I. II.

TITLE : CASE 3 X LINKED AGAMMAGLOBULINEMIA OBJECTIVES GENERAL: After the discussion, the medical students should be able to describe the anomalies in X-linked agammaglobulinemia. SPECIFIC: a. To be able to identify the genetic abnormality in Brutons Agammaglobulinemia. b. To be able to enumerate and describe the symptoms related to the disease. c. To be able to differentiate the patients problem with other immunologic abnormalities.

III.

DIAGNOSIS X-linked Aggamaglobulinemia or Brutons Agammagobulinemia is an inherited immunodeficiency in which the body is unable to produce the antibodies needed to defend against bacteria and viruses. There is a genetic defect in a gene called Bruton's Tyrosine Kinase (BTK), which prevents B cells from developing normally. B cells are responsible for producing the antibodies that the immune system relies on to fight off infection. The most common bacteria causing infection in XLA are Streptococcus, Staphylococcus and Haemophilus.

IV.

CLINICAL MANIFESTATION / DEFENSE OF THE DIAGNOSIS -Episodes of bacterial infections -Peripheral blood revealed an absence of cells responsive to pokeweed mitogen. -Aspirates of the bone marrow showed hypercellularity of pro-B cells.

V.

PHYSIOLOGICAL BASIS X-linked agammaglobulinemia is one of the more common forms of primary immunodeficiency. It is characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to mature into B cells . During normal B-cell maturation in the bone marrow, the immunoglobulin heavy-chain genes are rearranged first, followed by rearrangement of the light chain genes. In X-linked agammaglobulinemia, B-cell maturation stops after the rearrangement of heavy chain genes. Because light chains are not produced, the complete immunoglobulin molecule (which contains heavy and light chains) cannot be assembled and transported to the cell membrane. Free heavy chains can be found in the cytoplasm. This block in differentiation is due to mutations in a cytoplasmic tyrosine kinase, called B-cell tyrosine kinase (Btk).[95] Btk is a

protein tyrosine kinase associated with the antigen receptor complex of pre-B and mature B cells. It is needed to transduce signals from the antigen receptor that are critical for driving maturation. When it is mutated, the pre-B cell receptor cannot deliver signals, and maturation stops at this stage. The BTK gene maps to the long arm of the X chromosome at Xq21.22. VI. ANSWERS TO QUESTIONS:

1. What is your diagnosis? What genetic abnormality is involved and its significance? X-linked Aggamaglobulinemia or Brutons Agammagobulinemia X-Linked Agammaglobulinemia (XLA) is an inherited immunodeficiency in which the body is unable to produce the antibodies needed to defend against bacteria and viruses. There is a genetic defect in a gene called Bruton's Tyrosine Kinase (BTK), which prevents B cells from developing normally. B cells are responsible for producing the antibodies that the immune system relies on to fight off infection. The most common bacteria causing infection in XLA are Streptococcus, Staphylococcus and Haemophilus. 2. Why should your symptoms appear only after some time after birth? What type of pathogens would the patient be most likely susceptible to? Symptoms appear only after birth because the infant still has maternal immunoglobulins transferred via the placenta. After the immunoglobulins are waned off, the baby can not produce B lymphocytes to protect him/herself from the disease. The pathogens that the patient would be most likely susceptible to are: o Streptococcus Pneumoniae o Haemophilus Influenzae o Pseudomonas species 3. Differentiate the pateints problem with the following immunologic abnormalities: a. DiGeorge Syndrome DiGeorge syndrome is a genetic, congenital disorder that is present at birth. DiGeorge syndrome is rare and is caused by an abnormality of chromosome 22. Problems include an underactive parathyroid gland (hypoparathyroidism), an underdeveloped or missing thymus gland (hypoplastic thymus), heart defects, and cleft palate and/or cleft lip. b. Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome is a condition that affects blood cells and cells of the immune system. This condition is seen almost exclusively in males.

Individuals with this condition have microthrombocytopenia, which is a decrease in the number and size of blood cells involved in clotting (platelets). This platelet abnormality, which is typically present from birth, can lead to easy bruising or episodes of prolonged bleeding following minor trauma. Eczema, an inflammatory skin disorder characterized by abnormal patches of red, irritated skin, often occurs in people with this condition. Affected individuals also have an increased risk of infection due to dysfunction of many types of immune cells, such as T cells, B cells, dendritic cells, and natural killer cells. Some people develop autoimmune disorders, which occur when the immune system malfunctions and attacks the body's tissues and organs by mistake. The risk of developing some types of cancer, such as cancer of the immune system cells (lymphoma), is increased in people with Wiskott-Aldrich syndrome. c. Severe Combined Immunodeficiency (SCID) SCID is a group of very rare-and potentially fatal-inherited disorders related to the immune system. The immune system normally fights off attacks from dangerous bacteria and viruses. People with SCID have a defect in their immune system that leaves them vulnerable to potentially deadly infections. The most common form of SCID exhibits an X-linked recessive pattern of inheritance, and is therefore referred to as X-linked SCID. When a gene is located on the X chromosome, males are more often affected than females. Males do not have a second X chromosome to compensate for the defective one. They only need to inherit one bad copy of the gene to have the symptoms of the disorder. Symptoms usually appear in the first few months of life. Because the immune system cannot protect the baby's body, babies with the disorder tend to get one infection after another. Some of these bacterial infections may be life-threatening, including pneumonia (lung infection), meningitis (brain infection), and sepsis (blood infection).To make matters worse, SCID patients often don't respond to the antibiotics used to treat bacterial infections. They may suffer more frequently from ear infections, sinus infections, a chronic cough, and rashes on the skin. Reference: http://ghr.nlm.nih.gov/condition/wiskott-aldrich-syndrome http://learn.genetics.utah.edu/content/disorders/whataregd/scid/ http://www.rightdiagnosis.com/d/digeorge_syndrome/intro.htm