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Other entities represented in this entry:
SNOMEDCT: 65880007; ORPHA: 229717, 47; DO: 14179;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq22.1 | Agammaglobulinemia, X-linked 1 | 300755 | X-linked recessive | 3 | BTK | 300300 |
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. Also see 300310. The remaining 15% of cases constitute a heterogeneous group of autosomal disorders (Lopez Granados et al., 2002; Ferrari et al., 2007).
Genetic Heterogeneity of Agammaglobulinemia/Hypogammaglobulinemia
A form of X-linked hypogammaglobulinemia (IMD61; 300310) is caused by mutation in the SH3KBP1 gene (300374) on chromosome Xq22.
See agammaglobulinemia-1 (AGM1; 601495) for a discussion of genetic heterogeneity of autosomal forms of agammaglobulinemia.
X-linked agammaglobulinemia, the first genetic immunodeficiency to be specifically identified, was described by Bruton (1952). Patients are unusually prone to bacterial infection but not to viral infection. A clinical picture resembling rheumatoid arthritis develops in many. Before antibiotics, death occurred in the first decade. In the more usual X-linked form of the disease, plasma cells are lacking. A rarer form of agammaglobulinemia (Hitzig and Willi, 1961), which is inherited as an autosomal recessive (601457), shows marked depression of the circulating lymphocytes, and lymphocytes are absent from the lymphoid tissue. The alymphocytotic type (also see 300400) is even more virulent than the Bruton form, leading to death in the first 18 months after birth from severe thrush, chronic diarrhea, and recurrent pulmonary infections.
Seligmann et al. (1968) proposed a classification of immunologic deficiencies. Ament et al. (1973) pointed out that gastrointestinal infestation with Giardia lamblia is frequent in this and other forms of immunodeficiency. Infection with Campylobacter jejuni and Salmonella spp is also frequent (Melamed et al., 1983). Giardiasis may lead to malabsorption, while C. jejuni infection may result in recurrent fever (van der Meer et al., 1986; Kerstens et al., 1992).
Geha et al. (1973) showed that males with proven X-linked agammaglobulinemias lacked bone marrow-derived (B) lymphocytes from the circulating blood, whereas progenitor and thymus (T) cells were normal. See 301000 and 308230 for other X-linked deficiencies of immunoglobulins.
Although patients have recurrent bacterial infections, they generally have a normal response to viral infection, presumably because cell-mediated immunity is intact. A notable exception is the usually fatal echovirus-induced meningoencephalitis, which is often associated with the 'dermatomyositis-like' syndrome first described by Janeway et al. (1956). Mease et al. (1981) successfully treated a 32-year-old man who developed signs of myopathy and encephalopathy over a period of 3 months. Echo 11 virus was recovered from muscle and spinal fluid. In vitro lymphocyte transformation was temporarily markedly depressed by the infection. High doses of immune globulin given intravenously cured the man of this usually fatal complication.
Rosen et al. (1984) reviewed primary immunodeficiencies, giving a classification according to whether the immunodeficiency was predominantly one of antibody formation, was predominantly one of cell-mediated immunity, or was associated with other defects as in ataxia-telangiectasia.
Lederman and Winkelstein (1985) collected data from 96 patients cared for in 26 North American medical centers and representing a total experience of almost 1,200 patient-years.
Boys with agammaglobulinemia lack circulating B cells. Landreth et al. (1985) described 4 boys with agammaglobulinemia who lacked pre-B lymphocytes. In classic agammaglobulinemia, pre-B cells are present in normal numbers in the bone marrow but appear to be either blocked or aborted in their ability to mature, express surface immunoglobulins, or produce antibody. In the boys who lacked pre-B cells, clinical presentation with recurrent infections was delayed until the second or third year. None of the 4 boys had a history of recurrent infection or similar disease in maternal first cousins or uncles. Two of the patients were brothers. The mode of inheritance is unclear. The immune defect resembled that of the thymoma-agammaglobulinemia syndrome, but thymoma was not present in any of the 4.
Thorsteinsson et al. (1990) described studies in 3 brothers with IMD1, the first of whom was diagnosed in 1963 at the age of 9 years and died at the age of 23.
Van der Meer et al. (1993) reported the cases of 3 unrelated men with XLA who developed colorectal cancer at the ages of 26, 29, and 36 years. Van der Meer et al. (1993) suggested that there is an increased risk of colorectal cancer in these individuals and that it may be related to intestinal infections.
Ochs and Smith (1996) provided a comprehensive review of the clinical and molecular aspects of X-linked agammaglobulinemia.
Smith and Witte (1999) provided a comprehensive review of XLA. 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). Rudge et al. (1996) described a patient with XLA who had an enteroviral infection, presumably contracted at 8 years of age. Autopsy performed at 17 years of age, after several years of progressive dementia, showed severe thinning of the cerebral cortex, reduced subcortical and deep white matter, and marked dilatation of the lateral ventricles.
Wood et al. (2001) described a 25-year-old man with a selective antipolysaccharide antibody deficiency who was found to have a previously described mutation (300300.0005) in the BTK gene. From the age of 23 years, his IgG level had fallen slightly below the normal range, but he had remained well on antibiotic prophylaxis for 12 years. The authors suggested that male patients with antipolysaccharide antibody deficiency should be evaluated for B-cell lymphopenia and Btk mutations.
Edwards et al. (1978) showed reduced ecto-5-prime-nucleotidase (129190) activity in peripheral blood lymphocytes. This is an ectoenzyme that regulates the uptake of AMP into lymphocytes by converting the nontransportable nucleotide to its readily transported nucleoside, adenosine.
Lau et al. (1988) discussed the calculation of genetic risks in XLA, including allowance for nonallelic genetic heterogeneity.
Hendriks et al. (1989) described a family in which each of 2 sisters had a son with XLA. The 2 sisters with affected sons and another sister all showed exclusive inactivation of the paternal X chromosome in B lymphocytes, indicating that the gene for XLA came from their father, who, however, had no agammaglobulinemia. He was presumed to be an X chromosomal mosaic. RFLP segregation analyses in other XLA pedigrees suggested that this may be a frequent situation.
Sakamoto et al. (2001) suggested maternal germinal mosaicism to explain the finding of 2 sibs with XLA who had a single base deletion (563C) in exon 6 of the BTK gene and whose mother had no evidence of the mutation. Cytoplasmic expression of BTK protein in monocytes was not detected in either patient; normal cytoplasmic expression of BTK protein was found in monocytes of the mother.
Race and Sanger (1975) thought that the agammaglobulinemia locus was possibly linked to Xg; the lod scores were positive but low at a recombination fraction of 30%.
In 12 families, including an extensively affected Dutch kindred of 8 generations, Mensink et al. (1984) studied linkage with Xg (314700) and the 12E7 polymorphism that is closely linked to Xg. They concluded that XLA and Xg are at least 20 cM apart. Cohen et al. (1985) isolated a cDNA probe recognizing a family of genes, called Xlr (see 300113), on the mouse X chromosome, at least some members of which are closely linked to the xid trait. In accompanying studies, Cohen et al. (1985) presented data which, combined with the RFLP analysis closely linking the Xlr gene family to the xid mutation, suggest that the xid defect resides in a member of this family. From a study of the comparative mapping of the human and mouse X chromosomes, Buckle et al. (1985) predicted that the XLA locus of man may be on Xq between PGK1 (311800) and GLA (300644), i.e., in the segment Xq13-Xq22. This remarkable prediction was borne out by the findings of Kwan et al. (1986).
By RFLP studies in 11 families, they showed that XLA is linked to 2 markers, DXS3 and DXS17, both localized in region Xq21.3-q22 (lod = 3.65 at theta = 0.04 and lod = 2.17 at theta = 0.0, respectively). In a single 8-generation Dutch kindred, Mensink et al. (1986) found a maximum lod score of 3.30 at a recombination fraction of 0.06 for linkage of XLA and marker p19-2 (DXS3). In another pedigree, similar linkage to DXS3 was excluded (lod = -3.14 at theta 0.06). This suggested the existence of a second form of X-linked agammaglobulinemia; data obtained by Mensink et al. (1986) from all pedigrees suggested localization of a second XLA gene in the Xp22 band as defined by marker p99-6 (DXS41); see 300310. This is a possible parallel to the historic demonstration of heterogeneity in elliptocytosis (611804) by the linkage principle. Mensink et al. (1986) predicted that more detailed molecular studies 'will ultimately reveal phenotypic differences, reflecting different XLA gene loci, one of them probably coding for a recombinase involved in immunoglobulin heavy-chain rearrangements (Schwaber et al., 1983) and the other(s) being involved in later stages of precursor B cell differentiation (Levitt et al., 1984). 'With a multipoint linkage analysis in 9 families with XLA, Ott et al. (1986) concluded that there was 'clear evidence for heterogeneity of XLA.' The finding of possible linkage to Xg by Race and Sanger (1975) may have been related to their having a mixture of 'Xp' and 'Xq' families. Malcolm et al. (1989) presented further evidence, based on linkage data, for the existence of 2 loci.
Mensink et al. (1987) mapped XLA to Xq21.3-q22. No recombination was found between XLA and DXS17 (lod = greater than 6 at theta = 0); no recombinants were found between XLA and DXS17 in this study or in the study by Kwan et al. (1986)--with the exception of the remarkable Z pedigree which may have carried a different form of agammaglobulinemia. Malcolm et al. (1987) demonstrated close linkage to DNA markers in the Xq21.3-q22 region in studies of 15 families. Guioli et al. (1989) found close linkage of IMD1 and DXS178. No recombinants were observed, giving a maximum lod score of 5.92 at theta = 0. Kwan et al. (1990) demonstrated another marker closely linked to XLA, DXS178.
Fearon et al. (1987) used a strategy similar to that of Conley et al. (1986) to show that the defect in XLA is intrinsic to B cells as well as to detect the carrier state. According to their strategy, recombinant DNA probes simultaneously detect RFLPs and patterns of methylation of X-chromosome genes. (Different DNA methylation patterns reflect whether the X chromosome is active or inactive and these differences in methylation can be monitored by restriction endonucleases that have the capacity to recognize methylated cytosine residues.) Random X-inactivation patterns were observed in isolated peripheral blood granulocytes, T lymphocytes, and B lymphocytes of women who were not carriers. In contrast, 1 of the 2 X chromosomes was preferentially active in the B cells, but not the T cells or granulocytes, of 3 carriers of the disorder. Fearon et al. (1987) used X-chromosome inactivation analysis to demonstrate that the X chromosome with the wildtype allele at the agammaglobulinemia locus was the active one in all the B cells. Allen et al. (1994) tested carrier status by study of B lymphocytes and T lymphocytes separated by means of antibodies to the B-cell specific antigen CD19 (107265). B lymphocytes were isolated from the mononuclear cell fraction of 20 cc of blood by using anti-CD19 immunomagnetic beads. Quantitative PCR at the androgen-receptor locus was then used to examine patterns of X inactivation in CD19-positive B cells. The trinucleotide repeat at the androgen receptor locus (AR; 313700) is within approximately 100 bp of 2 HpaII restriction-enzyme sites that are methylated on the inactive X chromosome but unmethylated on the active X chromosome. Obligate carriers of XLA demonstrated more than 95% skewing of X inactivation in CD19-positive cells but not in CD19-negative cells. Allen et al. (1994) suggested that refinements in techniques for primary carrier testing and genetic mapping of XLA make possible an ordered approach to prenatal diagnosis and genetic counseling.
Schuurman et al. (1988) demonstrated the usefulness of linked RFLP markers in identifying the carrier state and in the early diagnosis of XLA in a newborn son.
Journet et al. (1992) demonstrated that the pregnant mother of a boy with XLA but no family history of immune disease was a carrier by demonstrating with a methylation-sensitive probe that the X-inactivation pattern was skewed in the woman's B cells but random in her polymorphonuclear cells. Using RFLP probes flanking the XLA locus on each side, they excluded the diagnosis of XLA in the fetus on the basis of a chorionic villus sample (risk of error less than 0.003). Subsequent studies of the baby confirmed normality.
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. (Cytoplasmic mu-chain protein has served as a marker for pre-B cells. Mu-chain gene expression precedes rearrangement and expression of light-chain genes.) Presumably the X chromosome codes for enzyme(s) specific for translocation of V(H) genes or a regulatory mechanism necessary for pre-B cells to differentiate to a stage using these enzymes.
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. There was also delayed expression of L chains. Peripheral blood and B-cell lines from the patient's mother and sister included 50% cells that expressed H chain without L chain. B-cell lines from the mother and sister produced both full-length mu and gamma H chains and truncated mu and delta chains corresponding to the H chains produced by the patient's B cells. Schwaber and Chen (1988) concluded that failure of variable region gene rearrangement may underlie the failure of B lymphoid development in XLA. They observed that immature B cells from a patient produced truncated mu and delta immunoglobulin H chains. In cases of XLA there is variability in the stage at which the arrest of development occurs; the major phenotype is arrested at the stage of pre-B cells, while a minor phenotype is arrested at the stage of immature B lymphocytes. The failure of B lymphoid development is associated in both phenotypes with a failure of Ig heavy chain variable region rearrangement. The immature B cells of a patient with the minor phenotype of XLA produce truncated gamma and delta heavy chains composed of a D-J-constant complex resulting from failure to rearrange a V segment. Schwaber et al. (1988) demonstrated that the fusion of these cells with mouse myeloma complemented the failure of V(H) gene rearrangement. H chains produced by such hybrid cells are composed of V(H)-D-J(H)-C. The genes encoding each of these elements were of human parental origin, indicating that the mouse myeloma provided a trans-acting regulatory element necessary for V(H) rearrangement which the XLA B cells lack. Complementation occurred in all hybrid cells examined, regardless of whether the human X chromosome was retained.
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.
X-Linked Agammaglobulinemia
Using probes derived for the Southern analysis of DNA from 33 unrelated families and 150 normal X chromosomes, Vetrie et al. (1993) detected restriction pattern abnormalities in 8 families. Five of them had deletions that were shown to be entirely intragenic to BTK, confirming involvement of BTK in XLA. Two single-base missense mutations (300300.0001 and 300300.0002) were identified in XLA patients. The failure of pre-B cells in the bone marrow of XLA males to develop into mature, circulating B cells could be the result of the product of the mutant ATK gene failing to fulfill its role in B-cell signaling.
For further information on the molecular genetics of XLA, see 300300.
X-Linked Hypogammaglobulinemia
Kornfeld et al. (1995) described the case of a 16-year-old boy who had recurrent upper respiratory tract infections at 13 months of age and was diagnosed as having transient hypogammaglobulinemia of infancy on the basis of low immunoglobulin levels, normal diphtheria and tetanus antibody responses, normal anterior and posterior cervical nodes, normal tonsillar tissue, and normal numbers of B cells in the blood. IgA levels returned to normal at 15 months of age and remained within normal limits over the next 12 months, and IgG and IgM levels remained relatively unchanged. At age 10, he began receiving intravenous gammaglobulin, which resulted in cessation of infections. The clinical picture was thought to be that of common variable immunodeficiency disease. However, gene studies revealed the deletion of exon 16 of the BTK gene resulting from a splice junction defect. The patient represents an example of the extreme variation that can occur in the XLA phenotype.
For information on animal models of XLA, including the X-linked immunodeficiency (xid) mouse mutation, see 300300.
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