$Unique_ID{BRK04214} $Pretitle{} $Title{Severe Combined Immunodeficiency} $Subject{Severe Combined Immunodeficiency SCID Autosomal recessive SCID Adenosine deaminase (ADA) deficiency ADA Deficiency X-linked recessive SCID Bare lymphocyte syndrome SCID with leukopenia reticular dysgenesis} $Volume{} $Log{} Copyright (C) 1986, 1987, 1988, 1989, 1990, 1992 National Organization for Rare Disorders, Inc. 77: Severe Combined Immunodeficiency ** IMPORTANT ** It is possible that the main title of the article (Severe Combined Immunodeficiency) is not the name you expected. Please check the SYNONYM listing to find the alternate names and disorder subdivisions covered by this article. Synonyms SCID DISORDER SUBDIVISIONS: Autosomal recessive SCID Adenosine deaminase (ADA) deficiency ADA Deficiency X-linked recessive SCID Bare lymphocyte syndrome SCID with leukopenia, also known as reticular dysgenesis General Discussion ** REMINDER ** The information contained in the Rare Disease Database is provided for educational purposes only. It should not be used for diagnostic or treatment purposes. If you wish to obtain more information about this disorder, please contact your personal physician and/or the agencies listed in the "Resources" section of this report. Severe Combined Immunodeficiency (SCID) comprises a group of congenital syndromes in which there appears to be no adaptive immune function whatever. Both the ability to acquire immunity (cell mediated immunity) and to form antibodies (humoral immunity) are absent. Thus the patient lacks all resistance against bacteria, viruses, fungi, and other infectious agents. Untreated SCID results in frequent, severe infections, growth retardation and a short life span. Several causes and types of SCID have been identified. Symptoms Young infants with SCID usually have some protection against infection because they retain maternal antibodies during the first few months of life. After this period, however, infections become extremely frequent. Otitis media, pneumonia, sepsis, diarrhea, and skin infections recur constantly. The child becomes thin and weak, and growth slows drastically. Opportunistic organisms that may cause fatal infections include Candida albicans (a yeast that normally causes thrush and related infections), vaccinia, varicella (chickenpox), measles, cytomegalovirus, and the live bacteria in the BCG vaccine against tuberculosis. Pneumocystis carinii is a common cause of pneumonia that is very difficult to treat. SCID patients also do not reject foreign tissue. Immunocompetant cells introduced into the patient's body may cause graft-versus-host-disease, reacting primarily against the recipient's skin, liver, gut, and bone marrow. Such cells may derive from the administration of fresh whole blood containing incompatible lymphocytes, or unmatched bone marrow. The patients do not reject transplants which facilitates the transplantation of bone marrow, one of the only effective treatments in this disorder. Patients do not have cutaneous reactions to antigens, and they do not develop allergic reactions. After immunization, no antibodies are formed; if immunization is with a live vaccine, fatal infections may ensue. Many individuals with SCID related to adenosine deaminase deficiency have skeletal abnormalities, particularly of the rib cage. T- and B-lymphocytes in the blood of SCID patients are usually severely reduced in number or absent, as are serum immunoglobulins (antibodies). In some patients, individual immunoglobin classes may be present in normal or even elevated concentrations, and rarely, a patient may have low or normal numbers of B- and/or T-lymphocytes. None of these cells, or proteins, however, function properly. SCID patients have small, undeveloped thymuses, their lymph nodes are devoid of lymphocytes, and tonsils, adenoids, and other lymphoid organs are poorly developed or absent. In SCID with leukopenia, sometimes known as reticular dysgenesis, granular leukocytes are also absent or greatly reduced in number. The granulocytes are white blood cells which engulf invading microorganisms, especially bacteria. Patients with SCID with leukopenia have virtually no means of removing invading organisms from the body. Causes Hereditary SCID occurs in autosomal recessive and X linked recessive forms. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene from each parent. If one receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will show no symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children will be carriers, but healthy as described above. Twenty-five percent of their children will receive both normal genes, one from each parent and will be genetically normal. X-linked recessive disorders are conditions which are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males have only one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a fifty percent risk of transmitting the carrier condition to their daughters, and a fifty percent risk of transmitting the disease to their sons.) Some cases of autosomal recessive SCID can be attributed to a deficiency of the enzyme adenosine deaminase (ADA). A lack of ADA results in high levels of adenosine in the plasma. Lymphocytes "trap" unusually high levels of this adenosine because they have an enzyme which converts it to deoxyadenosine triphosphate. This substance cannot leave the cell, and it affects the regulation of DNA synthesis. In this way, cell division, the production of antibodies, and other metabolic processes are severely disrupted. In the "bare lymphocyte" syndrome, clinical SCID is associated with a lack of histocompatibility antigens and B2 microglobin on the lymphocytes. Both of these proteins help distinguish cells belonging to the individual from foreign ones; in addition, it is thought that they are essential to the maturation of functional T-lymphocytes. Affected Population Severe Combined Immunodeficiency is estimated to occur with a frequency of about 1 in 100,000 to 500,000 live births. Related Disorders Various other forms of immunodeficiency exist. They include the acquired immune deficiency syndrome, isolated defects of T-cell function, and various antibody disorders. Therapies: Standard Bone marrow transplantation can cure this disorder if an identical match can be found to donate the marrow. Graft-versus-host (GVH) disease often occurs, and may be severe if the tissues are poorly matched. The use of haplo- identical bone marrow cells, treated to remove those cells likely to cause GVH disease, but leaving stem cells intact, has facilitated this procedure greatly. Fetal liver grafts, which contain lymphoid and white blood stem cells, have been effective in some cases in restoring T-cell function, but not in restoring the ability to produce antibodies. Fetal thymus grafts have usually been unsuccessful. In ADA deficiency, limited immunologic function may be restored by regularly transfusing red blood cells, which seem to be able to absorb and metabolize some of the excess circulating adenosine. Care must be taken to remove viable lymphocytes, as these could produce GVH disease. Iron overload is a possible side effect. In isolated cases, agents such as transfer factor, thymosin, and levamisole may augment existing cellular immunity. In 1990 the FDA approved PEG-ADA, an orphan drug that replaces the ADA enzyme deficiency in SCID. Children taking PEG-ADA through a weekly injection have had a normal immune system restored and they are recovering from infections that might previously have been deadly. For more information on PEG-ADA, please contact: Enzon Inc. 300C Corporate Court South Plainfield, NJ 07080 (201) 668-1800 Infections in people with SCID must be treated vigorously with antifungal, antibiotic, and supportive measures. P. carinii pneumonia can be particularly difficult to treat; the two drugs used are usually trimethoprim- sulfamethoxazole and the orphan drug pentamidine idethionate. (For further information on treatment, choose "AIDS" as your search term in the Rare Disease Database.) Cytomegalovirus and generalized herpes simplex infections are preferentially treated with idoxuridine, floxuridine, or cytabaradine. Severe candida and related fungii usually respond to amphotericin B therapy. Therapies: Investigational Scientists at Johns Hopkins University in Maryland are studying the use of thalidomide as a treatment for Graft vs. Host disease (GVHD). Preliminary studies indicate that it may have beneficial side effects on skin and hair symptoms. The major side effect of thalidomide is sedation, and it causes serious birth defects when given to pregnant women. More research is necessary to determine long-term safety and effectiveness of this treatment for GVHD. Thalidomide is available in England under special license from Penn Pharmaceuticals of Tredegar, South Wales. Scientists at the National Institutes of Health intend to try "gene therapy" on SCID patients with the hope of inserting a gene that manufactures ADA in these patients. The FDA Orphan Products Division awarded a grant in 1988 to Dr. Carol Michele Paradise, M.D., of Cetus Corporation, Emeryville, CA, for her treatment of Severe Combined Immunodeficiency with Interleukin-2. ADA deficient Severe Combined Immune Deficiency has been chosen as the first disease to be treated by "human gene therapy." The National Institutes of Health (NIH) are using the experimental procedure, in combination with the orphan drug PEG-ADA, to enhance the immune system of children with ADA deficient SCID. The procedure involves implanting a gene that makes human ADA into an activated virus. When the virus merges into the patient's cells, it manufactures the human enzyme. The corrected cells will be infused into the patient every few months. Patients interested in participating in this experimental protocol should ask their physicians to contact: Dr. Nelson Wivel Office of Recombinant DNA Activities National Institutes of Health, Bldg. 31, Rm. 4B11 Bethesda, MD 20892 Clinical trials are underway to study patients with genetically- determined immunodeficiency diseases. For infants with Severe Combined Immunodeficiency Disease (SCID), a highly effective new form of therapy is offered. Interested persons may contact: Rebecca H. Buckley, M.D. Box 2898 Duke University Medical Center Durham, NC 27710 (919) 684-2922 to see if further patients are needed for this study. This disease entry is based upon medical information available through January 1992. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder. Resources For more information on Severe Combined Immunodeficiency, please contact: National Organization for Rare Disorders (NORD) P.O. Box 8923 New Fairfield, CT 06812-1783 (203) 746-6518 Immune Deficiency Foundation 3565 Ellicott Mill Drive, Unit B2 Ellicott City, MD 21043 (800) 296-4433 (410) 461-3127 Dr. M. Hershfield Duke University Hospital Room 418 Sands Bldg. Durham, NC 27710 NIH/National Institute of Allergy and Infectious Diseases 9000 Rockville Pike Bethesda, MD 20892 (301) 496-5717 References Immunodeficiency. Buckley, R.H.; J Allergy Clin Immunol 1983 Dec; 72(6):627- 641. Metabolic Defects in Immunodeficiency Diseases. Webster, A.D.B.; Clin Exp Immunol 1982 Jul; 49(1):1-10. Combined Immunodeficiency and Thymic Abnormalities. Webster, A.D.B.; J Clin Pathol (Suppl) 1979; (13):10-14. MENDELIAN INHERITANCE IN MAN, 8th ed.: Victor A. MuKusick, Johns Hopkins University Press, 1986. Pp. 794, 18. THE METABOLIC BASIS OF INHERITED DISEASE, 5th Ed.: John B. Stanbury, et al.; eds; McGraw Hill, 1983. Pp. 2354.