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$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
     [phone]

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
     [phone]

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
     [phone]

     Immune Deficiency Foundation
     3565 Ellicott Mill Drive, Unit B2
     Ellicott City, MD 21043
     [phone]
     [phone]

     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
     [phone]

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.