by stem cell gene therapy with no cytoreductive conditioning.
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Otsu M, Yamada M, Nakajima S, Kida M, Maeyama Y, Hatano N, Toita N, Takezaki S, Okura Y, Kobayashi R, Matsumoto Y, Tatsuzawa O, Tsuchida F, Kato S, Kitagawa M, Mineno J, Hershfield MS, Bali P, Candotti F, Onodera M, Kawamura N, Sakiyama Y, and Ariga T
- Subjects
- Adenosine Deaminase immunology, Adenosine Deaminase therapeutic use, Adolescent, Agammaglobulinemia diagnosis, Agammaglobulinemia immunology, Age of Onset, Cell Differentiation, Child, Preschool, Enzyme Activation, Enzyme Replacement Therapy, Gammaretrovirus genetics, Gene Expression, Genetic Vectors genetics, Hematopoiesis, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Immunity, Immunophenotyping, Infant, Infant, Newborn, Japan, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism, Mutation, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency immunology, Transduction, Genetic, Transgenes, Treatment Outcome, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Agammaglobulinemia genetics, Agammaglobulinemia therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy
- Abstract
Objective: We here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency., Patients and Methods: Pt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34(+) cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the γ-retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed., Results: Treatment was well tolerated, and no serious adverse events were observed. Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in pts 1 and 2, peaked at 408/mm(3) and 1248/mm(3), approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential., Conclusions: Outcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT.
- Published
- 2015
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19. Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency.
- Author
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Van Eyck L Jr, Hershfield MS, Pombal D, Kelly SJ, Ganson NJ, Moens L, Frans G, Schaballie H, De Hertogh G, Dooley J, Bossuyt X, Wouters C, Liston A, and Meyts I
- Subjects
- Adenosine Deaminase blood, Adenosine Deaminase genetics, Adenosine Deaminase immunology, Agammaglobulinemia blood, Agammaglobulinemia genetics, Agammaglobulinemia immunology, Child, Preschool, Humans, Infant, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins genetics, Interleukin-6 blood, Lymphocyte Count, Male, Mutation, Phenotype, Severe Combined Immunodeficiency blood, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency immunology, Adenosine Deaminase deficiency, Agammaglobulinemia therapy, Hematopoietic Stem Cell Transplantation, Intercellular Signaling Peptides and Proteins deficiency, Severe Combined Immunodeficiency therapy
- Published
- 2015
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20. Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed-onset adenosine deaminase deficiency.
- Author
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Kanegane H, Taneichi H, Nomura K, Wada T, Yachie A, Imai K, Ariga T, Santisteban I, Hershfield MS, and Miyawaki T
- Subjects
- Adenosine Deaminase immunology, Agammaglobulinemia immunology, Busulfan administration & dosage, Child, Preschool, Humans, Living Donors, Male, Severe Combined Immunodeficiency immunology, Time Factors, Treatment Outcome, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Adenosine Deaminase deficiency, Agammaglobulinemia therapy, Bone Marrow Transplantation methods, Severe Combined Immunodeficiency therapy, Transplantation Conditioning methods
- Abstract
In this case report, we describe successful BMT with RIC in a patient with delayed-onset ADA deficiency. A three-yr-old Japanese boy was diagnosed with delayed-onset ADA deficiency because of recurrent bronchitis, bronchiectasia, and lymphopenia. In addition, autoimmune thyroiditis and neutropenia were present. At four yr of age, he underwent BMT with a RIC regimen, including busulfan and fludarabine, from an HLA-identical healthy sister. Engraftment after BMT was uneventful without GVHD. Decreased ADA levels in blood immediately increased following BMT, and the patient was disease-free 13 months after BMT. These results suggest that BMT with RIC may sufficiently restore immune regulation in delayed-onset ADA deficiency. A longer follow-up period is needed to confirm these observations., (© 2012 John Wiley & Sons A/S.)
- Published
- 2013
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21. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.
- Author
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Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, Schurman SH, Garabedian E, Kesserwan C, Jagadeesh GJ, Fu PY, Gschweng E, Cooper A, Tisdale JF, Weinberg KI, Crooks GM, Kapoor N, Shah A, Abdel-Azim H, Yu XJ, Smogorzewska M, Wayne AS, Rosenblatt HM, Davis CM, Hanson C, Rishi RG, Wang X, Gjertson D, Yang OO, Balamurugan A, Bauer G, Ireland JA, Engel BC, Podsakoff GM, Hershfield MS, Blaese RM, Parkman R, and Kohn DB
- Subjects
- Adenosine Deaminase deficiency, Adolescent, Antigens, CD34 metabolism, Child, Child, Preschool, Female, Humans, Infant, Male, Retroviridae genetics, Transduction, Genetic, Transplantation Conditioning, Young Adult, Agammaglobulinemia therapy, Bone Marrow Transplantation methods, Genetic Therapy methods, Genetic Vectors, Hematopoietic Stem Cell Transplantation methods, Severe Combined Immunodeficiency therapy
- Abstract
We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.
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- 2012
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22. Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis.
- Author
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Nakaoka H, Kanegane H, Taneichi H, Miya K, Yang X, Nomura K, Takezaki S, Yamada M, Ohara O, Kamae C, Imai K, Nonoyama S, Wada T, Yachie A, Hershfield MS, Ariga T, and Miyawaki T
- Subjects
- Adenosine Deaminase deficiency, Adenosine Deaminase immunology, Adenosine Deaminase metabolism, Agammaglobulinemia diagnosis, Agammaglobulinemia immunology, Autoantibodies blood, Autoantibodies immunology, Child, Preschool, Encephalomyelitis, Acute Disseminated diagnosis, Encephalomyelitis, Acute Disseminated immunology, Humans, Immunoglobulin Isotypes blood, Immunoglobulin Isotypes immunology, Lymphocyte Count, Magnetic Resonance Imaging, Male, Neuroimaging, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency immunology, Agammaglobulinemia complications, Encephalomyelitis, Acute Disseminated etiology, Severe Combined Immunodeficiency complications
- Abstract
Acute disseminated encephalomyelitis (ADEM) is a monophasic, immune-mediated demyelinating disorder that can appear after either immunizations or, more often, infections. Magnetic resonance imaging of patients shows inflammatory lesions in the brain and spinal cord. An immune-mediated mechanism may play a role in this disease, although its precise pathogenesis remains unclear. In this study, a 2-year-old boy presented with ADEM, and he showed improvement on treatment with high-dose intravenous corticosteroids. At the age of 3 years, the presence of recurrent bronchitis, bronchiectasia, and lymphopenia suggested that the patient was suffering from combined immunodeficiency. The patient was finally diagnosed with delayed onset adenosine deaminase deficiency. Delayed onset adenosine deaminase deficiency is frequently associated with autoimmune diseases, including thyroiditis and cytopenia, both of which were observed in the patient. The ADEM in this patient may be a presentation of delayed onset adenosine deaminase deficiency.
- Published
- 2012
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23. Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency.
- Author
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Sokolic R, Maric I, Kesserwan C, Garabedian E, Hanson IC, Dodds M, Buckley R, Issekutz AC, Kamani N, Shaw K, Tan B, Bali P, Hershfield MS, Kohn DB, Wayne AS, and Candotti F
- Subjects
- Adenosine Deaminase genetics, Adolescent, Adult, Agammaglobulinemia therapy, Bone Marrow Transplantation, Child, Child, Preschool, Female, Genetic Therapy, Humans, Infant, Male, Myelodysplastic Syndromes therapy, Severe Combined Immunodeficiency therapy, Young Adult, Adenosine Deaminase deficiency, Agammaglobulinemia complications, Bone Marrow pathology, Myelodysplastic Syndromes etiology, Severe Combined Immunodeficiency complications
- Abstract
Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319.
- Published
- 2011
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24. Diagnosis of deficiency of adenosine deaminase type 2 in adulthood.
- Author
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Betrains, A, Staels, F, Moens, L, Delafontaine, S, Hershfield, MS, Blockmans, D, Liston, A, Humblet-Baron, S, Meyts, I, Schrijvers, R, and Vanderschueren, S
- Subjects
ADENOSINE deaminase ,AGAMMAGLOBULINEMIA ,ADULTS ,SYMPTOMS ,INTESTINAL perforation ,DIAGNOSIS ,HEMATOPOIETIC stem cell transplantation - Abstract
(D) Schematic representation of clinical events for each patient We report on three patients who were diagnosed with DADA2 in adulthood. (B) Cellulitis of the hand during a neutropenic phase in patient 1 (left); small bowel perforation on laparoscopy in patient 2 (middle); cicatricial alopecia in patient 3 (right). Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease caused by loss-of-function mutations in I ADA2 i that result in a monogenic vasculitis syndrome ([1]). [Extracted from the article]
- Published
- 2021
- Full Text
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