Agammaglobulinemia is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of ... Agammaglobulinemia is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. The most common form of agammaglobulinemia is X-linked agammaglobulinemia (AGMX1, XLA; 300755), also known as Bruton disease, which is caused by mutation in the BTK gene (300300). AGMX1 accounts for anywhere from 85 to 95% of males who have the characteristic findings (Lopez Granados et al., 2002; Ferrari et al., 2007). Autosomal recessive inheritance of agammaglobulinemia, which has a similar phenotype to that of the X-linked form, has been observed in a small number of families, and accounts for up to 15% of patients with agammaglobulinemia (Ferrari et al., 2007). Conley (1999) gave a comprehensive review of autosomal recessive agammaglobulinemia. - Genetic Heterogeneity of Autosomal Agammaglobulinemia Autosomal agammaglobulinemia is a genetically heterogeneous disorder: see also AGM2 (613500), caused by mutation in the IGLL1 gene (146770); AGM3 (613501), caused by mutation in the CD79A gene (112205); AGM4 (613502), caused by mutation in the BLNK gene (604515); AGM5 (613506), caused by disruption of the LRRC8 gene (608360); AGM6 (612692), caused by mutation in the CD79B gene (147245); and AGM7 (615214), caused by mutation in the PIK3R1 gene (171833).
Conley and Sweinberg (1992) reported 2 girls with a recessive disorder phenotypically identical to the X-linked form (300755), but with a likely autosomal origin.
Yel et al. (1996) reported 2 consanguineous families with autosomal recessive agammaglobulinemia. ... Conley and Sweinberg (1992) reported 2 girls with a recessive disorder phenotypically identical to the X-linked form (300755), but with a likely autosomal origin. Yel et al. (1996) reported 2 consanguineous families with autosomal recessive agammaglobulinemia. The first was of Scottish-Irish descent living in Appalachia. The oldest patient was evaluated at age 9 months for fever, weakness, and rashes. He was found to have hypogammaglobulinemia and absent B cells, and died at age 4.5 years of chronic enteroviral encephalitis. Two other family members, including 1 girl, were later evaluated because of persistent early-onset infections and hypogammaglobulinemia. Another patient was diagnosed at age 1 month due to the family history. He did not develop infections after treatment with intravenous immunoglobulin (IV Ig). Two of the patients had previously been reported by McKinney et al. (1987). The second family reported by Yel et al. (1996) was of Turkish origin. Two sibs had recurrent infections in infancy and were found have hypogammaglobulinemia with absent B cells. A third patient, of Korean origin, had sporadic disease. All patients were treated with IV Ig. Meffre et al. (1996) described a young female patient with severe agammaglobulinemia in whom they demonstrated, by a detailed analysis of B cell subpopulations and B cell-specific transcripts, a blockage at an early pro-B cell stage of the B-cell differentiation pathway before the onset of immunoglobulin gene rearrangement. This case was considered reminiscent of the phenotype of Pax5 knockout mice (Urbanek et al., 1994), but since the coding sequence of the patient's PAX5 (167414) cDNA was normal, Meffre et al. (1996) speculated that the defect might result from an altered regulation of this gene. All the data indicated that the patient had a new genetic defect that resulted in an arrest of differentiation within the pro-B cell compartment, i.e., earlier than in X-linked agammaglobulinemia. Lopez Granados et al. (2002) reported 6 additional families with agammaglobulinemia-1 confirmed by mutation analysis of the IGHM gene. The families were of various origins, including Swedish, Spanish, Italian, and Argentinian. All of the patients had onset of recurrent infections in the first year of life. Infections included pneumonia, otitis, conjunctivitis, sinusitis, pseudomonas infections, and enteroviral infections. Many patients had failure to thrive and diarrhea. Some had neutropenia, 1 had skin infections, and several developed bronchiectasis. The phenotype in general was more severe than that observed in X-linked agammaglobulinemia; those with IGHM mutations had earlier onset and more severe complications. However, most patients responded well to gammaglobulin treatment.
In affected individuals from 2 consanguineous families with autosomal recessive agammaglobulinemia, Yel et al. (1996) demonstrated 2 different homozygous mutations in the IGHM gene on chromosome 14 (147020.0001-147020.0002). A third Korean boy with the disorder was compound heterozygous ... In affected individuals from 2 consanguineous families with autosomal recessive agammaglobulinemia, Yel et al. (1996) demonstrated 2 different homozygous mutations in the IGHM gene on chromosome 14 (147020.0001-147020.0002). A third Korean boy with the disorder was compound heterozygous for a mutation (147020.0003) and a deletion of the IGHM gene. Lopez Granados et al. (2002) identified different mutations in the IGHM gene (see, e.g., 147020.0004 and 147020.0005) in affected members of 9 unrelated families with agammaglobulinemia-1. Two of the mutations were large deletions that removed more than 40 kb of DNA at the IGHM locus. Six families carried the same splice site mutation (147020.0002) that was present on different haplotypes, indicating a hotspot for mutations. Lopez Granados et al. (2002) concluded that 20 to 30% of patients with autosomal recessive defects in B-cell development have mutations in the IGHM gene.