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 ... 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). See agammaglobulinemia-1 (AGM1; 601495) for a discussion of genetic heterogeneity of the 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, ... 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.
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 ... - 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.