Agammaglobulinemia związana z chromosomem x

Agammaglobulinemia związana z chromosomem x
Etiologia i przyczyny

Agammaglobulinemia związana z chromosomem X (XLA) jest pierwotnym niedoborem odporności spowodowanym mutacjami w genie BTK, kodującym kinazę tyrozynową Brutona, niezbędną do prawidłowego rozwoju limfocytów B. Mutacje w genie BTK, zlokalizowanym na chromosomie X (region Xq21.3-Xq22, pozycje 101349447-101390796), prowadzą do zatrzymania różnicowania limfocytów B na etapie pre-B-komórkowym, skutkując agammaglobulinemią i znacznym niedoborem immunoglobulin (IgG, IgA, IgM). Dziedziczenie jest recesywne sprzężone z chromosomem X, co powoduje, że choroba dotyka głównie chłopców. Diagnostyka opiera się na wykryciu niskich poziomów immunoglobulin, braku limfocytów B (CD19+ stanowiących około 1% limfocytów) oraz potwierdzeniu mutacji w genie BTK i zmniejszonej ekspresji białka BTK w badaniach cytometrii przepływowej lub Western blot. W około 30-50% przypadków występuje dodatni wywiad rodzinny, a pozostałe to mutacje de novo. Warto również uwzględnić autosomalne recesywne formy agammaglobulinemii (ARA), związane z mutacjami w genach takich jak UGHN, IGLL1, CD79A, CD79B i BLNK, które klinicznie przypominają XLA, ale często manifestują się wcześniej i mają cięższy przebieg.

Etiologia agammaglobulinemii związanej z chromosomem X

Agammaglobulinemia związana z chromosomem X (X-linked agammaglobulinemia, XLA), zwana również agammaglobulinemią Brutona, jest rzadkim wrodzonym pierwotnym niedoborem odporności spowodowanym mutacją w genie kodującym kinazę tyrozynową Brutona (BTK). Gen ten znajduje się na chromosomie X w regionie Xq21.3-Xq22.¹² Mutacje w genie BTK wpływają na rozwój i funkcjonowanie limfocytów B, co prowadzi do niezdolności organizmu do wytwarzania przeciwciał potrzebnych do obrony przed infekcjami.³

Mutacje genetyczne w XLA

Odkryto setki różnych mutacji w genie BTK, które mogą powodować XLA. Mutacje te mogą występować w przedziale par zasad od 101349447 do 101390796 na chromosomie X.⁴ Jednak żadna pojedyncza mutacja nie koreluje z więcej niż 3% znanych przypadków.⁵ Mutacje mogą być różnego typu, w tym mutacje zmiany sensu (missense), przesunięcia ramki odczytu (frameshift), delecje, insercje, przedwczesny kodon stop oraz mutacje punktowe.⁶ Większość mutacji prowadzi do całkowitego braku enzymu BTK lub produkcji nieprawidłowego białka BTK, które szybko ulega degradacji w komórce.⁷

Mutacje mogą wystąpić w każdej z pięciu domen białka BTK, co sugeruje, że każda z tych domen odgrywa kluczową rolę w rozwoju limfocytów B.⁸ Badania z różnych krajów wykazały zróżnicowanie w rozkładzie mutacji. Na przykład w Indiach najczęstsze były mutacje zmiany sensu w domenie kinazy tyrozynowej. Podobne wyniki zaobserwowano w Chinach, Afryce, Hong Kongu, Argentynie i Włoszech.⁹

Funkcja białka BTK i patofizjologia XLA

Gen BTK koduje białko – kinazę tyrozynową Brutona, które jest niezbędne do prawidłowego rozwoju i dojrzewania limfocytów B.¹⁰ Białko BTK działa jako transduktor sygnału napędzający końcowe etapy dojrzewania komórek B. Gdy występuje mutacja w genie BTK, proces różnicowania zostaje zatrzymany na etapie pre-B-komórkowym w szpiku kostnym.¹¹

W prawidłowych warunkach białko BTK uczestniczy w mechanizmie rozwoju, dojrzewania i proliferacji limfocytów B w szpiku kostnym. W XLA mutacja w genie BTK ostatecznie zatrzymuje proces rozwoju i dojrzewania komórek B. Pacjenci z tym rzadkim zaburzeniem mają mniej krążących komórek B lub nie mają ich wcale, co prowadzi do zmniejszenia stężenia immunoglobulin (hipogammaglobulinemia) lub całkowitego braku immunoglobulin (agammaglobulinemia) w organizmie.¹²

Główny blok rozwojowy występuje podczas przejścia z pro-limfocytów B do pre-limfocytów B, a następnie do dojrzałych limfocytów. Pacjenci mogą mieć pre-limfocyty B w szpiku kostnym, ale mają niewiele lub wcale funkcjonalnych (dojrzałych) limfocytów B we krwi obwodowej i tkankach limfatycznych.¹³ W konsekwencji, we krwi występuje znaczący niedobór lub całkowity brak wszystkich klas immunoglobulin.¹⁴

Wzorzec dziedziczenia

XLA dziedziczy się w sposób recesywny sprzężony z chromosomem X.¹⁵ Choroba dotyka prawie wyłącznie chłopców, ponieważ mają oni tylko jeden chromosom X. Jeśli mężczyzna odziedziczy chromosom X zawierający zmutowany gen BTK, rozwinie się u niego XLA.¹⁶¹⁷ W przypadku kobiet, które mają dwa chromosomy X, mutacja musiałaby wystąpić w obu kopiach genu BTK, aby spowodować zaburzenie, co jest niezwykle rzadkie.¹⁸ Kobiety z mutacją w jednym chromosomie X zwykle stają się jedynie nosicielkami zmutowanego genu.¹⁹

Nosicielki mają 1 na 2 (50%) szanse na przekazanie wadliwego chromosomu X dziecku przy każdej ciąży. Jeśli córka odziedziczy gen, najprawdopodobniej będzie zdrową nosicielką jak jej matka. Jeśli syn odziedziczy zmutowany gen, będzie miał XLA.²⁰ Kobieta, która jest nosicielką zaburzenia recesywnego sprzężonego z chromosomem X, ma 25% szans na urodzenie niechorego syna, 25% szans na urodzenie chorego syna, 25% szans na urodzenie niechorej córki i 25% szans na urodzenie córki, która również jest nosicielką.²¹

Mężczyzna z XLA przekaże gen choroby wszystkim swoim córkom, które staną się nosicielkami, co oznacza, że wszyscy męscy wnukowie pochodzący od córek pacjenta z XLA mają 50% szans na odziedziczenie XLA.²²

Mutacje de novo

Około 30-50% pacjentów z XLA ma pozytywny wywiad rodzinny w kierunku genetycznego dziedziczenia choroby.²³ Pozostałe przypadki występują jako losowe mutacje. W niektórych przypadkach dziecko może mieć wadliwy gen bez odziedziczenia go po rodzicu. Może to nastąpić, jeśli dojdzie do nowej zmiany (mutacji) na chromosomie X dziecka w momencie poczęcia.²⁴²⁵ W niektórych rodzinach nie obserwuje się sprzężonego z chromosomem X wzorca dziedziczenia. Może to wynikać z małej liczebności rodziny lub, w niektórych przypadkach, agammaglobulinemia jest wynikiem nowej mutacji na chromosomie X, która nie została odziedziczona od matki.²⁶

Formy autosomalne agammaglobulinemii

Podczas gdy większość przypadków agammaglobulinemii jest wynikiem dziedziczenia sprzężonego z chromosomem X mutacji genu BTK, około 10-15% przypadków jest wynikiem mutacji genów autosomalnych. Wynikający z tego stan znany jest jako autosomalna recesywna agammaglobulinemia (ARA) i opisuje fenotyp kliniczny obserwowany u kobiet z wrodzoną agammaglobulinemią, porównywalny do XLA u mężczyzn.²⁷²⁸

Defekty molekularne odpowiedzialne za ARA obejmują mutacje w następujących genach: łańcuch ciężki mu (UGHN), gamma 5 (IGLL1), Igalpha (CD79A), Igbeta (CD79B) i BLNK. Białka kodowane przez te geny funkcjonują we współpracy z BTK, promując przejście z pro-limfocytów B do pre-limfocytów B w szpiku kostnym, podczas dojrzewania komórek B.²⁹ Mutacje zidentyfikowano również w genach PI3K, TCF3, LRRC8A oraz PIK3R.³⁰

Osoby z mutacjami w którymkolwiek z tych genów mają objawy kliniczne i laboratoryjne bardzo podobne do tych obserwowanych u osób z mutacjami w BTK.³¹ W przeciwieństwie do XLA, autosomalnie recesywne formy agammaglobulinemii często pojawiają się w młodszym wieku i zwykle mają cięższe objawy kliniczne, co prowadzi do wcześniejszej diagnozy.³²

Implikacje diagnostyczne i screeningowe

Diagnoza XLA opiera się na wykryciu niskich poziomów immunoglobulin (IgG, IgA, IgM) i braku limfocytów B (1% wszystkich limfocytów to komórki CD19+, wykrywane za pomocą cytometrii przepływowej).³³ Potwierdzenie diagnozy wymaga dowodu na zmniejszoną ekspresję białka BTK w badaniu cytometrii przepływowej (lub w Western blot) oraz sekwencjonowanie genu BTK.³⁴

Ze względu na oczekiwane zmniejszenie liczby infekcji dolnych dróg oddechowych i śmiertelności wśród osób z wcześniejszym wiekiem diagnozy, badania sugerują włączenie XLA do programów badań przesiewowych noworodków.³⁵ Rekomendowane jest również prenatalne badanie genetyczne dla osób, u których w rodzinie zidentyfikowano mutację powodującą XLA.³⁶

Kobieta może poddać się badaniu na obecność genu. Jeśli jest znaną nosicielką, może również przeprowadzić badania prenatalne, aby dowiedzieć się, czy jej dziecko odziedziczyło gen. Takie badania mogą być przeprowadzone przy użyciu amniocentezy lub biopsji kosmówki.³⁷

Znaczenie kliniczne mutacji BTK

Brak korelacji między fenotypem a genotypem w XLA sprawia, że zarządzanie i przewidywanie wyników leczenia jest dość trudne.³⁸ Diagnoza XLA często jest opóźniona i może zostać przeoczona, jeśli pacjent ma łagodny fenotyp.

Pacjenci z XLA są szczególnie podatni na infekcje bakteryjne pozakomórkowe, jednak infekcje enterowirusowe często przebiegają ciężko i często są oporne na terapię.³⁹ U pacjentów z XLA często występuje neutropenia, która została zidentyfikowana jako częsty objaw.⁴⁰

Leczenie XLA polega głównie na terapii zastępczej immunoglobulinami. Przeszczep krwiotwórczych komórek macierzystych i terapia genowa są również przedmiotem badań jako potencjalne metody leczenia.⁴¹

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Materiały źródłowe

#1 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 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.
#2 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK549865/
XLA results from mutation of the Bruton’s tyrosine kinase gene (Btk) located on the long arm (q) of the X chromosome (Xq21.3-Xq22), affecting males almost exclusively. Hundreds of different mutations have been reported to cause XLA, including missense, frameshift, deletion, insertion, premature stop codon, and point mutations. The molecular location of these mutations encompasses base pairs 101349447 to 101390796 on the X chromosome. However, no single mutation correlates with more than 3% of the known cases. […] 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.
#3 X-Linked Agammaglobulinemia (XLA) – AmeriPharmaÂ® Specialty Care
https://ameripharmaspecialty.com/other-health-conditions/x-linked-agammaglobulinemia/
Agammaglobulinemia is more commonly known as X-Linked agammaglobulinemia (XLA), Brutonâs agammaglobulinemia, or congenital agammaglobulinemia. It is a disorder caused by the bodyâs inability to produce B cells or immunoglobulins (antibodies) that the B cells make. […] XLA is a congenital (at birth) condition that is caused by the result of a mutated gene. The mutated gene responsible for XLA codes for the protein Bruton tyrosine kinase, or BTK gene, is located on the X chromosome. […] In males (who only have one X chromosome), one altered copy of the BTK gene in each cell is enough to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the BTK gene to cause the disorder. […] Agammaglobulinemia is mainly caused by a mutation in a gene responsible for B cells development. Typically, B cells are the essential component of the immune system that are differentiated into a fully matured form called plasma cells.
#4 X-Linked Agammaglobulinemia – MD Searchlight
https://mdsearchlight.com/genetic-disorders/x-linked-agammaglobulinemia/?utm_source=pubmedlink&utm_campaign=MDS&utm_content=31430
XLA, also known as Brutons disease, is caused by changes or mutations in a specific gene called Brutons Tyrosine Kinase gene (Btk). This gene is found on the X chromosome, which is one of the sex chromosomes, and thats why it affects mostly boys. There are hundreds of different types of mutations that can cause XLA. These mutations can occur anywhere between positions 101349447 to 101390796 on the X chromosome. However, no single mutation is found in more than 3% of known cases. […] A mutation in the Btk gene interferes with the production of this BTK protein, preventing the B cells from developing fully. As a result, there are not enough mature B cells in the body to properly fight infections, leading to a severe lack or significant decrease in all types of antibodies in the blood. […] 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. This other form of the disease is called autosomal recessive agammaglobulinemia (ARA) and it happens in girls. It is similar to XLA in boys. The genes involved in ARA help the BTK protein facilitate the maturation of B cells. Therefore, mutations in these genes can also interfere with B cell development.
#5 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK549865/
XLA results from mutation of the Bruton’s tyrosine kinase gene (Btk) located on the long arm (q) of the X chromosome (Xq21.3-Xq22), affecting males almost exclusively. Hundreds of different mutations have been reported to cause XLA, including missense, frameshift, deletion, insertion, premature stop codon, and point mutations. The molecular location of these mutations encompasses base pairs 101349447 to 101390796 on the X chromosome. However, no single mutation correlates with more than 3% of the known cases. […] 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.
#6 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK549865/
XLA results from mutation of the Bruton’s tyrosine kinase gene (Btk) located on the long arm (q) of the X chromosome (Xq21.3-Xq22), affecting males almost exclusively. Hundreds of different mutations have been reported to cause XLA, including missense, frameshift, deletion, insertion, premature stop codon, and point mutations. The molecular location of these mutations encompasses base pairs 101349447 to 101390796 on the X chromosome. However, no single mutation correlates with more than 3% of the known cases. […] 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.
#7 X-linked agammaglobulinemia (XLA) – Immunodeficiency UKAccessibilityIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset
https://www.immunodeficiencyuk.org/x-linked-agammaglobulinemia-xla/
XLA is caused by mutations in the BTK gene, which is present on an X-chromosomes. The gene makes the enzyme Brutonâs 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 â and so a lack of antibodies â and this results in an increased susceptibility to bacterial infections. […] A genetic change in the btk (Brutonâs Tyrosine Kinase) gene causes XLA. This gene makes the enzyme Brutonâs tyrosine kinase, which is needed to instruct B-cells to mature and produce antibodies.
#8 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 (Geha et al., 1974). […] 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 (Vetrie et al., 1993; Tsukada et al., 1993). […] The gene was found to code for a protein kinase which had not yet been observed (Vetrie et al., 1993). […] Mutations causing XLA are distributed over all five domains as is shown in Table 1 below. […] 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. […] The observation that XLA was X-linked ruled out Bruton’s second hypothesis, indicating that the cause of the disease was genetic.
#9 Frontiers | Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.612323/full
In our cohort, missense variants in BTK gene involving tyrosine kinase domain were the most common mutations. Similar results have also been reported from China, Africa, Hong Kong, Argentina and Italy. Most variants were located in exon 15 as has also been reported from China and Italy. However, most variants were found to be located on exon 2 in a study from Hong Kong. Nine of 86 variants in our study were novel.
#10 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 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.
#11 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK549865/
XLA results from mutation of the Bruton’s tyrosine kinase gene (Btk) located on the long arm (q) of the X chromosome (Xq21.3-Xq22), affecting males almost exclusively. Hundreds of different mutations have been reported to cause XLA, including missense, frameshift, deletion, insertion, premature stop codon, and point mutations. The molecular location of these mutations encompasses base pairs 101349447 to 101390796 on the X chromosome. However, no single mutation correlates with more than 3% of the known cases. […] 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.
#12 X-Linked Agammaglobulinemia (XLA) – AmeriPharmaÂ® Specialty Care
https://ameripharmaspecialty.com/other-health-conditions/x-linked-agammaglobulinemia/
The mechanism of the B cells development, maturation, and proliferation processes are regulated by highly specialized genes in the bone marrow. One of the most crucial genes is the BTK gene, called Brutonâs kinase tyrosine. […] In XLA, a mutation in the BTK gene ultimately stops the B cellâs development and maturation process. In this rare disorder, people have fewer or no circulatory B cells, resulting in fewer immunoglobulins (hypogammaglobulinemia) or a lack of immunoglobulins (agammaglobulinemia) in the body.
#13 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 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.
#14 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. […] X-linked agammaglobulinaemia is an inherited genetic disorder characterised by the failure to produce mature B-lymphocytes and plasma cells. Affected patients have severe deficiencies in all immunoglobulins.
#15 X-linked agammaglobulinemia – Wikipedia
https://en.wikipedia.org/wiki/X-linked_agammaglobulinemia
XLA is caused by a mutation on the X chromosome (Xq21.3-q22) of a single gene identified in 1993 which produces an enzyme known as Bruton’s tyrosine kinase, or Btk. […] The disorder is inherited in an X-linked recessive fashion (as the gene linked to it is on the X chromosome) and is almost entirely limited to the sons of asymptomatic female carriers. […] There is 30-50% chance of XLA patients having a positive family history of genetic inheritance. The rest of the cases occur as random mutations. […] If a carrier female gives birth to a male child, there is a 50% chance that the male will have XLA. A carrier female has a 25% chance overall of giving birth to an affected male child. […] An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patient’s daughters have a 50% chance of inheriting XLA. […] A female XLA patient can arise only as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the fetus of a non-carrier mother.
#16 What is X-linked agammaglobulinemia?
https://www.medicalnewstoday.com/articles/x-linked-agammaglobulinemia
XLA is a genetic disorder, meaning it occurs due to a gene alteration. The gene variation that causes XLA is the gene responsible for coding the protein Bruton tyrosine kinase (BTK). This gene is present on the X chromosome, which is why medical professionals refer to the disorder as X-linked. […] Studies show that hundreds of different alterations may cause XLA. However, not one single variation is responsible for more than 3% of the known cases of the disorder. […] If a male inherits an X chromosome containing an altered BTK gene, they will develop XLA. This is because males only have one X chromosome. If a female inherits an X chromosome containing a BTK gene variant, they are highly unlikely to develop XLA. They will most likely only carry the altered gene. […] Alterations in the Bruton tyrosine kinase (BTK) gene on the X chromosome cause XLA to develop. As such, XLA predominantly affects males due to their single X chromosome.
#17 X-Linked Agammaglobulinemia (XLA) | NIAID: National Institute of Allergy and Infectious Diseases
https://www.niaid.nih.gov/diseases-conditions/x-linked-agammaglobulinemia
XLA is an inherited immune disorder caused by an inability to produce B cells or the immunoglobulins (antibodies) that the B cells make. […] The mutated gene responsible for XLA codes for the protein Bruton tyrosine kinase, or BTK, and is located on the X chromosome, and is an X-linked recessive disease. […] Because males only have one X chromosome, they are affected if they inherit an X chromosome containing a mutated BTK gene.
#18 X-Linked Agammaglobulinemia (XLA) – AmeriPharmaÂ® Specialty Care
https://ameripharmaspecialty.com/other-health-conditions/x-linked-agammaglobulinemia/
Agammaglobulinemia is more commonly known as X-Linked agammaglobulinemia (XLA), Brutonâs agammaglobulinemia, or congenital agammaglobulinemia. It is a disorder caused by the bodyâs inability to produce B cells or immunoglobulins (antibodies) that the B cells make. […] XLA is a congenital (at birth) condition that is caused by the result of a mutated gene. The mutated gene responsible for XLA codes for the protein Bruton tyrosine kinase, or BTK gene, is located on the X chromosome. […] In males (who only have one X chromosome), one altered copy of the BTK gene in each cell is enough to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the BTK gene to cause the disorder. […] Agammaglobulinemia is mainly caused by a mutation in a gene responsible for B cells development. Typically, B cells are the essential component of the immune system that are differentiated into a fully matured form called plasma cells.
#19 What is X-linked agammaglobulinemia?
https://www.medicalnewstoday.com/articles/x-linked-agammaglobulinemia
XLA is a genetic disorder, meaning it occurs due to a gene alteration. The gene variation that causes XLA is the gene responsible for coding the protein Bruton tyrosine kinase (BTK). This gene is present on the X chromosome, which is why medical professionals refer to the disorder as X-linked. […] Studies show that hundreds of different alterations may cause XLA. However, not one single variation is responsible for more than 3% of the known cases of the disorder. […] If a male inherits an X chromosome containing an altered BTK gene, they will develop XLA. This is because males only have one X chromosome. If a female inherits an X chromosome containing a BTK gene variant, they are highly unlikely to develop XLA. They will most likely only carry the altered gene. […] Alterations in the Bruton tyrosine kinase (BTK) gene on the X chromosome cause XLA to develop. As such, XLA predominantly affects males due to their single X chromosome.
#20 X-Linked Agammaglobulinemia in Children
https://cayugamed.staywellknowledgebase.com/Library/DiseasesConditions/Pediatric/ChildMentalHealth/90,P01666
X-linked agammaglobulinemia is caused by a faulty gene on the X chromosome. […] In some cases, a child may have the faulty gene without inheriting it. This can happen if there is a new change (mutation) on the child’s X chromosome at the time of conception. […] Women who are carriers have a 1 in 2 chance of passing the faulty X chromosome to a child. This is true for every pregnancy. If a daughter gets the gene, she will likely be a healthy carrier like her mother. If a son gets the gene, he will have X-linked agammaglobulinemia.
#21 Mayo Clinic Health Library – X-linked agammaglobulinemia | Swiss Medical Network
https://www.swissmedical.net/en/healtcare-library/con-20256723
X-linked agammaglobulinemia is caused by a change in a gene. People with the condition can’t produce proteins called antibodies that fight infection. About 40% of people with the condition have a family member who has it. […] Women can pass down X-linked recessive disorders such as X-linked agammaglobulinemia. Women who are carriers of an X-linked recessive disorder have a 25% chance of having an unaffected son, a 25% chance of having an affected son, a 25% chance of having an unaffected daughter and a 25% chance of having a daughter who also is a carrier.
#22 X-linked agammaglobulinemia – Wikipedia
https://en.wikipedia.org/wiki/X-linked_agammaglobulinemia
XLA is caused by a mutation on the X chromosome (Xq21.3-q22) of a single gene identified in 1993 which produces an enzyme known as Bruton’s tyrosine kinase, or Btk. […] The disorder is inherited in an X-linked recessive fashion (as the gene linked to it is on the X chromosome) and is almost entirely limited to the sons of asymptomatic female carriers. […] There is 30-50% chance of XLA patients having a positive family history of genetic inheritance. The rest of the cases occur as random mutations. […] If a carrier female gives birth to a male child, there is a 50% chance that the male will have XLA. A carrier female has a 25% chance overall of giving birth to an affected male child. […] An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patient’s daughters have a 50% chance of inheriting XLA. […] A female XLA patient can arise only as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the fetus of a non-carrier mother.
#23 X-linked agammaglobulinemia – Wikipedia
https://en.wikipedia.org/wiki/X-linked_agammaglobulinemia
XLA is caused by a mutation on the X chromosome (Xq21.3-q22) of a single gene identified in 1993 which produces an enzyme known as Bruton’s tyrosine kinase, or Btk. […] The disorder is inherited in an X-linked recessive fashion (as the gene linked to it is on the X chromosome) and is almost entirely limited to the sons of asymptomatic female carriers. […] There is 30-50% chance of XLA patients having a positive family history of genetic inheritance. The rest of the cases occur as random mutations. […] If a carrier female gives birth to a male child, there is a 50% chance that the male will have XLA. A carrier female has a 25% chance overall of giving birth to an affected male child. […] An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patient’s daughters have a 50% chance of inheriting XLA. […] A female XLA patient can arise only as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the fetus of a non-carrier mother.
#24 X-Linked Agammaglobulinemia in Children
https://www.nationwidechildrens.org/conditions/health-library/x-linked-agammaglobulinemia-in-children
X-linked agammaglobulinemia is caused by a faulty gene on the X chromosome. […] If their X chromosome carries a faulty gene, they will have symptoms. […] In some cases, a child may have the faulty gene without inheriting it. This can happen if there is a new change (mutation) on the childs X chromosome at the time of conception. […] Women who are carriers have a 1 in 2 chance of passing the faulty X chromosome to a child. […] A woman can get tested for the gene. If you are a known carrier, you can also have prenatal testing to find out if your child has inherited the gene. This testing might occur through an amniocentesis or chorionic villus sampling.
#25 X-linked Agammaglobulinemia | Children’s Hospital of Philadelphia
https://www.chop.edu/conditions-diseases/x-linked-agammaglobulinemia
X-linked agammaglobulinemia is caused by inheriting a faulty gene located on the X chromosome. […] Males, on the other hand, only have one X chromosome. So if their X chromosome carries a disease-causing gene, then they will express symptoms of the disease. […] In some cases, the agammaglobulinemia is the result of a new mutation on the child’s X chromosome that was not inherited from the mother.
#26 X-linked agammaglobulinemia | Children’s Wisconsin
https://childrenswi.org/medical-care/immune-deficiency/immune-disorders/x-linked-agammaglobulinemia
X-linked agammaglobulinemia is caused by inheriting a gene which is located on the X chromosome. […] Males, on the other hand, get only one X chromosome. So if their X chromosome carries a disease causing gene, they will have symptoms of the disease. […] In some families, an X-linked pattern of inheritance is not present. This could be because of a small family size, or because, in some cases, the agammaglobulinemia is the result of a new mutation on the X chromosome that was not inherited from the mother.
#27 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK549865/
While the majority of agammaglobulinemia cases result from X-linked inheritance of Btk gene mutations, approximately 10% of the cases are the result of autosomal gene mutations. The resulting condition is known as autosomal recessive agammaglobulinemia(ARA) and describes the clinical phenotype seen in females with congenital agammaglobulinemia, which is comparable to XLA in males. The molecular defects responsible for ARA include mutations to the following genes: mu heavy chain (UGHN); gamma 5 (IGLL1); Igalpha (CD79A); Igbeta (CD79B); and BLNK. The wild-type proteins encoded by these genes have been shown to operate in collaboration with BTK, to promote the transition from pro-B-cells to pre-B-cells in the bone marrow, during B cell maturation.
#28 X-Linked Agammaglobulinemia – MD Searchlight
https://mdsearchlight.com/genetic-disorders/x-linked-agammaglobulinemia/?utm_source=pubmedlink&utm_campaign=MDS&utm_content=31430
XLA, also known as Brutons disease, is caused by changes or mutations in a specific gene called Brutons Tyrosine Kinase gene (Btk). This gene is found on the X chromosome, which is one of the sex chromosomes, and thats why it affects mostly boys. There are hundreds of different types of mutations that can cause XLA. These mutations can occur anywhere between positions 101349447 to 101390796 on the X chromosome. However, no single mutation is found in more than 3% of known cases. […] A mutation in the Btk gene interferes with the production of this BTK protein, preventing the B cells from developing fully. As a result, there are not enough mature B cells in the body to properly fight infections, leading to a severe lack or significant decrease in all types of antibodies in the blood. […] 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. This other form of the disease is called autosomal recessive agammaglobulinemia (ARA) and it happens in girls. It is similar to XLA in boys. The genes involved in ARA help the BTK protein facilitate the maturation of B cells. Therefore, mutations in these genes can also interfere with B cell development.
#29 X-Linked Agammaglobulinemia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK549865/
While the majority of agammaglobulinemia cases result from X-linked inheritance of Btk gene mutations, approximately 10% of the cases are the result of autosomal gene mutations. The resulting condition is known as autosomal recessive agammaglobulinemia(ARA) and describes the clinical phenotype seen in females with congenital agammaglobulinemia, which is comparable to XLA in males. The molecular defects responsible for ARA include mutations to the following genes: mu heavy chain (UGHN); gamma 5 (IGLL1); Igalpha (CD79A); Igbeta (CD79B); and BLNK. The wild-type proteins encoded by these genes have been shown to operate in collaboration with BTK, to promote the transition from pro-B-cells to pre-B-cells in the bone marrow, during B cell maturation.
#30 Azthena logo with the word Azthena
https://www.news-medical.net/health/What-is-Agammaglobulinemia.aspx
While X-linked agammaglobulinemia (XLA) is the most frequent cause of congenital agammaglobulinemia, accounting for about 85% of cases, other genetic types of agammaglobulinemia have been discovered. […] A mutation in Bruton’s tyrosine kinase (BTK) causes this X-linked agammaglobulinemia. […] Neutropenia has been identified as a prevalent XLA symptom. […] Males with early-onset bacterial infections, substantial reductions in all classes of blood immunoglobulins, and missing B cells are suspected of having XLA. […] Mutations have been found in the mu heavy chain, Lambda 5, Ig alpha, Ig beta, BLNK, PI3K, and TCF3 genes so far. […] Mutations in numerous different genes have been linked to autosomal recessive agammaglobulinemia, including the heavy chain gene, 5, Ig, Ig, BLNK, PIK3R, and TCF3. […] Mutations in the LRRC8A gene on chromosome 9q34 and the TCF3 gene on 19p13.3 have been linked to autosomal dominant agammaglobulinemia.
#31 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
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. […] Since 1996, several genes that can cause agammaglobulinemia with autosomal recessive inheritance (ARA) have been identified. […] 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.
#32
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. […] In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis.
#33 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 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.
#34 Frontiers | Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.612323/full
X-linked agammaglobulinemia (XLA) is one of the most frequent inborn errors of immunity (IEI). Patients typically present with recurrent sinopulmonary and gastrointestinal infections. XLA results from loss of function variants in Bruton Tyrosine Kinase (BTK) gene which is located on long arm of X chromosome (Xq21.3 to Xq22). Pathogenic variants in BTK gene lead to maturation arrest of developing B-lymphocytes in the bone marrow at pre-B cell stage. Diagnosis is based on presence of pan-hypogammaglobulinemia and absence of mature B-lymphocytes in peripheral blood. Confirmation of diagnosis requires evidence of reduced expression of Btk protein on flow cytometry (or on Western blot) and BTK gene sequencing. […] There is paucity of literature on XLA from developing countries. This is largely because of lack of awareness and dearth of appropriate diagnostic facilities.
#35
https://link.springer.com/article/10.1007/s10875-022-01237-1
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by mutations in the Bruton tyrosine kinase (BTK) gene leading to B lymphocyte deficiency and susceptibility to infection. […] Given the expected finding of reduced LRTIs and mortality among those with earlier age at diagnosis, our study findings support inclusion of XLA in newborn screening programs.
#36 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). […] Prenatal genetic screening is recommended for people if a mutation that causes X-linked agammaglobulinemia has been identified in their family.
#37 X-Linked Agammaglobulinemia in Children
https://healthinfo.coxhealth.com/Library/DiseasesConditions/Adult/Cardiovascular/90,P01666
X-linked agammaglobulinemia is caused by a faulty gene on the X chromosome. […] In some cases, a child may have the faulty gene without inheriting it. This can happen if there is a new change (mutation) on the child’s X chromosome at the time of conception. […] Women who are carriers have a 1 in 2 chance of passing the faulty X chromosome to a child. […] A woman can get tested for the gene. If you are a known carrier, you can also have prenatal testing to find out if your child has inherited the gene. This testing might occur through an amniocentesis or chorionic villus sampling.
#38
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. […] In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis.
#39
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). The X-linked form accounts for approximately 85 to 90% of cases of the disorder. […] A form of X-linked hypogammaglobulinemia (IMD61; 300310) is caused by mutation in the SH3KBP1 gene (300374) on chromosome Xq22. […] XLA is characterized by an increased susceptibility mainly to extracellular bacterial infections; however, enteroviral infections frequently run a severe course and often resist therapy (Lederman and Winkelstein, 1985; McKinney et al., 1987; Ochs and Smith, 1996).
#40 Azthena logo with the word Azthena
https://www.news-medical.net/health/What-is-Agammaglobulinemia.aspx
While X-linked agammaglobulinemia (XLA) is the most frequent cause of congenital agammaglobulinemia, accounting for about 85% of cases, other genetic types of agammaglobulinemia have been discovered. […] A mutation in Bruton’s tyrosine kinase (BTK) causes this X-linked agammaglobulinemia. […] Neutropenia has been identified as a prevalent XLA symptom. […] Males with early-onset bacterial infections, substantial reductions in all classes of blood immunoglobulins, and missing B cells are suspected of having XLA. […] Mutations have been found in the mu heavy chain, Lambda 5, Ig alpha, Ig beta, BLNK, PI3K, and TCF3 genes so far. […] Mutations in numerous different genes have been linked to autosomal recessive agammaglobulinemia, including the heavy chain gene, 5, Ig, Ig, BLNK, PIK3R, and TCF3. […] Mutations in the LRRC8A gene on chromosome 9q34 and the TCF3 gene on 19p13.3 have been linked to autosomal dominant agammaglobulinemia.
#41 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 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.