X-linked severe combined immunodeficiency

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder that affects lymphocytes. It is a recessive trait stemming from a defective version of the gene responsible for the functionality of the Interleukin 2 receptor (IL2RG).

Symptoms
Persons afflicted with X-SCID often have infections very early in life, before three months of age. This is followed by pneumonitis, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath. In addition, moniliasis, a type of fungal infection, is a telltale sign of X-SCID. Moniliasis involves moist areas of the body such as skin, the mouth, respiratory tract, and vagina. Symptoms of moniliasis include difficulty in swallowing, pain on swallowing and oral lesions. Recurrent eczema-like rashes are also a common symptom. X-SCID is usually fatal in the first years of life.

Genetics
X-SCID is X-linked mutation, which means males born from a female carrier (either heterozygous or homozygous), will inherit X-SCID, and thus, express it. Many times, X-linked mutations can be passed by a healthy, unaffected mother. A heterozygous woman carrier will have a 50% chance of transmitting the disease-causing mutation. Females who are heterozygous are carriers, but will not be affected. Even though seeing this type in females is extremely rare, the mutation in both genes can cause a female to develop this x-linked disorder.

Molecular biology
Interleukins are produced by lymphocytes, among other cell types, and are released in response to antigenic and non-antigenic stimuli. The gene IL2RG codes for the common gamma chain protein, which is a common subunit of the individual receptors for Interleukin 2, Interleukin 4, Interleukin 7, Interleukin 9, Interleukin 15 and Interleukin 21. Signalling from these receptors normally promotes growth and differentiation of T-cells, B cells, natural killer cells, glial cells, and cells of the monocyte lineage, depending on the cell type and receptor activated. This gene is mutated in X-SCID. Its mutation is caused by large, or even single nucleotide, deletions in the IL2RG gene, that disable the common gamma chain so that it is unable to bind with other receptor subunits and signal cytokine activation. This change prevents the T-lymphocytes from signaling other cells, like B-lymphocytes and natural killer cells. Because these cells never receive these signals, they can never mature and differentiate into full grown immune cells. The gene is located on Xq13, with a DNA length of 4.2 kb. Analysis has shown that the mRNA length is 3.6 kb long. IL2RG has 369 amino acids, and contains eight exons and seven introns.

Diagnosis
Diagnosis of X-SCID is possible through observation and investigation of the immune system. A healthy immune system should contain large amounts of lymphocytes, but individuals with X-SCID will contain unusually small amounts of T-cells, non-functional B-cells, and no natural killer cells.

There are also tests of lymphocyte function. These tests introduce agents to the immune system and observation, one can see how the lymphocytes react. Antibody responses to introduced vaccines and infections are absent, and T-cell responses to mitogens, substances that stimulate lymphocyte transformation, are deficient. Immunoglobulins, substances that aid in fighting off infections, are very low. Also, the thymic shadow is absent on chest X-rays.

Since the mutation in X-SCID is X-linked, there are genetic tests for detecting carriers in XSCID pedigrees. One method is to look for family-specific IL2RG mutations. Finally, if none of those options are available, there is an unusual pattern of nonrandom X-chromosome inactivation on lymphocytes in carriers, thus looking for such inactivation would prove useful.

Pathophysiology
X-SCID is characterized by an abnormally low number of lymphocytes and susceptibility to various infections. Susceptibility is in part due to the atrophy of the thymus, an organ in which lymphocytes thrive and later become T-cells. There is a lack of delayed hypersensitivity, sensitivity regulated by T-lymphocytes.

In particular, IL2 promotes lymphocyte growth and differentiation. This process happens after interaction with its receptors (IL2R) which has three subunits, to which only its third, the gamma chain, is of importance. The gamma chain subunit is known as IL2RG, and is necessary of the function of IL2 receptors. Thus, a mutation in IL2RG results in a synergistic effect: a lack in the growth and differentiation in lymphocytes.

Treatment
Bone marrow transplantation is standard procedure for immune reconstitution. Though the BMT process is ‘common’, it requires immunodeficiency specialists for maximum potential. Infants, in which there is no donor, can undergo BMT, only if the marrow is first depleted of its mature T-cells. The T-cells must be depleted in order to remove mismatched T-cells which would cause a reaction in the infant.

Gene therapy is also available to replace the mutant allele. Though, this process can be achieved through various processes, it has been successful in treating X-SCID by insertion of functional, healthy genes with a retrovirus. This, coupled with the bone marrow stem cells, has been successful in treating individuals with X-SCID. Although over 10 children have now been cured almost completely of X-SCID, four of the children have gone on to develop leukemia probably as a direct result of the therapy.

Epidemiology
There is no information on birth ratios/rates, but “X-Linked SCID is the most common form of SCID and it has been estimated to account for 46% to 70% of all SCID cases."