Agammaglobulinemia and genetics
Agammaglobulinemia, specifically X-linked agammaglobulinemia (XLA), is an immunodeficiency disorder characterized by the absence of immunoglobulins due to a failure in the development of B lymphocytes, the immune cells responsible for producing antibodies. The condition is primarily inherited in an X-linked recessive manner, making males more susceptible since they possess only one X chromosome. The disorder is caused by mutations in the Bruton's tyrosine kinase (BTK) gene, which plays a crucial role in the maturation of B cells.
Individuals with XLA typically appear healthy at birth but begin to experience recurrent infections caused by specific bacteria and parasites as maternal antibodies decline. Diagnosis involves measuring serum immunoglobulin levels and conducting molecular genetic testing for BTK mutations. Treatment primarily consists of immunoglobulin replacement therapy, along with preventive measures against infections. Genetic counseling is recommended for families affected by XLA, as understanding the genetic factors can aid in managing the condition. With proper treatment, many individuals can lead healthy and productive lives.
Agammaglobulinemia and genetics
ALSO KNOWN AS: Bruton’s agammaglobulinemia; X-linked agammaglobulinemia (XLA); hypogammaglobulinemia
DEFINITION Agammaglobulinemia is a disorder of the immune system resulting from a failure of white blood cells, called "B lymphocytes," to develop. These cells are the source of the antibodies or immunoglobulins, which defend the body against infections.
Risk Factors
The disease is inherited as X-linked recessive. The defective gene is located on the X chromosome, which is one of two sex chromosomes (the other is the Y chromosome). In males, who have only one X chromosome, a defective gene causes agammaglobulinemia. In females, who have two X chromosomes, a defective gene on one chromosome is insufficient to cause disease but makes the woman a carrier capable of passing the abnormal gene to her children. Males cannot pass the disease to their sons, but they can pass the defective gene to their daughters, who will then be carriers. Rarely, spontaneous gene mutations cause the disease to appear without the mother being a carrier. These spontaneous mutations occur more often in the male gamete, and it has been observed that while the mother of a boy with X-linked agammaglobulinemia (XLA) has an 80 percent chance of being a carrier, the maternal grandmother is a carrier in only 25 percent of cases. XLA affects about three to six in one million males.
Etiology and Genetics
The defective gene responsible for this disease is Bruton’s tyrosine (BTK) gene, which is named in honor of the physician who first described the illness in 1952. The BTK gene is quite large, with nineteen exons encoding the 659 amino acids of the Btk and spanning 37.5 kilobase pairs (kb) on the long arm of the X chromosome (Xq21.33–q22). The BTK molecular location is from base pair 100,491,097 to base pair 100,527,837 on the X chromosome. More than eight hundred different mutations have been reported on the international mutation database. The Btk enzyme belongs to the Tec family of cytoplasmic tyrosine kinases and is expressed in hematopoietic cells, predominantly B cells. Btk is necessary for the development, differentiation, and functioning (signaling) of B cells. Btk deficiency blocks B cell development from the pro-B cell to pre-B cell transition, leading to a severe reduction in the number of circulating and failure of the humoral response associated with an inability to produce immunoglobulins. The specific BTK gene mutation may influence the severity of the illness, but environmental factors and functional aspects of other components of the immune system are also important influences.
Gross gene deletions of varying lengths may produce contiguous deletion syndrome affecting the X22q region. The defects in contiguous genes (TIMM8A, TAF7L, and DRP2) can complicate the problems of XLA by adding neurological impairment, sensorineural deafness, and dystonia. There are numerous other genetic causes for hypogammaglobulinemia or agammaglobulinemia, such as autosomal recessive agammaglobulinemia, hyper-IgM syndromes, and common variable immunodeficiency.
Symptoms
Patients with XLA are healthy at birth but start to have problems with infections after a few months, when the antibodies passed from the mother begin to dwindle. Patients have problems with common viral infections, but particularly with encapsulated bacteria (Streptococcus pneumoniae and Haemophilus influenzae) and a parasite (Giardia lamblia). Children are usually diagnosed during a hospitalization for a severe infection between the ages of two and five.
Screening and Diagnosis
The concentration of serum immunoglobulins can be measured, and the serum IgG level is typically lower than 200 milligrams per deciliter (mg/dL) in affected individuals. IgM and IgA are often low as well. The number of B (CD19+ cells) in the peripheral blood is markedly reduced. Finally, molecular genetic testing for mutations in the BTK gene can be employed for diagnosis, carrier detection, and prenatal diagnosis.
Treatment and Therapy
Since the original patient was described by Colonel Ogden Bruton in 1952, the primary treatment has been immunoglobulin replacement. The immunoglobulin may be administered intravenously once a month or subcutaneously each week. The dosages are adjusted to maintain a trough serum IgG level of 500 to 800 mg/dL as well as a satisfactory clinical response. Antibodies and other measures are employed when needed to manage infections. Live virus vaccines, such as oral polio vaccine, should be avoided. More recently, cures have been reported using stem cell transplants from the cord blood or bone marrow of histocompatible siblings.
Prevention and Outcomes
Genetic counseling should always be provided for the parents of an affected child. Fortunately, early diagnosis and aggressive treatment now enable most patients to lead moderately healthy and productive lives.
Bibliography
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Conley, Mary Ellen, et al. “Primary B Cell Immunodeficiencies: Comparisons and Contrasts.” Annual Review of Immunology 27 (2009): 199–227. Print.
Conley, Mary Ellen, and Vanessa C. Howard. "X-Linked Agammaglobulinemia." GeneReviews. U of Washington, Seattle, 17 Nov. 2011. Web. 14 July 2014.
Howard, Vanessa, et al. “The Health Status and Quality of Life of Adults with X-Linked Agammaglobulinemia.” Clinical Immunology 118 (2006): 201–8. Print.
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Mohamed, Abdalla J., et al. “Bruton’s Tyrosine Kinase (Btk): Function, Regulation, and Transformation with Special Emphasis on the pH Domain.” Immunological Reviews 228 (2009): 58–73. Print.