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Severe Combined Immunodeficiency Disorder (SCID)

By: Nastaran Soroori

History of SCID
First discovered by Glanzmann and Riniker in 1950 Swiss infants with the condition were very lymphopenic and died of infection before their first birthdays Within years, differences were noted in inheritance patterns for SCID More than one cause was noted for this fatal syndrome characterized by the absence of T-cells and all adaptive immunity

History of SCID continued

In some cases, there was an X-linked recessive mode of inheritance while in others an autosomal recessive mode of inheritance The first discovered molecular cause of human SCID, adenosine deaminase deficiency, was reported in 1972 In 1993, another cause of the conditions was found-the molecular basis of X-linked human SCID

History of SCID Continued

Advances in molecular biology and the Human Genome Project increased the knowledge of the various components of the immune system Studies of mutant mice and humans with genetically determined immunodeficiencies have contributed to the understanding of SCID SCID is known to be caused by at least mutations in 10 different genes

Bubble Boy

David Vetter

Symptoms of SCID
Recurrent infections-constantly the infant has new infections (i.e. pneumonia, meningitis, chickenpox, measles, and sepsis) Ear infections, sinus infections, chronic cough, thrush infections, diarrhea, liver infection, and rashes on the skin are more frequent Blood disorders, middle ear inflammation, weight loss, weakness, retarded growth, absent tonsils, absent lymphoid organs, lack of lymphocytes, and cold sores These symptoms do not directly confirm SCID, however, the recurrence of these symptoms with further testing can lead to the diagnosis of SCID

Symptoms of SCID Continued

A doctor can do a blood test to count the number of lymphocytes (the white blood cells affected in SCID) and test their function Parents need to be protective of where they take their child (i.e. dirty places, crowds of people, near contagious people should be avoided) If necessary, antibiotics, antifungal or antiviral medications as a preventative measure

Cause of SCID:Inheritance
The most common form of SCID exhibits an Xlinked 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

Cause of SCID: Inheritance

They only need to inherit one bad copy of the gene to have the symptoms of the disorder Females, on the other hand, have two X chromosomes and if they inherit one defective X chromosome, they still have its healthy pair They don't develop symptoms of the disorder, but they still carry the faulty gene and can pass it on to their children

Inheritance Patterns

Cause of SCID: The Immune System

The immune system is made up of organs and cells that work together to protect the body from infection and disease The immune system uses white blood cells to fight infections The white blood cells identify and attack cells that they do not recognize as belonging in the body

Cause of SCID: The Immune System

There are three types of lymphocytes
a) B cells make antibodies. Antibodies are proteins that attach to foreign cells and mark them to be attacked and destroyed. b) T cells direct B cells to make antibodies against foreign cells. T cells also direct the rest of the immune system when to attack or stop attacking foreign cells. They also help in the attack c) Natural killer cells (NK cells) destroy infected cells and cancer cells

Lymphocytes Photos

B Cells

T Cells

Natural Killer Cells

Cause of SCID Continued

People with SCID have a defect in their immune system that leaves them vulnerable to potentially deadly infections The most common form is caused by a mutation in the SCIDX1 gene located on the X chromosome This gene encodes a protein that is used to construct a receptor called IL2RG (interleukin-2 receptor) These receptors reside in the plasma membrane of immune cells Their job is to allow two types of immune cells - T cells and B cells - to communicate

Cause of SCID Continued

SCID can be caused in humans by mutations in at least 10 different genes The gene products of 3 of these mutated genes are components of cytokine receptors (the IL-2 receptor chain that is also shared with 5 other cytokine receptors [IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R]

Cause of SCID Continued

The products of 5 more genes (RAG1, RAG2, Artemis, CD3, and CD3) are necessary for antigen-receptor development The product of one gene (adenosine deaminase) is necessary for detoxification of metabolic products of the purine salvage pathway that cause lymphocytes to apoptose The final gene encodes CD45, a phosphatase that serves as a critical regulator of signaling thresholds in immune cells

Cause of SCID Continued

The most common form of human SCID is the X-linked type, caused by mutations in IL-2RG, which accounts for 46% of cases This is followed by adenosine deaminase deficiency in 16.1% of cases and IL-7Rchain deficiency in 10.3% of cases The relative frequencies of these different molecular types of human SCID may vary in other geographic areas

IL2RG Gene

Cause of SCID Continued

When the gene is mutated, the receptors cannot form and are absent from immune cells Results: the immune cells can't communicate with one another about invaders in the environment Not enough T and B cells are produced to fight off the infection, and the body is left defenseless

Treatment: Preventing Infections

The first concern is to prevent infections; Children with SCID need to be protected from germs This includes keeping them away from crowds and sick people They are treated with antibiotics to prevent infections such as Candida albicans (a type of yeast) and Pneumocystis pneumonia (PCP) infections They will also be given intravenous immune globulin (IVIG)

Treatment Continued
It contains antibodies that would normally be made by healthy B cells to help the body fight infection Immune globulin is usually infused into a vein Patients require IVIG infusions once every 3-4 weeks (each infusion may take from one to five hours) Side effects: chills, headaches, fever, nausea and chest tightness

Treatment: Enzyme therapy for ADA deficiency SCID

The standard treatment for ADA deficiency SCID is treatment with a form of the ADA enzyme called PEG-ADA Treatment with PEG-ADA is effective in about 90% of children However, despite PEG-ADA therapy, some children continue to require IVIG treatments.

Treatment: Gene Therapy

A treatment option being studied in clinical trials is gene therapy Gene therapy has shown promising results for some patients with ADA deficiency SCID Gene therapy appeared to be a promising treatment for X-linked SCID, but some children treated with gene therapy developed leukemia New trials of gene therapy are in progress Gene therapy remains an experimental treatment for SCID

Treatment: Transplant
The only known cure for SCID is a bone marrow or cord blood transplant (also called a BMT) This procedure replaces the child's abnormal blood-forming cells and immune system with healthy blood-forming cells from a family member or unrelated donor or cord blood unit The donor must closely match the patients tissue type The best donor is usually a matched sibling

Treatment: Transplant Continued

Each sibling has a 25% chance of being a suitable match, many children with SCID do not have a healthy matched sibling Parent might also be a good match Each parent's tissue type matches half of the child's tissue type (a haploidentical match) For SCID, survival rates have been high enough to make them a good option for patients who do not have a matched sibling donor The sooner the treatment begins and the better match, the higher chance of a good outcome

Bone Marrow Transplant Photo

Identifications of SCID
Newborn screening tests Nearly all babies will have a blood test to check for disorders that are not apparent immediately after the baby is born Genetic Counseling: Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the diseasecausing IL2RG mutation has been identified in the family

Identifications Continued
If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50% Males who inherit the mutation will be affected Molecular Genetic Testing: IL2RG gene Lymphocyte functional tests: White blood cell count

Work Cited
Allenspach, Eric. "Summary." X-Linked Severe Combined Immunodeficiency. U.S. National Library of Medicine, 26 Aug. 2003. Web. 25 Feb. 2013. "Learning About Severe Combined Immunodeficiency (SCID)." Learning About Severe Combined Immunodeficiency (SCID). N.p., 3 Oct. 2011. Web. 27 Feb. 2013. Naynesh Kamani, M. "Severe Combined Immunodeficiency (SCID) and Transplant." Severe Combined Immunodeficiency. N.p., 2011. Web. 27 Feb. 2013. Severe combined immunodeficiency." Severe Combined Immunodeficiency. N.p., n.d. Web. 27 Feb. 2013. "Severe Combined Immunodeficiency (SCID)." Severe Combined Immunodeficiency (SCID). Children's Hospital of Wisconsin in Milwaukee, n.d. Web. 27 Feb. 2013. "X-linked Severe Combined Immunodeficiency." X-linked SCID. N.p., n.d. Web. 27 Feb. 2013.