Materiały źródłowe

• #1 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549865/

  X-linked agammaglobulinemia or XLA is a primary immunodeficiency disorder that prevents affected individuals from making antibodies and requires them to rely on lifelong immunoglobulin replacement therapy for survival. […] The molecular basis for XLA is a disruption in B cell development due to mutation in Bruton’s tyrosine kinase (Btk). Affected individuals inherit a defect that prevents precursor B cells in the bone marrow from forming mature, circulating B-lymphocytes that would otherwise be capable of proliferating and differentiating into antibody-producing plasma cells in secondary lymphoid organs like the tonsils and lymph nodes. This dysfunction results in dangerously low, clinically undetectable levels of all immunoglobulin isotypes in the serum. […] The gene for Btk codes for a cytoplasmic tyrosine kinase protein, BTK, which acts as a signal transducer driving the final stages of B cell maturation. The inheritance of disease-causing mutation of the Btk gene interferes with BTK protein expression, resulting in the arrest of differentiation at the pre-B-cell stage in the bone marrow, causing a profound lack of mature B lymphocytes in the peripheral circulation and a corresponding absence or severe reduction in all immunoglobulin isotypes from the serum.

• #2 X-Linked Agammaglobulinemia | SpringerLink

  https://link.springer.com/10.1007/978-1-4939-2401-1_248

  X-linked agammaglobulinemia (XLA) was first described by Bruton in 1952 (Bruton 1952). It is a prototypical humoral immunodeficiency characterized by early onset of bacterial infections, profound hypogammaglobulinemia, and marked decrease of the peripheral B-lymphocyte population. […] Mutations in btk in patients with presumed X-linked agammaglobulinemia. […] Molecular and cellular aspects of X-linked agammaglobulinemia. […] Mutations of the human BTK gene coding for Bruton tyrosine kinase in X-linked agammaglobulinemia.

• #3 Agammaglobulinemia: X-linked (XLA) and autosomal recessive (ARA) | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/agammaglobulinemia-x-linked-and-autosomal

  The first form of agammaglobulinemia to be recognized, X-Linked agammaglobulinemia (XLA), was described in 1952 by Colonel Ogden Bruton, MD. […] Most individuals with XLA have normal numbers of B cell precursors, but very few of these are able to go on to become mature B cells. People with XLA have variants, or changes, in a gene that is necessary for the normal development of B cells. This gene, discovered in 1993, is named Brutons tyrosine kinase (BTK) in honor of Dr. Bruton. […] After BTK variants were identified as the cause of XLA, it became clear that only about 85% of children with agammaglobulinemia and absent B cells had variants in BTK. […] All of these genes code for proteins involved in the maturation of B cells. Individuals with variants in any of these genes have clinical and laboratory findings that are very similar to those seen in those with variants in BTK.

• #4 X-Linked (Bruton) Agammaglobulinemia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1050956-overview

  X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is an inherited immunodeficiency disease caused by mutations in the gene coding for Bruton tyrosine kinase (BTK). […] The BTK gene defect has been mapped to the long arm of the X chromosome at band Xq21.3 to Xq22, spanning 37.5kb with 19 exons forming 659 amino acids to complete the BTK cytosolic tyrosine kinase. […] In the absence of BTK, B lymphocytes do not differentiate or mature. Without mature B lymphocytes, antibody-producing plasma cells are also absent. […] Mutations in each of the 5 domains of BTK can lead to disease. The single most common genetic event is a missense mutation. […] Most mutations lead to truncation of the BTK enzyme. […] BTK is necessary for the proliferation and the differentiation of B lymphocytes.

• #5 X-Linked (Bruton) Agammaglobulinemia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/884942-overview

  X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is an inherited immunodeficiency disease caused by mutations in the gene coding for Bruton tyrosine kinase (BTK). […] The BTK gene defect has been mapped to the long arm of the X chromosome at band Xq21.3 to Xq22, spanning 37.5kb with 19 exons forming 659 amino acids to complete the BTK cytosolic tyrosine kinase. […] In the absence of BTK, B lymphocytes do not differentiate or mature. Without mature B lymphocytes, antibody-producing plasma cells are also absent. […] Mutations in each of the 5 domains of BTK can lead to disease. […] Most mutations lead to truncation of the BTK enzyme. […] BTK is necessary for the proliferation and the differentiation of B lymphocytes. […] The BTK mutations underlying X-linked agammaglobulinemia (XLA) interferes with the development and the function of B lymphocytes and their progeny. […] The major block occurs in the development of proB cells to preB cells and then to mature lymphocytes.

• #6 Agammaglobulinemia, X-Linked – CAGS

  https://cags.org.ae/en/ctga-details/1428/agammaglobulinemia-x-linked

  X-linked agammaglobulinemia (XLA) is a rare immune disorder characterized by a complete deficiency of B lymphocytes. In the absence of normal mature B cells, affected patients have impaired immunity and are susceptible to infections and illnesses, particularly in the first two years of life, which can sometimes be fatal. […] XLA is caused by mutations in the BTK (Bruton Tyrosine Kinase) gene. This gene, located on the X-chromosome, codes for a tyrosine kinase that plays an essential role in the development, differentiation and signaling of B lymphocytes. XLA is, therefore, transmitted in an X-linked recessive manner. The BTK gene is a 36Kb long stretch of DNA. The protein functions as a non-receptor tyrosine kinase.

• #7 X-linked agammaglobulinemia (XLA) – Immunodeficiency UKAccessibilityIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://www.immunodeficiencyuk.org/x-linked-agammaglobulinemia-xla/

  X-linked agammaglobulinemia (XLA) is caused by mutations in the BTK gene, which is present on an X-chromosome. The gene makes the enzyme Bruton’s tyrosine kinase, which is needed to instruct B-cells to mature and produce antibodies. […] More than 600 different mutations in the BTK gene have been found to cause XLA. Most mutations result in the absence of the BTK enzyme or an abnormal BTK protein that is quickly broken down in the cell. Without functional BTK enzyme there is no development of B-cells – and so a lack of antibodies – and this results in an increased susceptibility to bacterial infections. […] A genetic change in the btk (Bruton’s Tyrosine Kinase) gene causes XLA. This gene makes the enzyme Bruton’s tyrosine kinase, which is needed to instruct B-cells to mature and produce antibodies.

• #8 Frontiers | Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1252765/full

  Background: Bruton’s tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. […] XLA is caused by mutation in the Bruton’s tyrosine kinase (BTK). The BTK gene is located on the chromosome X, Xq21.3-Xq22, encompassing 37.5 kb genomic DNA. BTK gene contains 19 exons that encodes for a cytoplasmic protein tyrosine kinase, which is important in the B cell differentiation. […] According to a BTK database, BTK gene mutations scattered throughout the gene, affecting both coding and non-coding regions. Patients with missense mutation in a non-conserved residue or mutation involving non-coding regions have milder phenotypes. On the other hand, patients with non-sense mutation involving premature stop codon have severe phenotypes.

• #9 X-Linked Agammaglobulinemia – MD Searchlight

  https://mdsearchlight.com/genetic-disorders/x-linked-agammaglobulinemia/?utm_source=pubmedlink&utm_campaign=MDS&utm_content=31430

  XLA happens when a gene called Brutons tyrosine kinase, which helps develop B cells, isnt working correctly. […] A mutation in the Btk gene interferes with the production of this BTK protein, preventing the B cells from developing fully. […] Most cases of this disease are due to mutations in the Btk gene and are linked to the X chromosome. […] However, about 10% of the cases result from changes in other genes that are not sex-linked. […] The Btk gene gives instructions for making a protein, named BTK, that is crucial for maturing a type of immune cell called B cells. […] Therefore, mutations in these genes can also interfere with B cell development.

• #10 X-Linked Agammaglobulinemia

  https://www.bio.davidson.edu/movies/Immunology/Students/spring2000/magnussen/restricted/paper.html

  X-Linked Agammaglobulinemia (XLA) was the first immunodeficiency disease to be described. […] The cause of the condition was further narrowed with the discovery that patients with XLA lack mature B lymphocytes. […] A major step toward the understanding of the cause of XLA was taken in 1993 with the independent isolation of the gene which, when mutated, causes XLA. […] Btk is believed to play a role in a kinase signaling cascade that promotes the rearrangement of the light chain in pre B-cells after the pre B-cell receptor is displayed on the B-cell’s surface, although the exact role of Btk in this pathway is not yet known. […] Mutations causing XLA are distributed over all five domains. […] The fact that mutations occurring in any of the five domains can cause XLA suggests that each of Btk’s domains plays a vital role in B-cell development.

• #11 X-linked agammaglobulinemia – Knowledge and References – Taylor & Francis

  https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Allergology_%26_clinical_immunology/X-linked_agammaglobulinemia/

  X-linked agammaglobulinemia (XLA) is a genetic disease caused by mutations in the BTK gene, resulting in a deficiency of Btk tyrosine kinase. This deficiency leads to a lack of mature B cells and immunoglobulins, making individuals with XLA highly susceptible to infections, particularly during the first year of life when maternal immunoglobulins have been catabolized. XLA is inherited in an X-linked recessive pattern, meaning it primarily affects males and is passed down from carrier females. […] X-linked agammaglobulinemia (XLA) results from mutations of the Bruton’s tyrosine kinase (BTK) gene. BTK is located on the X chromosome and regulates signaling through the pre-B-cell receptor (pre-BCR) and the BCR. BTK deficiency results in a block at the pro-B to pre-B cell stage in B-cell differentiation in the bone marrow. Accordingly, patients with XLA have a severe reduction or absence of circulating B cells, associated with profound deficiency of all immunoglobulin isotypes.

• #12 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549865/

  Individuals with XLA have one of several inherited defects in the Btk gene that interferes with the production of mature B-lymphocytes in circulation. T lymphocytes are unaffected. […] B cell development is a process that occurs in the bone marrow, where pro-B cells develop into pre-B cells before fully mature B cells enter the peripheral circulation. Normally, pre-B cells express the pre-BCR complex, which undergoes activation by BTK to initiate downstream signaling events involved in the maturation process. This process becomes blocked at the pre-B cell stage in individuals with inherited mutations that prevent BTK expression. […] B cell differentiation becomes arrested at the Pre-B cell stage with an associated failure of immunoglobulin heavy chain rearrangement; this abrogates the production of immunoglobulins and prevents secondary lymphoid organs from developing fully.

• #13 X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature | Clinical and Molecular Allergy | Full Text

  https://clinicalmolecularallergy.biomedcentral.com/articles/10.1186/1476-7961-6-5

  Btk functions to transduce signals from the B cell immunoglobulin receptor (BCR) and absence of Btk has been shown to halt normal B cell development at the pre-B transitional cell stage with premature induction of apoptosis. […] In patients with XLA, studies have shown pro-B and pre-B1 cells to comprise more than 80% of the bone marrow B cell population compared with less than 20% in normal individuals. […] The Btk genome sequence consist of 19 exons and mutations have been reported in all five of the domains of the Btk gene including the Pleckstrin Homology (PH), Tec homology (TH), Src homology 1 (SH1), Src homology 2 (SH2), and Src homology 3 (SH3). […] Mutations in this domain such as the hemizygous point mutation in our patient may inhibit the signaling needed for recruitment of Btk to the cell membrane where it functions to transduce signals from the B cell receptor (BCR) of pre-B cells. […] Variation in severity of specific mutations may account for „mild” phenotypic variants of XLA allowing certain individual’s CD19+ B cells to survive long enough to produce sufficient amounts of immunoglobulins to avoid life-threatening infections in childhood.

• #14 X-Linked (Bruton) Agammaglobulinemia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1050956-overview

  The BTK mutations underlying X-linked agammaglobulinemia (XLA) interferes with the development and the function of B lymphocytes and their progeny. The major block occurs in the development of proB cells to preB cells and then to mature lymphocytes. […] Patients can have preB cells in the marrow, but they have few, if any, functional (mature) B cells in the peripheral blood and the lymphoid tissues.

• #15 Composition of Precursor B-Cell Compartment in Bone Marrow from Patients with X-Linked Agammaglobulinemia Compared with Healthy Children | Pediatric Research

  https://www.nature.com/articles/pr200228

  X-linked agammaglobulinemia (XLA) is characterized by a severe B-cell deficiency, resulting from a differentiation arrest in the bone marrow (BM). […] Eight patients had amino acid substitutions in the Bruton’s tyrosine kinase (BTK) domain or premature stop codons, resulting in the absence of functional BTK proteins. In seven of these eight patients a major differentiation arrest was observed at the transition between cytoplasmic Ig pre-B-I cells and cytoplasmic Ig+ pre-B-II cells, consistent with a role for BTK in pre-B-cell receptor signaling. […] We conclude that the absence of functional BTK proteins generally leads to an almost complete arrest of B-cell development at the pre-B-I to pre-B-II transition. […] XLA is caused by mutations in the gene encoding BTK, located on Xq21.3. […] So far, 341 unique mutations have been reported, which are scattered throughout the gene.

• #16 Composition of Precursor B-Cell Compartment in Bone Marrow from Patients with X-Linked Agammaglobulinemia Compared with Healthy Children | Pediatric Research

  https://www.nature.com/articles/pr200228

  XLA is a heterogeneous disease, which could be the result of differences in mutations in the BTK gene, in combination with other genetic or environmental factors, infections, or age of the patients. […] However, controversy exists regarding the stage in B-cell development that is primarily affected by mutations in the BTK gene. […] The localization of this arrest at the transition between CyIg and CyIg+ pre-B cells in seven of the eight XLA patients with absence of functional BTK proteins suggests that BTK proteins are required for the expansion of the CyIg+ pre-B-II population by signaling via the pre-BCR, which is expressed on CyIg+ pre-B cells. […] The flow cytometric data of the XLA patients clearly show a relative accumulation of CyIg precursor B cells, particularly of pre-B-I cells. […] In conclusion, the B-cell differentiation arrest in the majority of XLA patients appeared to be homogeneous, with approximately 80% of the precursor B-cell compartment being negative for CyIg expression.

• #17 Bruton’s agammaglobulinemia – WikiLectures

  https://www.wikilectures.eu/w/Bruton%27s_agammaglobulinemia

  X-linked agammaglobulinemia (XLA) was the first described genetic immunodeficiency (described by Brutonon in 1952). It belongs to antibody immunodeficiencies. […] The protein kinase BTK (Bruton tyrosine kinase), which is expressed in large quantities in B-lymphocytes precursors. Under normal conditions, B-lymphocyte development first involves the rearrangement of genes for the immunoglobulin heavy chain, followed by the rearrangement of genes for the light chain. It turns out that if BTK is mutated, development ends with rearrangement of the immunoglobulin heavy chain gene. Light chains are not synthesized and immunoglobulin molecules cannot be assembled. BTK kinase is responsible for biosignal transmission from B-lymphocyte receptors (and their precursors) to effector mechanisms. […] The critical section in this disease is part of the long arm of the X chromosome Xq21.3-q22. Thus, as a GR hereditary disease, it occurs much more often in boys.

• #18

  https://www.omim.org/entry/300755

  A number sign (#) is used with this entry because X-linked agammaglobulinemia/hypogammaglobulinemia (XLA) is caused by mutation in the gene encoding Bruton tyrosine kinase (BTK; 300300) on chromosome Xq22. […] X-linked agammaglobulinemia is an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. The defect in this disorder resides in BTK, also known as BPK or ATK, a key regulator in B-cell development (Rawlings and Witte, 1994). […] Pearl et al. (1978) showed that precursor B lymphocytes containing IgM heavy chains can be demonstrated in the bone marrow in XLA. This suggested that an arrest in the differentiation of precursor B lymphocytes into B lymphocytes may be involved. Schwaber et al. (1983) found that about 5% of normal pre-B cells and 100% of XLA pre-B cells produce incomplete mu chains (147020), i.e., C(mu) polypeptide without associated V(H). Thus, XLA represents a block in differentiation secondary to failure to express V(H) genes.

• #19 Agammaglobulinemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK555941/

  X- linked agammaglobulinemia is caused by a mutation in the Bruton tyrosine kinase (BTK) gene, located on the long arm of the X-chromosome. BTK is critical in the maturation of pre-B cells to mature B cells, a process that occurs in the bone marrow. The disease has been associated with 544 mutations that include mainly missense mutations, insertions, deletions, and splice-site mutations. […] The mutation in the BTK gene results in the failure of B cell development, leading to significantly low levels of mature B lymphocytes in peripheral blood circulation. As a result, B cells fail to generate plasma cells, leading to significantly reduced levels (hypogammaglobulinemia) or absence (agammaglobulinemia) of all classes of immunoglobulins. […] Lack of humoral immunity leads to recurrent sinopulmonary infections.

• #20 X-linked Agammaglobulinemia – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/x-linked-agammaglobulinemia

  X-linked agammaglobulinemia is characterized by low levels or absence of immunoglobulins and absence of B cells, leading to recurrent infections with encapsulated bacteria. […] X-linked agammaglobulinemia is a primary immunodeficiency disorder that involves humoral immunity deficiencies. It results from mutations in a gene on the X chromosome that encodes Bruton tyrosine kinase (BTK). BTK is essential for B-cell development and maturation; without it, maturation stops before the B-cell development, resulting in no mature B cells and hence no antibodies. […] Diagnosis of X-linked agammaglobulinemia is by detecting low (at least 2 standard deviations below the mean) levels of immunoglobulins (IgG, IgA, IgM) and absent B cells (1% of all lymphocytes are CD19+ cells, detected by flow cytometry). […] Treatment of X-linked agammaglobulinemia is immune globulin replacement therapy. Hematopoietic stem cell transplantation and gene therapy are also under investigation.

• #21

  https://journals.lww.com/md-journal/fulltext/2006/07000/x_linked_agammaglobulinemia__report_on_a_united.1.aspx

  X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton tyrosine kinase (BTK) that result in the deficient development of B lymphocytes and hypogammaglobulinemia. […] Affected individuals have hypogammaglobulinemia, markedly reduced levels of serum antibodies, and markedly reduced levels of B cells. […] As a result, they have an increased susceptibility to a variety of encapsulated bacteria and enteroviruses, microorganisms for which antibody plays an especially critical role in host defense. […] Patients were considered to have XLA if they had 1) a mutation in the BTK gene and/or defective expression of the BTK protein, or 2) a positive family history of a maternally related lateral male relative with XLA (for example, either a mutation of the BTK gene or defective expression of the BTK protein or markedly reduced numbers of B lymphocytes in their blood [2%] and hypogammaglobulinemia), or 3) markedly reduced numbers of B lymphocytes in their blood (2%) and hypogammaglobulinemia.

• #22

  https://journals.lww.com/ijaa/fulltext/2023/37020/diagnosis_of_a_case_of_x_linked_agammaglobulinemia.6.aspx

  Most of the mutations are familial, and mothers are healthy carriers. After 6 months of age, when transplacentally acquired maternal IgG fades, then XLA patients become symptomatic. […] Currently there is no absolute cure for the XLA patients. Intravenous Ig therapy in every 4 weeks and appropriate antibiotics are usually given in XLA patients for their treatment. […] Ig level measurement and flow cytometric evaluation of peripheral blood lymphocytes with intracellular BTK protein detection can play a vital role in the early diagnosis of XLA among the suspected PIDD patients. Flow cytometric evaluation is rapid, accurate, and less costly.

• #23 X-Linked Agammaglobulinemia – Immune Disorders – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/immune-disorders/immunodeficiency-disorders/x-linked-agammaglobulinemia

  X-linked agammaglobulinemia is a hereditary immunodeficiency disorder due to a mutation in a gene on the X (sex) chromosome. […] X-linked agammaglobulinemia is a primary immunodeficiency disorder and results from a mutation in a gene on the X (sex) chromosome (called an X-linked disorder). […] The tonsils are very small, and lymph nodes do not develop because immunoglobulin-producing B cells, which are normally present there, are absent. […] X-linked agammaglobulinemia increases the risk of developing infections in the joints (infectious arthritis), irreversible widening due to chronic inflammation of the airways (bronchiectasis), and certain cancers. […] Hematopoietic stem cell transplantation and gene therapy are under investigation.

• #24

  https://link.springer.com/article/10.1007/s12016-021-08870-5

  Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin production. While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified. […] The diagnosis of XLA is often delayed, and can be missed if patient has a mild phenotype. The lack of correlation between phenotype and genotype in this condition makes management and predicting outcomes quite difficult. […] Some diagnostic innovations, such as KREC level measurements and serum BCMA measurements, may aid in facilitating an earlier identification of agammaglobulinemia leading to prompt treatment. Earlier diagnosis may improve the overall health of patients with XLA.

• #25 X-Linked Agammaglobulinemia

  https://www.bio.davidson.edu/movies/Immunology/Students/spring2000/magnussen/restricted/paper.html

  It has been shown that mutations in either the TH or SH3 domains can lead to a decrease in the avidity of binding between the two domains. […] The fact that mutations in these domains do interfere with Btk activity are further evidence that Btk is a member of a kinase cascade which is critical to B-cell development. […] As research into XLA continues, more of Btk’s roles are likely to be discovered. […] The most recent research in this field has yielded encouraging results on the possibility of the use of transgenes to restore Btk activity.

• #26 Clinical and genetic profiles of patients with X-linked agammaglobulinemia from southeast Turkey: Novel mutations in BTK gene | Allergologia et Immunopathologia

  https://www.elsevier.es/es-revista-allergologia-et-immunopathologia-105-articulo-clinical-genetic-profiles-patients-with-S0301054618300740

  In our study, we determined 22 XLA patients who had 12 different mutations in BTK. […] Our results suggest that the correlation between the specific mutation in BTK and the severity of the disease alone may not be sufficient to predict clinical progress in a patient with XLA based on the mutation. […] In conclusion, we have identified our mutation profile to be different from those in the rest of the world.

• #27 X linked agammaglobulinemia #Bruton Agammaglobulinemia #Ayurveda in Agammaglobulinemia | PPT

  https://www.slideshare.net/slideshow/x-linked-agammaglobulinemia-bruton-agammaglobulinemia-ayurveda-in-agammaglobulinemia/249770664

  Bruton agammaglobulinemia is X-linked inherited immunodeficiency disease. It is caused by mutations in the gene coding for Bruton tyrosine kinase (BTK). The disease was first elucidated by Bruton in 1952, for whom the gene is named. Also known as X-linked agammaglobulinemia (XLA). […] XLA is an inherited disease that occurs in approximately 1 in 250,000 males. Female carriers have no clinical manifestations. Infections begin once transferred maternal immunoglobulin G (IgG) antibodies have been catabolized, typically at about 6 months of age. Baby has small or absent tonsils and lymph nodes with recurrent or severe bacterial infections. Children typically clinically manifest the disease at age 3-9 months with pneumonia, otitis media, cellulitis, meningitis, osteomyelitis, diarrhea, or sepsis. Rare cases of adults in their second decade have been diagnosed with a milder form.

• #28

  https://www.omim.org/entry/300755

  In 2 sisters heterozygous for both XLA and G6PD A-/B polymorphism, Conley et al. (1986) found that B cells showed activity of only the A- form of G6PD, whereas T cells and neutrophils had about equal amounts of A- and B enzyme activity. This indicates that the basic defect in XLA is intrinsic to the B cell. […] Schwaber et al. (1988) found an unusual phenotype of B cells in a patient with XLA, and cellular evidence for lyonization of B cells from the mother and sister. The patient had a failure of B-cell maturation at the stage of early B lymphocytes, associated with production of truncated mu and delta heavy chains composed of D-J(H)-C resulting from abortive rearrangement of variable region genes. […] Schwaber (1992) presented direct evidence that there is a failure of V(D)J recombination which causes arrest in the transition from pre-B cell to B lymphocyte. He pointed out that the arrest in B-cell development is not absolute: rare B lymphocytes have been identified in peripheral blood of some patients, and B-cell lines have been established from these cells by Epstein-Barr virus transformation. Leakiness of the mutation would not be inconsistent with the proposed mechanism.

• #29 Frontiers | Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1252765/full

  Our analysis revealed that XLA patients exhibited various clinical presentations, ranging from common to atypical presentations. […] It is described that Bruton’s tyrosine kinase (BTK) is not only indispensable to the biology and function of B cells but also other innate myeloid immune cells such as monocytes, macrophages, neutrophils, and dendritic cells. […] In this cohort, thirteen patients had absent or minimal intracellular BTK expression (0-15%) in the monocytes. A complete BTK protein deficiency was observed in two patients (P6 and P7) with missense mutations affecting the kinase domain of BTK protein. […] The combination of genetic analysis using cDNA and genomic DNA may provide insights into BTK RNA splicing mechanism. […] More than two thirds of the pathogenic variants are caused by splicing defects, frameshift mutations or premature stop codons. The most frequently recurrent mutation sites in BTK are the invariant splice site in the intron 9 (c.839 + 1G>C). This mutation was observed in three patients from two unrelated families, resulting in skipping of the exon 9.

• #30 Agammaglobulinemia: X-linked (XLA) and autosomal recessive (ARA) | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/agammaglobulinemia-x-linked-and-autosomal

  The diagnosis of XLA can be confirmed by demonstrating the absence of BTK protein in monocytes or platelets or by the detection of a variant in the BTK gene. Almost every family has a different variant in BTK; members of the same family, however, usually have the same mutation. […] As the name XLA suggests, the BTK gene (which is mutated in XLA) is located on the X chromosome. Since XLA is an X-linked disorder, typically only boys are affected because they have only one X chromosome (XY). […] Now that the precise gene that causes XLA has been identified, it is possible to test the female siblings (sisters) of a male with XLA, and other female relatives, such as the child’s maternal aunts, to determine if they are carriers of the disease and could transmit it to their sons.

• #31 Clinical and genetic findings in two siblings with X-Linked agammaglobulinemia and bronchiolitis obliterans: a case report | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-022-03245-x

  X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. […] Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder. […] The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751GA(p.Gly584Glu) in BTK gene of both patients. […] We also identified a gain-of-function mutation in TGF1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGF1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment.

• #32

  https://step2.medbullets.com/pediatrics/322236/x-linked-agammaglobulinemia

  defective maturation of B-cells […] impaired signaling from pre-B cell receptor […] impaired antibody immune response […] X-linked recessive […] defect in Bruton tyrosine kinase (BTK) […] confirmed with DNA, mRNA, or protein analysis showing mutation in BTK.

• #33 X-linked-agammaglobulinaemia

  https://dermnetnz.org/topics/x-linked-agammaglobulinaemia

  X-linked agammaglobulinaemia is caused by mutations on Brutons Tyrosine Kinase (BTK) gene, which was discovered in 1993. The gene normally promotes the maturation of B-lymphocytes. Since the BTK gene is found on the X-chromosome, X-linked agammaglobulinaemia presents exclusively in males. […] There is no cure for X-linked agammaglobulinaemia. However, treatment can greatly improve quality of life for X-linked agammaglobulinaemia patients. […] Immunoglobulin replacement therapy reduces the risk of invasive infection. Chronic lung disease still develops and overall survival is reduced.

• #34 News: The Long and Winding Road to a CRISPR Gene Therapy for X-Linked Agammaglobulinemia – CRISPR Medicine

  https://crisprmedicinenews.com/news/the-long-and-winding-road-to-a-crispr-gene-therapy-for-x-linked-agammaglobulinemia/

  Targeted integration of a corrective cDNA donor into the BTK exon 2 target site led to efficient integration and expression. […] The next big challenge is to progress this research into the pre-clinical stage. Gray and his colleagues expect the therapy to be even more successful in human subjects due to positive selection and a more severe disease phenotype. […] Gray hopes his work will not only lead to a cure for XLA but that his hours of troubleshooting and optimising will help smooth the path forward for other students and researchers who are struggling to develop gene therapies.

• #35 News: The Long and Winding Road to a CRISPR Gene Therapy for X-Linked Agammaglobulinemia – CRISPR Medicine

  https://crisprmedicinenews.com/news/the-long-and-winding-road-to-a-crispr-gene-therapy-for-x-linked-agammaglobulinemia/

  X-Linked Agammaglobulinemia (XLA) is caused by mutations in the Bruton’s tyrosine kinase (BTK) gene. These mutations result in defective B cell receptor (BCR) signalling, which, in turn, impedes the development of B lymphocytes. With no mature B lymphocytes to differentiate into plasma cells to produce immunoglobulin, patients lack antibodies to protect them from pathogens. […] XLA is a monogenic disorder, but that’s really where the similarities end. While a single pathogenic mutation causes SCD, XLA can be caused by a myriad of mutations in the BTK gene; for a gene therapy to work for a broad range of patients, the team would have to edit almost the entire gene delivering a functional copy via CRISPR knock-in. […] For XLA, there’s a vast range of pathogenic mutations throughout the entire gene; there’s not even really a hotspot. So we thought if we’re adding in the full-length cDNA at the start of the gene, any patient that has an exonic mutation after that should, in theory, be cured by it, Gray explains.

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