X-linked Severe Combined Immunodeficiency

X-linked severe combined immunodeficiency is an inherited genetic disorder affecting the immune system's ability to ward off infections. It belongs to a family of immune disorders called severe combined immunodeficiencies (SCIDs).

The immune system protects the body against bacteria, parasites, viruses, and fungi. Adapted from: NCI.

Other Names

• X-SCID
• SCID-X1
• The "boy-in-the-bubble" disease

Video of a child with SCID, which renders the body unable to fight off infection.

Signs and Symptoms

The clinical presentation of the different SCID conditions is fairly uniform and is characterized by the early onset of infections (usually in the respiratory tract and the gut). Common opportunistic organisms such as Pneumocystis carinii and Aspergillus and intracellular organisms such as cytomegalovirus can cause recurrent infections and a failure to thrive. Infants with X-linked severe combined immunodeficiency experience recurrent and persistent infections caused by certain bacteria, viruses, and fungi. This results in a myriad of symptoms associated with infections, such as fever, skin rashes, and diarrhea. The severity of these clinical manifestations makes SCID a medical emergency that, in the absence of treatment, leads to death within the first year of life.

Causes

Mutations in the IL2RG gene cause X-linked severe combined immunodeficiency.

The IL2RG gene encodes for a protein that is essential to immune system function. This protein is necessary for the growth and maturation of developing immune system cells called lymphocytes, which are a type of white blood cell. Lymphocytes defend the body against infection, make antibodies to sustain immunity, and help regulate the entire immune system. Mutations in the IL2RG gene prevent these cells from developing and functioning normally. Without functional lymphocytes, the body is unable to fight off infections.

The official name of this gene is “interleukin 2 receptor, gamma (severe combined immunodeficiency).” The IL2RG gene provides instructions for making a protein called the common gamma chain. This receptor protein is located on the surface of immature blood-forming cells in bone marrow. It has one end outside the cell like an antenna and the other end inside to transmit signals to the cell's nucleus. The common gamma chain partners with other proteins to direct blood-forming cells to form lymphocytes. The receptor also directs the growth and maturation of lymphocyte subtypes: T cells, B cells, and natural killer cells. These cells kill viruses, make antibodies, and help regulate the entire immune system.

More than 200 different mutations in the IL2RG gene have been identified in people with X-linked severe combined immunodeficiency (SCID). Most of these mutations involve changes in only one or a few DNA building blocks (nucleotides) in the gene. These changes lead to the production of a nonfunctional version of the common gamma chain or no protein at all. Without the common gamma chain, important chemical signals are not relayed to the nucleus and lymphocytes cannot develop normally. A lack of functional mature lymphocytes disrupts the immune system's ability to protect the body from infection.

Diagnosis

X-SCID, like other forms of inherited SCID, are most often diagnosed by only after the infant has had serious infections. Several groups are working to institute newborn screening tests to detect SCID before severe infections occur. Since, effective treatment with stem cell transplantation is widely established, the best outcome for SCID is achieved if hematopoietic stem cell transplantation is performed in the first months of life. The current basis for the screening test is measurement of the number of lymphocytes at the time of birth that are normally very high, but very low in SCID infants. Newer gene-based screening tests are also being developed. ^[1]

Treatment

The most common treatment for X-linked SCID is bone marrow transplantation. Bone marrow is taken from the parents or siblings of the patient.

In utero bone marrow transplants have also been performed with success.^[2][3]

While bone marrow transplants can save the lives of SCID children, transplants do not always work or they do not always completely correct the defects. A new type of therapy — gene therapy — involves introducing genetic material to correct or compensate for genetic defects. Because of the deadly nature of SCIDs, patients with this disease are prime candidates for gene therapy approaches. In 1990, two girls with ADA deficiency SCID were treated several times over a two-year period with T-cells carrying corrected DNA. While this trial did not produce a completely successful correction of the girls' immune systems, it did, however, indicate that if the correct gene is put into enough cells in a patient, there is a chance of correcting the disease.

In 2000, a study presented two cases of X-linked SCID that had been treated by gene therapy.^[4] These children had no prior treatment such as bone marrow transplantation. In all, 10 X-SCID patients were treated in this trial. However, two of the boys treated developed a form of T-cell proliferation similar to leukemia as a result of insertion of the corrected DNA next to a specific leukemia inhibitor. Because of this, most XSCID gene therapy trials were placed on hold worldwide. Currently, new ADA and XSCID trails have begun or are in the process. However, gene therapy still holds the greatest hope for a true cure for this disease.

Prognosis

Transplants done before birth and in the first three months of life typically have a high success rate.

Without treatment, patients usually do not live beyond one year of age.

Risk Factors

Since the IL2RG mutation(s) causing X-linked severe combined immunodeficiency reside on the X-chromosome, males are at increased risk of developing the disorder through inheritance of the mutation(s) from their mothers.

References

1. ↑ Puck JM et al. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J Allergy Clin Immunol. 2007 Oct;120(4):760-8. Abstract
2. ↑ AW Flake, M Roncarolo, JM Puck, G Almeida-Porada, et al. Treatment of X-Linked Severe Combined Immunodeficiency by in Utero Transplantation of Paternal Bone Marrow. N Engl J Med 1996 335: 1806-1810 Full Text
3. ↑ Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood. 2002 Feb 1;99(3):872-8. Abstract | Full Text
4. ↑ M Cavazzana-Calvo, S Hacein-Bey, G de Saint Basile, F Gross, et al. Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 Disease. (2000) Science 288 (5466), 669. Abstract | Full Text

External Links

• Genetics Home Reference
• X-linked severe combined immunodeficiency. Diagnosis in males with sporadic severe combined immunodeficiency and clarification of clinical findings. J Clin Invest. 1990 May; 85(5): 1548–1554.
• NHGRI Division of Intramural Research
• SCID.net
• National primary Immunodeficiency Resource Center