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Proceedings of the National Academy of... Sep 1994X chromosome-linked agammaglobulinemia is a life-threatening disease that involves a failure in normal development of B lymphocytes and is associated with missense...
Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia.
X chromosome-linked agammaglobulinemia is a life-threatening disease that involves a failure in normal development of B lymphocytes and is associated with missense mutations in BTK, a gene encoding a cytoplasmic tyrosine kinase (Bruton agammaglobulinemia tyrosine kinase, EC 2.7.1.112), a member of the Tec family of protein-tyrosine kinases. The genomic organization has been determined by using conventional restriction fragment mapping, extended DNA sequencing, and PCR fragment-sizing approaches. The DNA sequences of the 18 coding exons composing BTK and their flanking-region sequences are reported; an additional exon(s) encodes a 5' untranslated segment. Single-base-pair substitutions and 4-nt deletions resulted in amino acid replacement, premature termination, frameshift, and exon deletion in a group of X chromosome-linked agammaglobulinemia patients exhibiting different clinical presentations and courses. The nature of the mutations is interpreted in terms of the genomic organization of the BTK gene and the disease course in individual patients. Several examples are found in which the same mutation occurs in unrelated patients, and one of these mutations occurs at the same codon that is substituted in the murine form of BTK, resulting in X chromosome-linked immunodeficiency disease. Considerable variation in presentation and disease course in X chromosome-linked agammaglobulinemia appears associated with the nature and position of different missense mutations.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Age Factors; Base Sequence; Child; Child, Preschool; DNA Primers; Exons; Female; Genes; Humans; Infant; Male; Molecular Sequence Data; Point Mutation; Protein-Tyrosine Kinases; X Chromosome
PubMed: 8090769
DOI: 10.1073/pnas.91.19.9062 -
BMJ Case Reports Feb 2021
Topics: Agammaglobulinemia; Genetic Diseases, X-Linked; Humans; Skin Neoplasms
PubMed: 33547107
DOI: 10.1136/bcr-2020-240523 -
Canadian Medical Association Journal Mar 1966
Topics: Adult; Agammaglobulinemia; Antibody Formation; Bronchiectasis; Humans; Hypersensitivity, Delayed; Lymphocytes; Malabsorption Syndromes; Male; Transplantation Immunology
PubMed: 5907322
DOI: No ID Found -
Pediatric Blood & Cancer Apr 2018
Topics: Agammaglobulinemia; Female; Humans; Immunotherapy, Adoptive; Male; Time Factors
PubMed: 29230962
DOI: 10.1002/pbc.26914 -
Clinical and Genetic Study of X-linked Agammaglobulinemia Patients (The Benefit of Early Diagnosis).Iranian Journal of Allergy, Asthma, and... Jun 2020X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by genetic defects in the Bruton tyrosine kinase (Btk) gene. XLA is characterized as an antibody...
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by genetic defects in the Bruton tyrosine kinase (Btk) gene. XLA is characterized as an antibody deficiency by recurrent bacterial infections, the absence of peripheral B cells, and profound reductions in all immunoglobulin isotypes. This study aims to report the clinical and genetic features of five Iranian patients with XLA. Five male cases with recurrent bacterial infection entered this study based on clinical evaluation and Immunological screening tests. The levels of T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) were also measured in dried blood spot (DBS) samples. Sanger sequencing was applied to PCR products of DNA samples of the patients for genetic studies. All patients were from unrelated families with a mean age of 6.7 years (2.5-11) at the time of diagnosis with 4.8 mean years of delay in diagnosis. The most frequent clinical manifestations were recurrent respiratory infections and arthritis. In these patients, five previously reported mutations were found including four mutations (p.Q496X, p.Q497X, p.R520X, and p.R641H) in the Kinase domain besides one mutation (p.L37P) in the pleckstrin homology (PH) domain. Evaluations of KREC and TREC level in patients' DBS showed low-to-undetectable copies of KREC (0-2 copies/3.2mm DBS) with normal copies of TREC. As patients with XLA have complete immunoglobulin defects and develop severe and recurrent infections, early diagnosis would be beneficial for the improvement of their quality of life. The study results may provide valuable information for the diagnosis, genetic counseling and prenatal diagnosis for the patients and their family members and emphasize performing KREC as an early diagnostic test in patients with XLA.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; B-Lymphocytes; Bacterial Infections; Child; Child, Preschool; Early Diagnosis; Genetic Diseases, X-Linked; Humans; Immunoglobulins; Immunoglobulins, Intravenous; Male
PubMed: 32615664
DOI: 10.18502/ijaai.v19i3.3458 -
BMJ Case Reports Jun 2022Barth syndrome (BTHS) is an X linked recessive disorder caused by a mutation in the tafazzin (TAZ) gene classically associated with the triad of neutropaenia and cardiac...
Barth syndrome (BTHS) is an X linked recessive disorder caused by a mutation in the tafazzin (TAZ) gene classically associated with the triad of neutropaenia and cardiac and skeletal myopathies. Here we present a case of BTHS in a 2-month-old male patient found to have a novel variant of the TAZ gene (hemizygous c.639G>A) leading to early termination of the tafazzin protein (p.Trp213Ter) with presumed loss of function. Our patient was found to have dilated cardiomyopathy, cyclic neutropaenia and growth delays, which in combination with genetic work-up confirmed the diagnosis of BTHS. He also experienced repeated bacterial and viral infections, prompting an immunological work-up which revealed persistent B cell lymphopaenia and hypogammaglobulinaemia. He ultimately required subcutaneous immunoglobulin replacement and GM-CSF for ongoing hypogammaglobulinaemia and neutropaenia. To our knowledge, this case is the first report of BTHS associated with B cell lymphopaenia and hypogammaglobulinaemia.
Topics: Acyltransferases; Agammaglobulinemia; Barth Syndrome; Humans; Infant; Male; Neutropenia; Transcription Factors
PubMed: 35732368
DOI: 10.1136/bcr-2022-249254 -
Journal of Clinical Immunology May 2019Pulmonary complications occur frequently in primary antibody deficiency (PAD). While the impact of antibody deficiency may appear implicit for certain respiratory...
PURPOSE
Pulmonary complications occur frequently in primary antibody deficiency (PAD). While the impact of antibody deficiency may appear implicit for certain respiratory infections, immunoglobulin replacement therapy does not completely ameliorate pulmonary complications in PAD. Thus, there may be antibody-independent factors influencing susceptibility to respiratory disease in PAD, but these remain incompletely defined.
METHODS
We harnessed the multicenter US Immunodeficiency Network primary immunodeficiency registry to compare prevalence of asthma, bronchiectasis, interstitial lung disease (ILD), and respiratory infections between two forms of PAD: common variable immunodeficiency (CVID) and x-linked agammaglobulinemia (XLA). We also defined the clinical and immunological characteristics associated with ILD and asthma in CVID.
RESULTS
Asthma, bronchiectasis, ILD, pneumonia, and upper respiratory infections were more prevalent in CVID than XLA. ILD was associated with autoimmunity, bronchiectasis, and pneumonia as well as fewer B and T cells in CVID. Asthma was the most common chronic pulmonary complication and associated with lower IgA and IgM in CVID. Age of symptom onset or CVID diagnosis was unrelated with ILD or asthma.
CONCLUSION
Despite having less severe immunoglobulin deficiency than XLA, respiratory infections, ILD, and asthma were more common in CVID. Among CVID patients, ILD was associated with autoimmunity and reduced lymphocytes and asthma with lower immunoglobulins. Though our results are tempered by registry limitations, they provide evidence that factors beyond lack of antibody promote pulmonary complications in PAD. Efforts to understand how genetic etiology, nature of concurrent T cell deficiency, and propensity for autoimmunity shape pulmonary disease may improve treatment of PAD.
Topics: Adult; Agammaglobulinemia; Biomarkers; Disease Susceptibility; Female; Humans; Immunoglobulin A; Immunoglobulin G; Lung Diseases; Male; Middle Aged; Odds Ratio; Risk Factors; Young Adult
PubMed: 31089938
DOI: 10.1007/s10875-019-00640-5 -
Pediatrics International : Official... Jan 2022Subcutaneous immunoglobulin is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (Hizentra ;...
BACKGROUND
Subcutaneous immunoglobulin is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (Hizentra ; l-proline-stabilized 20% human subcutaneous immunoglobulin) is approved for agammaglobulinemia or hypogammaglobulinemia due to PID or secondary immunodeficiency (SID); however, its safety and effectiveness has not previously been assessed in a real-world setting.
METHODS
This multicenter, open label post-marketing surveillance study was conducted between January 2014 and March 2019. Patients who received IgPro20 due to PID or SID were included after informed consent. Physicians completed a case report form for each patient. Safety was determined from reported adverse events (AEs), adverse drug reactions, and serious AEs (SAEs); effectiveness was assessed by infection rates after the first IgPro20 dose.
RESULTS
Of 85 patients receiving IgPro20 in the safety analysis, 39 developed AEs (45.9%; PID n = 28, SID n = 11). At least one adverse drug reaction was observed in 27 patients (31.8%; PID n = 21, SID n = 6), and the most common were injection site reactions (n = 17, 20.0%). Four patients (PID n = 3, SID n = 1) reported SAEs but two were unrelated to IgPro20 administration. The infection rate decreased from 0.54 per patient during the 6 months before IgPro20 to 0.39 per patient during IgPro20 treatment. Serious bacterial infections occurred in six patients before IgPro20 (7.9%; PID n = 2; SID n = 4) but in only one patient with SID during IgPro20 treatment (1.2%).
CONCLUSIONS
In Japan, IgPro20 was considered safe and effective among patients with agammaglobulinemia or hypogammaglobulinemia due to PID or SID.
Topics: Humans; Agammaglobulinemia; Immunoglobulins, Intravenous; Immunologic Deficiency Syndromes; Injections, Subcutaneous; Japan
PubMed: 36151913
DOI: 10.1111/ped.15362 -
Journal of Clinical Immunology Jan 2022Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined...
Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available.
Topics: Agammaglobulinemia; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Severe Combined Immunodeficiency; Transplantation Conditioning; Unrelated Donors
PubMed: 34654999
DOI: 10.1007/s10875-021-01145-w -
Iranian Journal of Allergy, Asthma, and... Oct 2023Most patients with X-linked agammaglobulinemia are susceptible to infections, while some cases also suffer from inflammatory or autoimmune complications. We describe a... (Review)
Review
Most patients with X-linked agammaglobulinemia are susceptible to infections, while some cases also suffer from inflammatory or autoimmune complications. We describe a patient with progressive encephalitis who improved after the use of immunomodulatory treatment with corticosteroids, fluoxetine, and nitazoxanide. In most of the cases the evolution of the progressive encephalitis is complicated and catastrophic. Based on our experience and the review of the literature, we propose the use of this combined treatment to control this devastating complication.
Topics: Humans; Genetic Diseases, X-Linked; Encephalitis; Agammaglobulinemia; Combined Modality Therapy
PubMed: 38085151
DOI: 10.18502/ijaai.v22i5.13999