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An agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes in the blood and lymph. Antibodies are proteins (immunoglobulins, (IgM), (IgG), etc) that are critical and key components of the immune system. They are essential if the immune system is to do its job of fighting off bacteria, viruses, and other foreign substances that threaten the body. The specialized precursor cells that produce gammaglobulins, fail to develop or function properly leading to the deficiency in the number of mature lymphocyte cells called B cells.
The agammaglobulinemia is X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia (ARAG). All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin to fight off infections.
Agammaglobulinemia is comprised of the following types:
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X-linked agammaglobulinemia (XLA), was discovered in 1952 by Dr. Ogden Bruton.[rx]
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X-linked agammaglobulinemia with growth hormone deficiency
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Autosomal recessive agammaglobulinemia (ARAG)
Symptoms
The major symptoms of agammaglobulinemia are serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such infections only late in the first year of life, after the IgG antibodies from the mother have been depleted.
Infections by almost any of the enterovirus family and the poliomyelitis virus can result in unusually severe illness in children with agammaglobulinemia. Echovirus infection can cause a group of symptoms that closely resembles dermatomyositis. These symptoms may include muscle weakness, often in the hip and shoulder areas, and difficulty swallowing. Areas of patchy, reddish skin may appear around the eyes, knuckles, and elbows and occasionally on the knees and ankles. (For more information on this disorder, choose “dermatomyositis” as your search term in the Rare Disease Database.)
Infections caused by mycoplasma bacteria can lead to severe pain, swelling, stiffness, or reduced movement. সহজ বাংলা: জয়েন্টের প্রদাহ।" data-rx-term="arthritis" data-rx-definition="Arthritis means joint inflammation causing pain, swelling, stiffness, or reduced movement. সহজ বাংলা: জয়েন্টের প্রদাহ।">arthritis including joint swelling and pain, in children with primary agammaglobulinemia. Hemophilus influenzae is the most common mucous-producing infection (pyogenic) that occurs in people with X-linked agammaglobulinemia. Children may also have repeated infections with pneumococci, streptococci, staphylococci bacteria, and infrequently pseudomonas infections.
Males with an X-linked form of agammaglobulinemia have very low levels of IgA, IgG, and IgM antibodies circulating in their blood. Specialized white blood cells (neutrophils) are impaired in their ability to destroy bacteria, viruses, or other invading organisms (microbes). This occurs because neutrophils require antibodies from the immune system to begin to destroy invading bacteria (opsonization). The levels of circulating neutrophils in children with agammaglobulinemia may be persistently low or may wax and wane (cyclic, transient bacterial infection. সহজ বাংলা: ব্যাকটেরিয়ার বিরুদ্ধে লড়াই করা শ্বেত রক্তকণিকা।" data-rx-term="neutrophil" data-rx-definition="Neutrophil is a white blood cell important for fighting bacterial infection. সহজ বাংলা: ব্যাকটেরিয়ার বিরুদ্ধে লড়াই করা শ্বেত রক্তকণিকা।">neutrophil count, which may increase infection risk. সহজ বাংলা: নিউট্রোফিল কম থাকা, সংক্রমণের ঝুঁকি বাড়তে পারে।" data-rx-term="neutropenia" data-rx-definition="Neutropenia means low neutrophil count, which may increase infection risk. সহজ বাংলা: নিউট্রোফিল কম থাকা, সংক্রমণের ঝুঁকি বাড়তে পারে।">neutropenia) in people with these disorders. The number of B-lymphocytes in children with X-linked agammaglobulinemia is less than one-hundredth of the normal number.
Only about 10 persons in 5 or 6 families have been diagnosed with X-linked agammaglobulinemia with growth hormone deficiency. The boys in these families have reduced or undetectable numbers of B-lymphocytes. Clinicians and geneticists speculate that a second mutation in the BTK gene, very close to the mutation in this gene that causes XLA, is responsible for the combination of agammaglobulinemia and very short stature.
Symptoms include frequent episodes of:
- Bronchitis (airway infection)
- Chronic diarrhea
- Conjunctivitis (eye infection)
- Otitis media (middle ear infection)
- Pneumonia (lung infection)
- Sinusitis (sinus infection)
- Skin infections
- Upper respiratory tract infections
Infections typically appear in the first 4 years of life.
Other symptoms include:
- Bronchiectasis (a disease in which the small air sacs in the lungs become damaged and enlarged)
- Asthma without a known cause
Autosomal recessive agammaglobulinemia has been reported to be due to genes that affect B cell development.
Causes
X-linked agammaglobulinemia (B-lymphocyte defect) is inherited as an X-linked recessive genetic trait. The abnormal gene, named BTK, has been mapped to gene locus Xq21.3-q22. A different mutation in the BTK gene causes X-linked agammaglobulinemia with growth hormone deficiency. The genetic cause of ARAG is much more complex involving other genes that have been mapped to loci on different chromosomes: 22q11.21, 14q32.33, and 9q34.13. The genes at three sites are known as IGLL1, IGHM, and LCRR8 respectively.
Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 21q11.21” refers to band 11.21 on the long arm of chromosome 21. Similarly, 14q32.33 refers to band 32.33 on the long arm of chromosome 14, and 9q34.13 refers to band 34.13 on the long arm of chromosome 9. The site described as Xq21.3-q22 refers to a region on the long arm of the X chromosome between bands 21.3 and 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Treatment
The administration of intravenous gammaglobulin replacement therapy is a standard treatment for agammaglobulinemia. Intravenous gammaglobulin or subcutaneous. is used to treat agammaglobulinemias and common variable immunodeficiency.
Antibiotics are prescribed for people with agammaglobulinemia when bacterial infections occur. Some patients are treated with antibiotics as a preventive measure (prophylactically). All immunodeficient people should be protected as much as possible from exposure to infectious diseases. Corticosteroids or any drug that depresses the immune system (immunosuppressant drugs) should be avoided as much as possible, as well as physical activities such as rough contact sports that risk damage to the spleen.
Replacement of IV immunoglobulins (IVIG) has altered the outcome & quality of life in patients with X-linked agammaglobulinemia. Being the cornerstone of treatment, immunoglobulins are replaced every 3-4 weeks intravenously or every 1-2 weeks subcutaneously. Patients might require a loading dose (e.g., 1 dose of 1 g/kg body weight or divided into separate doses), followed by maintenance therapy (400 to 600 mg/kg/month). These doses and intervals are adjusted to maintain serum trough level at least above 500 mg/dl and may vary on a case by case basis. For instance, patients with chronic refractory sinusitis or chronic lung disease may require higher trough levels (>800 mg/dl).[rx]
Though IVIG is the main treatment option for these patients, it has its drawbacks such as;
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It protects against most pathogens, but protection against uncommon pathogens is limited if the donor pool has not been exposed to them.
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During treatment, only IgG is replaced while the rest of the immunoglobulins are not; these include IgA, and IgM, which have their unique functions, particularly protecting mucosal surfaces.
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Replacement IVIG therapy is very costly and not sustainable – especially in areas with limited resources.
Subcutaneous administration of IgG is an alternative to IVIG in case of difficult IV access or adverse reaction to IVIG. Just as safe as IVIG, with fewer systemic adverse effects, and smaller fluctuations in serum concentrations, the ability to self-administer IgG at home brings added convenience to this method. Overall this method will improve the patient’s quality of life. In very rare cases with subcutaneous IgG, local side effects like swelling, erythema, and tenderness may occur. These side effects tend to resolve within 24 hours.[rx]
Hematopoietic stem cell transplantation (HSCT) is an alternate treatment for these patients. It is a tedious procedure with difficulty in matching suitable donors, making this treatment less popular. Additionally, there are heightened risks of allogeneic HSCT, including rejection and graft-versus-host disease. Often people in developing countries opt for HSCT because of a lack of resources and high costs, making IVIG less suitable.
A potential therapy for XLA is stem cell gene therapy, which has the potential to cure XLA. However, this technology is still in its developing stages and is associated with severe complications because of the random integration of the vector into chromosomes; this can lead to an increased risk of cancer, and in some cases, even death. While adenovirus vectors have been under investigation as a method to repair the BTK gene, the long-term success of this treatment is still unknown.[rx]
In addition to IVIG, these patients will require aggressive antibiotic therapy for any suspected or documented infections. The prolonged use of antibiotic therapy may be indicated in some patients for ongoing pulmonary infections or chronic sinusitis. In prophylactic therapy, many antibiotic options exist, but with little reliable data available, the effectiveness of a specific regimen for patients with XLA is lacking. It is typically initiated with amoxicillin, trimethoprim-sulfamethoxazole, or azithromycin. If these are deemed non-effective, others such as amoxicillin-clavulanate or clarithromycin may be used. Some practitioners opt between full therapeutic doses or half-doses, some rotate preventative antibiotics every 1 to 6 months, and others stick with one agent.
The goal of the regimen is to ensure coverage over the following organisms: Enterococcus faecalis, Staphylococcus species, Streptococcus species, Streptococcus pneumonia, and also some gram-negative bacteria like Escherichia coli, Hemophilus influenzae, Proteus mirabilis, and Neisseria gonorrhoeae.
Patients that develop bronchiectasis may benefit from bronchopulmonary hygiene, regular macrolide, and inhaled corticosteroids. The need for short- and long-acting inhaled B2 agonists, in bronchiectasis, is debatable.[rx]
In people with immunodeficiency with elevated IgM, there is a tendency to bleed excessively associated with abnormally low levels of circulating platelets in the blood (thrombocytopenia). This may complicate any surgical procedure.
Genetic counseling is recommended for people with agammaglobulinemias and their families. Another treatment is symptomatic and supportive.
References
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