RARE DISEASE
X-linked agammaglobulinemia
X-linked agammaglobulinemia
X-linked agammaglobulinemia
Synonyms: BTK-deficiency, Bruton type agammaglobulinemia
Synonyms: BTK-deficiency, Bruton type agammaglobulinemia
Synonyms: BTK-deficiency, Bruton type agammaglobulinemia
Drug discovery
0
drugs
With orphan designations
Overview
X-linked agammaglobulinemia (XLA) is an X-linked recessive immunodeficiency caused by mutations in the BTK gene, disrupting B-cell maturation and antibody production [1][7][12]. Affected males present with recurrent bacterial infections starting in infancy, hypogammaglobulinemia, and absent lymphoid tissue [2][6][12]. Diagnosis involves low immunoglobulins, absent B cells, and genetic confirmation [12][18]. Management focuses on immunoglobulin replacement and infection prevention [3][6][18].
Burden
Morbidity: Chronic lung disease (57%), enteroviral infections (15%), arthritis (12%) [9][14]
Mortality: 27% in untreated cases; main causes: respiratory failure (64%), sepsis (18%) [9][14]
Lifespan: Near-normal with early IVIG (initiated <3 years) [3][6][12]
Costs: Lifetime immunoglobulin therapy averages $50,000-$100,000/year [12][14]
Therapies
Immunoglobulin replacement: IVIG (400-600 mg/kg monthly) or SCIG (100 mg/kg weekly) [3][13][18]
Antibiotic prophylaxis: Continuous or pulse therapy for infection prevention [3][9][12]
Contraindications: Live vaccines (polio, MMR, varicella) [3][6][18]
Emerging approaches: Gene therapy and antisense oligonucleotides showing preclinical promise [4][8]
Categories: rare genetic diseases, rare immunological diseases
Research Papers
491 drug discovery papers about X-linked agammaglobulinemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
491 drug discovery papers about X-linked agammaglobulinemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-15 | Comparison of variably specific Bruton tyrosine kinase inhibitors on platelet aggregation mediated by Fcγ receptor (FcγR) IIa, glycoprotein VI, and platelet endothelial aggregation receptor (PEAR) 1: implications for Bruton tyrosine kinase inhibitors as antithrombotic therapy.
Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been proposed as therapy for thrombosis driven by immune complex activation of platelets via FcγRIIa. Since patients who lack BTK (X-linked agammaglobulinemia [XLA]) do not have excessive bleeding, highly specific BTKi may be antithrombotic without increasing the risk of hemorrhage. Our knowledge of the full range of effects of BTKi on platelet function is incomplete, in particular, the role of BTKi on signaling via platelet endothelial aggregation receptor (PEAR) 1, a receptor linked to thrombotic cardiovascular disease. This study assessed the role of BTK in platelet aggregation initiated through Fcγ receptor (FcγR)IIa, glycoprotein (GP)VI, PEAR1, and other receptors. Platelets of control and patients with XLA were treated with BTKi of varying specificity and analyzed by light transmission aggregometry and immunoblotting. Both nonspecific and highly specific BTKi profoundly inhibited platelet aggregation mediated by FcγRIIa, PEAR1, and GPVI, but not protease-activated receptor 1, the thromboxane receptor, α2β1, or GPIb/von Willebrand factor. Inhibition of phosphorylation of BTK Y223 correlated with inhibition of aggregation. Platelets of 4 patients with XLA had markedly reduced or no responses to activation via GPVI and FcγRIIa. BTK plays important roles in signaling via FcγRIIa, GPVI, and PEAR1, but clinical studies are required to assess the optimal BTKi for inhibiting thrombotic disorders mediated via these receptors.
2026-07-09 | Bruton Tyrosine Kinase as Therapeutic Target in Cardiovascular Diseases-Executive Summary.
Bruton tyrosine kinase (Btk) is an intracellular enzyme belonging to the Tec family tyrosine kinases. Initially identified for its role in B cell signaling, it has now emerged as a pivotal mediator in thrombosis and cardiovascular diseases (CVD). Beyond its established role in B cell malignancies, Btk is expressed in platelets, macrophages, neutrophils, and other innate immune cells, orchestrating platelet activation, atherothrombosis, venous thrombosis, immunothrombosis/thrombo-inflammation, and vascular inflammation. Patients with X-linked agammaglobulinemia (XLA), genetically lacking Btk, do not bleed, indicating that selective platelet Btk inhibition may provide a safe antithrombotic strategy. Indeed, highly selective Btk inhibitors (BTKi) show no or only minor bleeding in autoimmune disease trials, and rilzabrutinib, approved in 2025, reduces bleeding in patients with immune thrombocytopenia (ITP). This executive summary of a recent state-of-the-art review synthesizes current understanding of Btk's mechanistic contributions to thrombosis and CVD, evaluates the evolution of BTKi, and explores their therapeutic potential.
2026-07-09 | Inborn errors of immunity in Low German Mennonite communities in Mexico: a case series and narrative literature review.
Inborn errors of immunity (IEI) comprise a genetically heterogeneous group of disorders with increased prevalence in consanguineous and endogamous populations due to founder effects. Low German Mennonite (LGM) communities in Mexico represent a high-risk population characterized by genetic isolation and an increased frequency of autosomal recessive conditions. Although IEI have been reported in LGM populations from Canada and Europe, systematic data from Mexican LGM communities remain limited. This study describes four novel clinical cases of IEI in LGM patients evaluated at two tertiary referral centers in Mexico and contextualizes these findings within a comprehensive review of previously reported IEI in this population. A retrospective case series was conducted at two tertiary pediatric referral centers in Mexico between 2020 and 2025, including four patients from LGM communities with clinically and/or genetically confirmed IEI. Clinical, immunological, and genetic data were extracted from medical records. Genetic diagnoses, when available, were established using next-generation sequencing or whole-exome sequencing, with variant classification according to ACMG criteria. A narrative literature search was performed in PubMed, Embase, SciELO, and Web of Science to identify previously reported IEI cases in LGM populations. Four patients with distinct IEI were identified: one with glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, one with X-linked agammaglobulinemia (XLA) due to a pathogenic variant in the Bruton tyrosine kinase (BTK) gene, and two with severe combined immunodeficiency (SCID). All patients required disease-specific therapy, including granulocyte colony-stimulating factor, immunoglobulin replacement, and/or hematopoietic cell transplantation. The literature review identified a broad spectrum of IEI in LGM populations, including cellular and humoral immunodeficiencies, phagocyte disorders, DNA repair defects, autoinflammatory conditions, and bone marrow failure syndromes. This exploratory case series contributes to the growing body of evidence on IEI in LGM populations and highlights the potential impact of founder variants in this community. Given the small sample size and retrospective design, generalization of these findings requires prospective, population-based validation. Early diagnosis through newborn screening, accessible genetic testing, and timely clinical intervention remains essential to improve outcomes.
2026-05-22 | Quality of life of X-linked agammaglobulinemia patients in the United Kingdom.
Due to limitations in current therapies (immunoglobulin replacement therapy), complications in X-linked agammaglobulinemia (XLA) such as bronchiectasis may continue to occur, with subsequent significant impacts on health-related quality of life (HRQoL). There were no significant differences in PedsQL 4.0 total scores against UK healthy norms (self 80.98, P = 0.277; parent 79.76, P = 0.465). There were no significant differences in the SF36v2 physical component score (PCS) against UK healthy norms (49.10, P = 0.712). However, XLA patients with bronchiectasis had significantly worse PCS than patients without (47.88 versus 55.14, P < 0.001) and significantly worse PCS than UK healthy norms (P = 0.004). In the absence of bronchiectasis, HRQoL is comparable to UK healthy norms. However, XLA patients with bronchiectasis have significantly worse HRQoL than patients without bronchiectasis and UK healthy norms. These data demonstrate that further work into novel therapies are needed to prevent bronchiectasis to enable XLA patients to have a normal quality of life.
2026-05-13 | The Intertwining Between Arthritis and Inborn Errors of Immunity.
Immune dysregulation is being increasingly recognized as a prominent feature of a wide range inborn errors of immunity (IEIs) with different molecular backgrounds. Among the manifestations of immune dysregulation, inflammatory arthritis has emerged as an important yet underrecognized complication that may occur across multiple IEI categories, including humoral immunodeficiencies (such as X-linked agammaglobulinemia, hyper-IgM syndrome, common variable immunodeficiency, and others), complement deficiencies, disorders of immune dysregulation (STAT3 gain of function mutation, CTLA4 and LRBA haploinsufficiency), and combined immunodeficiencies. In some patients, arthritis may represent the first or predominant clinical manifestation, resulting in a diagnostic challenge in the rheumatologic setting. The pathogenesis of arthritis in IEIs reflects different immunological mechanisms, including the defective clearance of immune complexes, dysregulated B- and T-cell responses, impaired regulatory T-cell function, and aberrant cytokine signaling. Clinically, IEI-associated arthritis may mimic classical rheumatologic conditions such as juvenile idiopathic arthritis, rheumatoid arthritis, or other connective tissue diseases, although distinctive immunological and histopathological features are often present. Recognizing arthritis as a potential manifestation of IEIs has important clinical implications. The presence of specific "red flags", including treatment refractoriness, recurrent infections, or additional signs of immune dysregulation (other autoimmune diseases, atopy, lymphoproliferation, enteropathy), should prompt targeted immunological evaluation. While management often relies on conventional immunosuppressive therapies, advances in the molecular characterization of IEIs are increasingly enabling the use of targeted treatments directed at the underlying pathogenic mechanisms. This paper provides an overview of the current knowledge of arthritis associated with IEIs, highlighting diagnostic challenges, underlying immunopathogenic mechanisms, and emerging therapeutic perspectives.
2026-08-15 | Comparison of variably specific Bruton tyrosine kinase inhibitors on platelet aggregation mediated by Fcγ receptor (FcγR) IIa, glycoprotein VI, and platelet endothelial aggregation receptor (PEAR) 1: implications for Bruton tyrosine kinase inhibitors as antithrombotic therapy.
Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been proposed as therapy for thrombosis driven by immune complex activation of platelets via FcγRIIa. Since patients who lack BTK (X-linked agammaglobulinemia [XLA]) do not have excessive bleeding, highly specific BTKi may be antithrombotic without increasing the risk of hemorrhage. Our knowledge of the full range of effects of BTKi on platelet function is incomplete, in particular, the role of BTKi on signaling via platelet endothelial aggregation receptor (PEAR) 1, a receptor linked to thrombotic cardiovascular disease. This study assessed the role of BTK in platelet aggregation initiated through Fcγ receptor (FcγR)IIa, glycoprotein (GP)VI, PEAR1, and other receptors. Platelets of control and patients with XLA were treated with BTKi of varying specificity and analyzed by light transmission aggregometry and immunoblotting. Both nonspecific and highly specific BTKi profoundly inhibited platelet aggregation mediated by FcγRIIa, PEAR1, and GPVI, but not protease-activated receptor 1, the thromboxane receptor, α2β1, or GPIb/von Willebrand factor. Inhibition of phosphorylation of BTK Y223 correlated with inhibition of aggregation. Platelets of 4 patients with XLA had markedly reduced or no responses to activation via GPVI and FcγRIIa. BTK plays important roles in signaling via FcγRIIa, GPVI, and PEAR1, but clinical studies are required to assess the optimal BTKi for inhibiting thrombotic disorders mediated via these receptors.
2026-07-09 | Bruton Tyrosine Kinase as Therapeutic Target in Cardiovascular Diseases-Executive Summary.
Bruton tyrosine kinase (Btk) is an intracellular enzyme belonging to the Tec family tyrosine kinases. Initially identified for its role in B cell signaling, it has now emerged as a pivotal mediator in thrombosis and cardiovascular diseases (CVD). Beyond its established role in B cell malignancies, Btk is expressed in platelets, macrophages, neutrophils, and other innate immune cells, orchestrating platelet activation, atherothrombosis, venous thrombosis, immunothrombosis/thrombo-inflammation, and vascular inflammation. Patients with X-linked agammaglobulinemia (XLA), genetically lacking Btk, do not bleed, indicating that selective platelet Btk inhibition may provide a safe antithrombotic strategy. Indeed, highly selective Btk inhibitors (BTKi) show no or only minor bleeding in autoimmune disease trials, and rilzabrutinib, approved in 2025, reduces bleeding in patients with immune thrombocytopenia (ITP). This executive summary of a recent state-of-the-art review synthesizes current understanding of Btk's mechanistic contributions to thrombosis and CVD, evaluates the evolution of BTKi, and explores their therapeutic potential.
2026-07-09 | Inborn errors of immunity in Low German Mennonite communities in Mexico: a case series and narrative literature review.
Inborn errors of immunity (IEI) comprise a genetically heterogeneous group of disorders with increased prevalence in consanguineous and endogamous populations due to founder effects. Low German Mennonite (LGM) communities in Mexico represent a high-risk population characterized by genetic isolation and an increased frequency of autosomal recessive conditions. Although IEI have been reported in LGM populations from Canada and Europe, systematic data from Mexican LGM communities remain limited. This study describes four novel clinical cases of IEI in LGM patients evaluated at two tertiary referral centers in Mexico and contextualizes these findings within a comprehensive review of previously reported IEI in this population. A retrospective case series was conducted at two tertiary pediatric referral centers in Mexico between 2020 and 2025, including four patients from LGM communities with clinically and/or genetically confirmed IEI. Clinical, immunological, and genetic data were extracted from medical records. Genetic diagnoses, when available, were established using next-generation sequencing or whole-exome sequencing, with variant classification according to ACMG criteria. A narrative literature search was performed in PubMed, Embase, SciELO, and Web of Science to identify previously reported IEI cases in LGM populations. Four patients with distinct IEI were identified: one with glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, one with X-linked agammaglobulinemia (XLA) due to a pathogenic variant in the Bruton tyrosine kinase (BTK) gene, and two with severe combined immunodeficiency (SCID). All patients required disease-specific therapy, including granulocyte colony-stimulating factor, immunoglobulin replacement, and/or hematopoietic cell transplantation. The literature review identified a broad spectrum of IEI in LGM populations, including cellular and humoral immunodeficiencies, phagocyte disorders, DNA repair defects, autoinflammatory conditions, and bone marrow failure syndromes. This exploratory case series contributes to the growing body of evidence on IEI in LGM populations and highlights the potential impact of founder variants in this community. Given the small sample size and retrospective design, generalization of these findings requires prospective, population-based validation. Early diagnosis through newborn screening, accessible genetic testing, and timely clinical intervention remains essential to improve outcomes.
2026-05-22 | Quality of life of X-linked agammaglobulinemia patients in the United Kingdom.
Due to limitations in current therapies (immunoglobulin replacement therapy), complications in X-linked agammaglobulinemia (XLA) such as bronchiectasis may continue to occur, with subsequent significant impacts on health-related quality of life (HRQoL). There were no significant differences in PedsQL 4.0 total scores against UK healthy norms (self 80.98, P = 0.277; parent 79.76, P = 0.465). There were no significant differences in the SF36v2 physical component score (PCS) against UK healthy norms (49.10, P = 0.712). However, XLA patients with bronchiectasis had significantly worse PCS than patients without (47.88 versus 55.14, P < 0.001) and significantly worse PCS than UK healthy norms (P = 0.004). In the absence of bronchiectasis, HRQoL is comparable to UK healthy norms. However, XLA patients with bronchiectasis have significantly worse HRQoL than patients without bronchiectasis and UK healthy norms. These data demonstrate that further work into novel therapies are needed to prevent bronchiectasis to enable XLA patients to have a normal quality of life.
2026-05-13 | The Intertwining Between Arthritis and Inborn Errors of Immunity.
Immune dysregulation is being increasingly recognized as a prominent feature of a wide range inborn errors of immunity (IEIs) with different molecular backgrounds. Among the manifestations of immune dysregulation, inflammatory arthritis has emerged as an important yet underrecognized complication that may occur across multiple IEI categories, including humoral immunodeficiencies (such as X-linked agammaglobulinemia, hyper-IgM syndrome, common variable immunodeficiency, and others), complement deficiencies, disorders of immune dysregulation (STAT3 gain of function mutation, CTLA4 and LRBA haploinsufficiency), and combined immunodeficiencies. In some patients, arthritis may represent the first or predominant clinical manifestation, resulting in a diagnostic challenge in the rheumatologic setting. The pathogenesis of arthritis in IEIs reflects different immunological mechanisms, including the defective clearance of immune complexes, dysregulated B- and T-cell responses, impaired regulatory T-cell function, and aberrant cytokine signaling. Clinically, IEI-associated arthritis may mimic classical rheumatologic conditions such as juvenile idiopathic arthritis, rheumatoid arthritis, or other connective tissue diseases, although distinctive immunological and histopathological features are often present. Recognizing arthritis as a potential manifestation of IEIs has important clinical implications. The presence of specific "red flags", including treatment refractoriness, recurrent infections, or additional signs of immune dysregulation (other autoimmune diseases, atopy, lymphoproliferation, enteropathy), should prompt targeted immunological evaluation. While management often relies on conventional immunosuppressive therapies, advances in the molecular characterization of IEIs are increasingly enabling the use of targeted treatments directed at the underlying pathogenic mechanisms. This paper provides an overview of the current knowledge of arthritis associated with IEIs, highlighting diagnostic challenges, underlying immunopathogenic mechanisms, and emerging therapeutic perspectives.
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