RESUMO
Yellow fever vaccine (YFV) is a live attenuated vaccine that can cause a mild infection in immunocompetent patients. However, it may not be self-limiting in patients with inborn errors of immunity (IEI) and may be the first and most severe presentation in these patients. A 10-month-old female infant sought emergency care presenting fever for three days and diffuse exanthema. She was a previous healthy child of consanguineous parents. The child had received YFV 28 days before the onset of symptoms. Upon hospital admission, petechial rash on the limbs and hepatosplenomegaly were noted on physical exam. Laboratory tests showed thrombocytopenia, increased serum aminotransferases and elevated gamma-glutamyl transferase (GGT) and alkaline phosphatase levels. During hospitalization she developed hypoactivity, drowsiness, and hypotonia. The possibility of viscerotropic and neurotropic vaccine associated disease was suspected and a possible primary immunodeficiency disease considered. The patient was tested for antibodies against the yellow fever virus (MAC ELISA) on serum and cerebrospinal fluid (CSF) samples, showing positive IgM results. Immunophenotyping showed low levels of lymphocytes and absence of T-cell receptor excision circles (TREC), leading to diagnose of severe combined immunodeficiency disease (SCID). Despite treatment, after 35 days of hospitalization, she evolved to cardiorespiratory arrest and death. Serious adverse events after administration of the YFV are rare and associated with neurological or visceral involvement in most cases. The unfavorable outcome highlights the importance of neonatal screening for SCID and the clinical suspicion of primary immunodeficiencies in infants who have serious adverse events to live virus vaccines.
Assuntos
Imunodeficiência Combinada Severa , Vacina contra Febre Amarela , Humanos , Feminino , Vacina contra Febre Amarela/efeitos adversos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/imunologia , Lactente , Evolução FatalRESUMO
Adenosine deaminase 2 (ADA2) deficiency is an autosomal recessively inherited autoinflammatory disorder caused by loss-of-function mutations in the ADA2 gene. Although the pathogenesis involves the triggering of a proinflammatory cascade due to increased production of inflammatory cytokines such as tumor necrosis factor (TNF)-α and dysregulation of neutrophil extracellular trap formation resulting from an excess accumulation of extracellular adenosine, the pathogenetic mechanism still needs further clarification due to the broad clinical spectrum. In addition to the initially described vasculitis-related symptoms, hematological, immunological, and autoinflammatory symptoms are now well recognized. The diagnosis is made by demonstration of pathogenic variants of ADA2 with biallelic loss of function and identification of low plasma ADA2 catalytic activity. Currently, TNF-α inhibitors are the treatment of choice for controlling vasculitis manifestations and preventing strokes. However, in patients presenting with severe hematologic findings, TNF-α inhibitors are not the treatment of choice and hematopoietic stem cell transplantation has been shown to be successful in selected cases. Recombinant ADA2 protein and gene therapy are promising treatment modalities for the future. In conclusion, ADA2 deficiency has a broad phenotype and should be considered in the differential diagnosis of different clinical situations. In this review, we summarize the disease manifestations of ADA2 deficiency and available treatment options.
Assuntos
Adenosina Desaminase , Humanos , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/terapia , Agamaglobulinemia/genética , Transplante de Células-Tronco Hematopoéticas , Fenótipo , Terapia Genética/métodos , Gerenciamento Clínico , Fator de Necrose Tumoral alfa , Mutação , Imunodeficiência Combinada Severa , Doenças Hereditárias AutoinflamatóriasRESUMO
We present the case of a 3-month-old immunocompromised infant who developed a vascular catheter-related bloodstream infection caused by Pantoea septica. Susceptibility testing results for this isolate and 10 additional clinical strains are provided to help define the susceptibility profile of this infrequently recovered organism.
Assuntos
Bacteriemia , Infecções por Enterobacteriaceae , Pantoea , Imunodeficiência Combinada Severa , Humanos , Bacteriemia/microbiologia , Bacteriemia/tratamento farmacológico , Bacteriemia/diagnóstico , Lactente , Pantoea/isolamento & purificação , Imunodeficiência Combinada Severa/complicações , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/diagnóstico , Infecções por Enterobacteriaceae/tratamento farmacológico , Masculino , Testes de Sensibilidade Microbiana , Antibacterianos/uso terapêutico , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/tratamento farmacológico , Infecções Relacionadas a Cateter/diagnóstico , Hospedeiro ImunocomprometidoRESUMO
Early diagnosis and effective management of Primary immunodeficiency diseases (PIDs), particularly severe combined immunodeficiency (SCID), play a crucial role in minimizing associated morbidities and mortality. Newborn screening (NBS) serves as a valuable tool in facilitating these efforts. Timely detection and diagnosis are essential for swiftly implementing isolation measures and ensuring prompt referral for definitive treatment, such as allogeneic hematopoietic stem cell transplantation. The utilization of comprehensive protocols and screening assays, including T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), is essential in facilitating early diagnosis of SCID and other PIDs, but their successful application requires clinical expertise and proper implementation strategy. Unfortunately, a notable challenge arises from insufficient funding for the treatment of PIDs. To address these issues, a collaborative approach is imperative, involving advancements in technology, a well-functioning healthcare system, and active engagement from stakeholders. The integration of these elements is essential for overcoming the existing challenges in NBS for PIDs. By fostering synergy between technology providers, healthcare professionals, and governmental stakeholders, we can enhance the efficiency and effectiveness of early diagnosis and intervention, ultimately improving outcomes for individuals with PIDs.
Assuntos
Estudos de Viabilidade , Triagem Neonatal , Imunodeficiência Combinada Severa , Humanos , Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Recém-Nascido , Malásia , Países em Desenvolvimento , Diagnóstico PrecoceRESUMO
Store-operated calcium entry (SOCE) plays a crucial role in maintaining cellular calcium homeostasis. This mechanism involves proteins, such as stromal interaction molecule 1 (STIM1) and ORAI1. Mutations in the genes encoding these proteins, especially STIM1, can lead to various diseases, including CRAC channelopathies associated with severe combined immunodeficiency. Herein, we describe a novel homozygous mutation, NM_003156 c.792-3C > G, in STIM1 in a patient with a clinical profile of CRAC channelopathy, including immune system deficiencies and muscle weakness. Functional analyses revealed three distinct spliced forms in the patient cells: wild-type, exon 7 skipping, and intronic retention. Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function. We developed an antisense oligonucleotide treatment that improves STIM1 splicing and highlighted its potential as a therapeutic approach. Our findings provide insights into the complex effects of STIM1 mutations and shed light on the multifaceted clinical presentation of the patient.
Assuntos
Cálcio , Mutação , Proteínas de Neoplasias , Molécula 1 de Interação Estromal , Humanos , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Cálcio/metabolismo , Canalopatias/genética , Masculino , Canais de Cálcio Ativados pela Liberação de Cálcio/genética , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Feminino , Imunodeficiência Combinada Severa/genética , Proteína ORAI1/genética , Proteína ORAI1/metabolismoRESUMO
Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.
Assuntos
Mutação , Doenças da Imunodeficiência Primária , Receptores CXCR4 , Transdução de Sinais , Verrugas , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Humanos , Doenças da Imunodeficiência Primária/genética , Verrugas/genética , Animais , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Trombocitopenia/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismoRESUMO
For successful engraftment of donor hematopoietic stem cells (HSC), conditioning with chemotherapy and/or radiation prior to hematopoietic cell transplantation (HCT) has been required to open marrow niche space and minimize the risk of immune rejection. Briquilimab, a humanized IgG1 monoclonal antibody that blocks the interaction between the c-Kit receptor and stem cell factor on various C-Kit expressing tissues including HSC, is a potential nonmyeloablative conditioning agent in clinical development for patients with severe combined immunodeficiency (SCID), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). This study aimed to characterize pharmacokinetics (PK) and develop a population PK model of briquilimab after single intravenous infusions of 4 different doses in patients with SCID, MDS, or AML receiving HCT. The PK data was collected from 2 different studies: JAS-BMT-CP-001 and JSP-CP-003. JAS-BMT-CP-001 is a phase 1/2 open-label study of briquilimab as a conditioning agent prior to allogenic HCT in SCID patients. The participants received single intravenous infusions of 0.1, 0.3, 0.6, or 1.0 mg/kg. JSP-CP-003 was a phase 1a/b open-label study of briquilimab in combination with a standard conditioning regimen of low dose total body irradiation and fludarabine in MDS or AML subjects undergoing HCT. The participants received a single intravenous dose of 0.6 mg/kg briquilimab. In both studies, briquilimab PK samples were obtained at pre-treatment, 5 minutes post-end of infusion, 4- and 24-hours post-start of infusion, any time between 2 days and 30 days postinfusion, and on the day of HCT prior to donor cell infusion.The population PK model was developed using the PK data from these 2 clinical studies, and the effect of participants' baseline characteristics on the briquilimab PK was evaluated. PK simulations were performed using the developed PK model to calculate the time to reach target concentrations for HCT. A total of 49 participants (21 SCID adult and pediatric participants with a median age of 12 yr and 28 MDS/AML adult participants with a median age of 70 yr) were included in the PK analysis. A 2-compartment model with combined linear and non-linear elimination best described the PK of briquilimab. Body weight was determined as the sole covariate of the PK parameters among the explored covariates. For a typical subject with a body weight 70 kg, the estimated parameters for clearance, maximum metabolic rate of Michaelis Menten elimination, Michaelis Menten constant, central volume, peripheral volume, and intercompartmental clearance were 17.6 mL/h, 51,434.8 ng/h, 71.5 ng/mL, 3444.0 mL, 1613.3 mL, and 21.2 mL/h, respectively. The median time to reach target concentrations of 500, 1000, and 2000 ng/mL after a single dose of 0.6 mg/kg was calculated as 12.3, 10.4, and 7.7 days, respectively. The PK of intravenous briquilimab was characterized in subjects with SCID, MDS, or AML receiving HCT, and a population PK model was developed to estimate briquilimab clearance to use as a guide to the timing of donor cell infusion post-briquilimab. Body weight was identified as a significant covariate on elimination and volume of distribution of briquilimab.
Assuntos
Anticorpos Monoclonais Humanizados , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Imunodeficiência Combinada Severa , Condicionamento Pré-Transplante , Humanos , Condicionamento Pré-Transplante/métodos , Leucemia Mieloide Aguda/terapia , Imunodeficiência Combinada Severa/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Síndromes Mielodisplásicas/terapia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Adulto JovemAssuntos
Adenosina Desaminase , Imunodeficiência Combinada Severa , Humanos , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/diagnóstico , Agamaglobulinemia/terapia , Agamaglobulinemia/genética , Agamaglobulinemia/tratamento farmacológico , Masculino , Lactente , Feminino , Terapia de Reposição de EnzimasRESUMO
BACKGROUND: Severe combined immunodeficiency secondary to adenosine deaminase deficiency is rare. The deficiency of this enzyme results in the accumulation of substrates in the tissues, including the brain. Clinical signs of neurological involvement may include seizures, neurodevelopmental disorders, hypotonia, and sensorineural hearing loss. Hematopoietic stem cell transplantation corrects the failure of the immune system but not the neurological involvement. OBJECTIVES: To describe the spectrum of neurological complications identified in a series of children with severe combined immunodeficiency due to adenosine deaminase deficiency. Additionally, we propose a neurological approach including electrophysiological, radiological, and neurocognitive studies to address this group of children in an efficient and timely manner. METHODS: A descriptive, observational, retro-, and prospective analysis of patients with a confirmed immunological diagnosis seen between 1996 and 2021 and referred to the Department of Neurology for neurological evaluation was conducted. RESULTS: Ten patients met the inclusion criteria. The median age at diagnosis was 4 months (range, 1-36 months). All patients had neurodevelopmental delay with hypotonia in six, language delay in three, sensorineural hearing loss in four, and spastic paraparesis in one patient. Two children developed an epileptic syndrome, consisting of generalized epilepsy in one and focal epilepsy in the other. Neuroimaging showed brain calcifications in the basal ganglia and/or centrum semiovale in four patients and enlarged subarachnoid spaces in two other patients. CONCLUSION: In this pediatric series, the rate of neurological involvement associated with abnormalities on neuroimaging was high. Although this involvement could be related to accumulation of adenosine metabolites in the central nervous system, the possibility of associated chronic infections should be ruled out. Given the neurological manifestations, it is important to involve the pediatric neurologist in the multidisciplinary follow-up team.
Assuntos
Adenosina Desaminase , Agamaglobulinemia , Imunodeficiência Combinada Severa , Humanos , Adenosina Desaminase/deficiência , Pré-Escolar , Lactente , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Feminino , Masculino , Agamaglobulinemia/complicações , Estudos Prospectivos , Estudos RetrospectivosRESUMO
PURPOSE OF REVIEW: In this review, an update is provided on the current knowledge and pending questions about human adenosine deaminase type 2 deficiency. Patients have vasculitis, immunodeficiency and some have bone marrow failure. Although the condition was described ten years ago, the pathophysiology is incompletely understood RECENT FINDINGS: Endothelial instability due to increased proinflammatory macrophage development is key to the pathophysiology. However, the physiological role of ADA2 is a topic of debate as it is hypothesized that ADA2 fulfils an intracellular role. Increasing our knowledge is urgently needed to design better treatments for the bone marrow failure. Indeed, TNFi treatment has been successful in treating DADA2, except for the bone marrow failure. Major advances have been made in our understanding of DADA2. More research is needed into the physiological role of ADA2.
Assuntos
Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Humanos , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Doenças Hereditárias AutoinflamatóriasRESUMO
BACKGROUND: Major histocompatibility complex class II deficiency, a combined immunodeficiency, results from loss of HLA class II expression on antigen-presenting cells. Currently, hematopoietic stem cell transplantation stands as the sole curative approach, although factors influencing patient outcomes remain insufficiently explored. OBJECTIVES: To elucidate the clinical, immunologic, and genetic profiles associated with MHC-II deficiency and identify prognostic indicators that affect survival rates. METHODS: In this multicenter retrospective analysis, we gathered data from 35 patients with a diagnosis of MHC-II deficiency across 12 centers in Turkey. We recorded infection histories, gene mutations, immune cell subsets, and surface MHC-II expression on blood cells. We conducted survival analyses to evaluate the impact of various factors on patient outcomes. RESULTS: Predominant symptoms observed were pneumonia (n = 29; 82.9%), persistent diarrhea (n = 26; 74.3%), and severe infections (n = 26; 74.3%). The RFXANK gene mutation (n = 9) was the most frequent, followed by mutations in RFX5 (n = 8), CIITA (n = 4), and RFXAP (n = 2) genes. Patients with RFXANK mutations presented with later onset and diagnosis compared with those with RFX5 mutations (P =.0008 and .0006, respectively), alongside a more significant diagnostic delay (P = .020). A notable founder effect was observed in five patients with a specific RFX5 mutation (c.616G>C). The overall survival rate for patients was 28.6% (n = 10), showing a significantly higher proportion in individuals with hematopoietic stem cell transplantation (n = 8; 80%). Early death and higher CD8+ T-cell counts were observed in patients with the RFX5 mutations compared with RFXANK-mutant patients (P = .006 and .009, respectively). CONCLUSIONS: This study delineates the genetic and clinical panorama of MHC-II deficiency, emphasizing the prevalence of specific gene mutations such as RFXANK and RFX5. These insights facilitate early diagnosis and prognosis refinement, significantly contributing to the management of MHC-II deficiency.
Assuntos
Proteínas de Ligação a DNA , Mutação , Fatores de Transcrição de Fator Regulador X , Humanos , Masculino , Feminino , Pré-Escolar , Lactente , Estudos Retrospectivos , Criança , Proteínas de Ligação a DNA/genética , Fatores de Transcrição de Fator Regulador X/genética , Fatores de Transcrição/genética , Turquia/epidemiologia , Proteínas Nucleares/genética , Transativadores/genética , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe II/genética , Pneumonia/genética , Adolescente , Estudos de Coortes , Diarreia/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , PrognósticoRESUMO
BACKGROUND: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient outcomes. In 2013, Ontario became the first Canadian province to perform newborn screening (NBS) for SCID by T cell receptor excision circles (TRECs) analysis, a surrogate marker of thymic function and lymphocyte maturation. METHODS: This retrospective study reports on nearly 10 years of NBS for SCID at a quaternary referral centre. RESULTS: From August 2013 to April 2023, our centre's densely populated catchment area flagged 162 newborns with low TRECs levels, including 10 cases with SCID. Follow-up revealed other causes of low TRECs, including non-SCID T cell lymphopenia (secondary/reversible or idiopathic causes, and syndromic conditions) and prematurity. A small number of cases with normal repeat TRECs levels and/or T cell subsets were also flagged. Province-wide data from around this period revealed at least 24 diagnosed cases of SCID or Leaky SCID. CONCLUSIONS: This is the first report of NBS outcomes in a Canadian province describing the causative genetic defects, and the non-SCID causes of a positive NBS for SCID.
Assuntos
Triagem Neonatal , Imunodeficiência Combinada Severa , Humanos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/epidemiologia , Imunodeficiência Combinada Severa/imunologia , Recém-Nascido , Triagem Neonatal/métodos , Ontário/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linfopenia/genética , Linfopenia/diagnósticoRESUMO
BACKGROUND: Artemis deficiency is an autosomal recessive disorder characterized by a combined immunodeficiency with increased cellular radiosensitivity. In this review, the clinical and genetic characteristics of 15 patients with DCLRE1C variants are presented. METHODS: The demographic, clinical, immunologic, and genetic characteristics of patients with confirmed DCLRE1C variants diagnosed between 2013 and 2023 were collected retrospectively. Three patients were evaluated for radiosensitivity by the Comet assay, compared with age- and sex-matched healthy control. RESULTS: Seven patients who had severe infections in the first 6 months of life were diagnosed with T-B-NK+ SCID (severe combined immunodeficiency). Among them, four individuals underwent transplantation, and one of those died due to post-transplant complications in early life. Eight patients had hypomorphic variants. Half of them were awaiting a suitable donor, while the other half had already undergone transplantation. The majority of patients were born into a consanguineous family (93.3%). Most patients had recurrent sinopulmonary infections (73.3%), and one patient had no other infection than an acute respiratory infection before diagnosis. Two patients (13.3%) had autoimmunity in the form of autoimmune hemolytic anemia. Growth retardation was observed in only one patient (6.6%), and no malignancy was detected in the surviving 11 patients during the median (IQR) of 21.5 (12-45) months of follow-up. Three patients who had novel variants exhibited increased radiosensitivity and compromised DNA repair, providing a potential vulnerability to malignant transformation. CONCLUSION: Early diagnosis, radiation avoidance, and careful preparation for transplantation contribute to minimizing complications, enhancing life expectancy, and improving the patient's quality of life.
Assuntos
Proteínas de Ligação a DNA , Tolerância a Radiação , Imunodeficiência Combinada Severa , Humanos , Tolerância a Radiação/genética , Masculino , Feminino , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Lactente , Proteínas de Ligação a DNA/genética , Pré-Escolar , Estudos Retrospectivos , Endonucleases/genética , Proteínas Nucleares/genética , Criança , Estudos de CoortesRESUMO
BACKGROUND: Many newborn screening programs worldwide have introduced screening for diseases using DNA extracted from dried blood spots (DBS). In Germany, DNA-based assays are currently used to screen for severe combined immunodeficiency (SCID), spinal muscular atrophy (SMA), and sickle cell disease (SCD). METHODS: This study analysed the impact of pre-analytic DNA carry-over in sample preparation on the outcome of DNA-based newborn screening for SCID and SMA and compared the efficacy of rapid extraction versus automated protocols. Additionally, the distribution of T cell receptor excision circles (TREC) on DBS cards, commonly used for routine newborn screening, was determined. RESULTS: Contaminations from the punching procedure were detected in the SCID and SMA assays in all experimental setups tested. However, a careful evaluation of a cut-off allowed for a clear separation of true positive polymerase chain reaction (PCR) amplifications. Our rapid in-house extraction protocol produced similar amounts compared to automated commercial systems. Therefore, it can be used for reliable DNA-based screening. Additionally, the amount of extracted DNA significantly differs depending on the location of punching within a DBS. CONCLUSIONS: Newborn screening for SMA and SCID can be performed reliably. It is crucial to ensure that affected newborns are not overlooked. Therefore a carefully consideration of potential contaminating factors and the definition of appropriate cut-offs to minimise the risk of false results are of special concern. It is also important to note that the location of punching plays a pivotal role, and therefore an exact quantification of TREC numbers per µl may not be reliable and should therefore be avoided.
Assuntos
DNA , Atrofia Muscular Espinal , Triagem Neonatal , Imunodeficiência Combinada Severa , Humanos , Triagem Neonatal/métodos , Recém-Nascido , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , DNA/genética , DNA/sangue , DNA/análise , Teste em Amostras de Sangue Seco/métodos , Ensaios de Triagem em Larga Escala/métodos , Reação em Cadeia da Polimerase/métodosRESUMO
BACKGROUND: Severe combined immunodeficiency (SCID) is the most fatal form of inherited primary immunodeficiency disease. Known molecular defect mutations occur in most children with SCID. METHODS: Herein, we report Adenosine Deaminase-SCID (ADA-SCID) using whole-exome sequencing (WES), explore exome mutational landscape and significance for 17 SCID samples, and verify the mutated exon genes using the Gene Expression Omnibus (GEO) datasets. A total of 250 patients, who were hospitalized at the Neonatal Intensive Care Unit (NICU) of The Seventh Medical Center of the PLA General Hospital for 3 years (from 2017 to 2020), were screened for SCID. We collected mutated genes from the WES data of 17 SCID children. GSE609 and GSE99176 cohorts were used to identify the expressions of mutated exon genes and molecular features in SCID. Gene set variation analyses (GSVA) and correlation analyses were performed. RESULTS: The detection rate with approximately 6.8 % (17/250) of SCID is high in the NICU. A total of 16 genes were identified among 17 SCID samples, of which the Top 2 genes (MUC6 and RP11-683L23.1) might be crucial in the progression of SCID with 94 % mutation frequency. Furthermore, CNN2 and SCGB1C1 had significant co-mutations and may cooperate to affect SCID development. Importantly, the phylogenetic tree classification results of 17 SCID samples are more correlated to MUC6 with the most significant mutations. Expression profiles of seven mutated genes and five mutated genes were documented in GSE609 and GSE99176 cohorts based on microarray, respectively. Several immune-related pathways were significantly enriched, and Foxd4, differing from the other four mutated genes, was inversely correlated with the GSVA-enriched pathway. CONCLUSION: Due to its high detection rate (6.8%) and fatality rate (100%), the inclusion of SCID in newborn screening (NBS) is urgent for children in China. The WES successfully identified several common exonic variants (e.g., MUC6) and depicted the feature of mutations and evolution, which will help develop new diagnostic methods for SCID.
Assuntos
Sequenciamento do Exoma , Triagem Neonatal , Imunodeficiência Combinada Severa , Humanos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/diagnóstico , Recém-Nascido , China , Masculino , Feminino , Éxons/genética , Mutação , Adenosina Desaminase/genéticaRESUMO
A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.
Assuntos
DNA Ligase Dependente de ATP , Homozigoto , Mutação , Imunodeficiência Combinada Severa , Feminino , Humanos , Masculino , DNA Ligase Dependente de ATP/genética , DNA Ligase Dependente de ATP/metabolismo , Fibroblastos , Simulação de Dinâmica Molecular , Mutação/genética , Imunodeficiência Combinada Severa/genética , LactenteRESUMO
Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.
Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 18 , Humanos , Masculino , Feminino , Cromossomos Humanos Par 18/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Adulto , Pessoa de Meia-Idade , Idade de Início , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/complicaçõesAssuntos
Vírus da Hepatite E , Hepatite E , Quinase I-kappa B , Hepatite E/diagnóstico , Hepatite E/genética , Hepatite E/imunologia , Hepatite E/terapia , Feminino , Pessoa de Meia-Idade , Quinase I-kappa B/genética , Mutação , Ribavirina/uso terapêutico , Vírus da Hepatite E/fisiologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Evolução Fatal , Hepatite Crônica/diagnóstico , Hepatite Crônica/genética , Hepatite Crônica/imunologia , Hepatite Crônica/terapia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologiaRESUMO
AIOLOS, a vital member of the IKAROS protein family, plays a significant role in lymphocyte development and function through DNA binding and protein-protein interactions. Mutations in the IKZF3 gene, which encodes AIOLOS, lead to a rare combined immunodeficiency often linked with infections and malignancy. In this study, we evaluated a 1-year-4-month-old female patient presenting with recurrent infections, diarrhea, and failure to thrive. Laboratory investigations revealed decreased T lymphocyte and immunoglobulin levels. Through whole-exome and Sanger sequencing, we discovered a de novo mutation in IKZF3 (NM_012481; exon 5 c.571G > C, p.Gly191Arg), corresponding to the third DNA-binding zinc finger region of the encoded protein AIOLOS. Notably, the patient with the AIOLOS G191R mutation showed reduced recent thymic emigrants in naïve CD4+T cells compared to healthy counterparts of the same age, while maintaining normal levels of Th1, Th2, Th17, Treg, and Tfh cells. This mutation also resulted in decreased switched memory B cells and lower CD23 and IgM expression. In vitro studies revealed that AIOLOS G191R does not impact the expression of AIOLOS but compromises its stability, DNA binding and pericentromeric targeting. Furthermore, AIOLOS G191R demonstrated a dominant-negative effect over the wild-type protein. This case represents the first reported instance of a mutation in the third DNA-binding zinc finger region of AIOLOS highlighting its pivotal role in immune cell functionality.
Assuntos
Fator de Transcrição Ikaros , Mutação , Humanos , Fator de Transcrição Ikaros/genética , Feminino , Mutação/genética , Lactente , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/diagnóstico , Sequenciamento do Exoma , Linfócitos B/imunologiaRESUMO
Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain-containing 3 (NUDCD3). Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T -B- SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.