X-linked severe combined immunodeficiency
X-linked severe combined immunodeficiency | |
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Other names | X-SCID |
X-linked recessive is the inheritance pattern of this disorder | |
Specialty | Hematology |
X-linked severe combined immunodeficiency (X-SCID) is an
In the absence of
Symptoms and signs
People with X-SCID often have infections very early in life, before three months of age. This occurs due to the decreased amount of
In some patients symptoms may not appear for the first six months after birth.[6] This is likely due to passive immunity received from the mother in order to protect the baby from infections until the newborn is able to make their own antibodies.[6] As a result, there can be a silent period where the baby displays no symptoms of X-SCID followed by the development of frequent infections.[citation needed]
Genetics
X-SCID is caused by a mutation occurring in the xq13.1 locus of the X-chromosome.
Pathophysiology
The gene that encodes the common gamma chain in these interleukin receptors is mutated in X-SCID. The mutation leads to an absent or abnormally functioning common gamma chain. The mutation can occur through 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.[11] Normally, when the interleukin binds to the trimeric receptor protein containing the alpha, beta, and gamma subunits, the common gamma subunit activates Janus Kinase 3 (JAK3), which leads to the phosphorylation of Signal Transducer and Activator of Transcription 5, STAT5. The STAT5 proteins dimerize and translocate to the nucleus, controlling subsequent downstream signalling.[1] Due to the fact that the common gamma chain is absent or abnormal, this downstream pathway is inhibited. 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.[citation needed]
Diagnosis
Diagnosis of X-SCID is possible through lymphocyte cell counts, lymphocyte function tests, and
Cell type | Normal lymphocyte count average (range) | X-SCID count average (range) | Refs |
---|---|---|---|
T-cells | 3,680 (2,500–5,500) | 200 (0-800) | [9] |
B-cells | 730 (300–2,000) | 1,300 (44 - >3,000) | |
NK cells | 420 (170–1,100) | <100 | |
Total | 0–3 months: 5,400 (3,400–7,300) | <2,000 |
Individuals with X-SCID often have decreased lymphocyte function. This can be tested through the introduction of agents to the immune system; the reaction of the lymphocytes is then observed. In X-SCID,
The absence of a
Since the mutation in X-SCID is X-linked, there are
If a mother is pregnant and the family has a known history of immunodeficiency, then doctors may perform diagnostic assessment in-utero. Chorionic Villus Sampling, which involves sampling of the placental tissue using a catheter inserted through the cervix, can be performed 8 to 10 weeks into gestation.[14] Alternatively, Amniocentesis, which entails extracting a sample of the fluid which surrounds the fetus, can be performed 15 to 20 weeks into gestation.[14]
Early detection of X-SCID (and other types of SCID) is also made possible through detection of T-cell recombination excision circles, or TRECs. TRECs are composed of excised DNA fragments which are generated during normal splicing of T-cell surface antigen receptors and T-cell maturation.
Treatments
Treatment for X-linked SCID can be divided into two main groups, the prophylactic treatment (i.e. preventative) and curative treatment.[22] The former attempts to manage the opportunistic infections common to SCID patients[22] and the latter aims at reconstituting healthy T-lymphocyte function.[23]
From the late 60s to early 70s, physicians began using "bubbles", which were plastic enclosures used to house newborns suspected to have SCIDS, immediately after birth.
Bone marrow transplantation (BMT) is a standard curative procedure and results in a full immune reconstitution, if the treatment is successful.
Gene therapy is another treatment option which is available only for clinical trials.[34] X-linked SCID is a monogenic disorder, the IL2RG gene is mutated, so gene therapy will replace this mutated gene with a normal one.[39] This will result in a normal functioning gamma chain protein of the interleukin receptor.[35] In order to transfer a functional gene into the target cell, viral or non-viral vectors can be employed.[35] Viral vectors, such as the retrovirus, that incorporate the gene into the genome result in long-term effects.[34] This, coupled with the bone marrow stem cells, has been successful in treating individuals with X-SCID.[40] In one particular trial by Cavazzana-Calvo et al., ten children were treated with gene therapy at infancy for X-SCID.[41] Nine of the ten were cured of X-SCID.[41] However, about three years after treatment, two of the children developed T-cell leukemia due to insertion of the IL2RG gene near the LMO2 gene and thereby activating the LMO2 gene (a known oncogene).[42] A third child developed leukemia within two years of that study being published, likely as a direct result of the therapy.[43] This condition is known as insertional mutagenesis, where the random insertion of a gene interferes with the tumor suppressor gene or stimulates an oncogene.[34] There is currently no approved gene therapy on the market, but there are many clinical trials into which X-SCID patients may enroll. Therefore, research in the field of gene therapy today and in the future is needed to avoid the occurrence of leukemia.[35] In particular, research into the use of insulator and suicide genes is warranted as this may prevent cancer from developing.[34] The insulator gene inhibits the activation of adjacent genes. On the other hand, the suicide gene is stimulated when a tumour begins to form, and this will result in the deactivation of the therapeutic gene.[34] Moreover, the use of restriction enzymes such as the zinc-finger nuclease (ZFN) is being studied.[34] The ZFN allows the researcher to choose the site of gene integration.[34] Vector safety is important in the field of gene therapy, hence vectors that self-inactivate the promoter and enhancer (SIN) and adenoviruses that creates no immune response are prominent areas of research for vector biologists.[34]
Prognosis
X-linked SCID is a known pediatric emergency which primarily affects males.[31] If the appropriate treatment such as intravenous immunoglobulin supplements, medications for treating infections or a bone marrow transplant is not administered, then the prognosis is poor.[17] The patients with X-linked SCID usually die two years after they are born.[38] For this reason, the diagnosis of X-linked SCID needs to be done early to prevent any pathogens from infecting the infant.
However, the patients have a higher chance of survival if the diagnosis of X-linked SCID is done as soon as the baby is born.[17] This involves taking preventative measures to avoid any infections that can cause death. For example, David Vetter had a high chance of having X-linked SCID because his elder sibling had died due to SCID.[44] This allowed the doctors to place David in the bubble and prevented infections.[44] In addition, if X-linked SCID is known to affect a child, then live vaccines should not be administered and this can save the infant's life. Live attenuated vaccines, which consist of weakened pathogens inserted into the body to create an immune response, can lead to death in infants with X-linked SCID.[45] Moreover, with proper treatments, such as a bone marrow transplant, the prognosis is good. The bone marrow transplant has been successful in treating several patients and resulted in a full immune reconstitution and the patient can live a healthy life.[46] The results of bone marrow transplant are most successful when the closest human leukocyte antigen match has been found.[47] If a close match is not found, however, there is a chance of graft-versus-host-disease which means the donor bone marrow attacks the patient's body.[35] Hence, a close match is required to prevent any complications.
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."[48]
See also
Notes and references
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- ^ ISBN 978-0-470-31986-4.
- ^ PMID 22069950.
- ^ PMID 11253129.
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- ^ Shwartz, R.A. "Pediatric Severe Combined Immunodeficiency". MedScape. Retrieved January 18, 2012.
- ^ a b c d e GeneReviews 2016
- PMID 17549248.
- ^ PMID 17953510.
- ^ S2CID 5466985.
- ^ Rehan, Kelly M. "An Overview of the Thymus: The Gland that Protects You Long after It's Gone". EndocrineWeb.
- ^ PMID 11091267.
- PMID 22285280.
- PMID 22277197.
- ^ S2CID 14226544.
- PMID 15696101.
- PMID 22012274.
- ^ "IDF SCID Newborn Screening Campaign". Immune Deficiency Foundation.
- ^ Wilkerson, Sarah. "Updates from Washington – Day 2". Save Babies Through Screening Foundation.
- ^ PMID 11091267.
- ^ PMID 19492655.
- ^ .
- S2CID 205434961.
- PMID 477026.
- PMID 8852117.
- PMID 22771788.
- S2CID 26258054.
- ^ PMID 21479529.
- ^ PMID 15545990.
- ^ PMID 11799529.
- S2CID 35195857.
- ^ S2CID 62790581.
- ^ PMID 19492655.
- ^ PMID 10021471.
- ^ PMID 12615892.
- ^ PMID 11091267.
- PMID 15545990.
- S2CID 4418027.
- ^ PMID 10784449.
- ^ "Gene Therapy Insertional Mutagenesis Insights" (PDF). Science. 16 January 2004.
- ^ "X-SCID Gene Therapy Poses Substantial Cancer Risk". Medical News Today. 30 April 2006.
- ^ PMID 21078154.
- ISBN 978-3-540-78537-8.
- S2CID 9424204.
- PMID 22430378.
- PMID 20301584.[clarification needed]
References
This article includes a list of general references, but it lacks sufficient corresponding inline citations. (April 2020) |
- https://web.archive.org/web/20081122091233/http://www.scid.net/about.htm
- Allenspach E, Rawlings DJ, Scharenberg AM (2016) [1993]. "X-Linked Severe Combined Immunodeficiency". In Pagon RA, Bird TD, Dolan CR, Stephens K (eds.). GeneReviews [Internet]. Seattle WA: University of Washington. PMID 20301584. NBK1410.
- Online Mendelian Inheritance in Man (OMIM): Interleukin 2 receptor, Gamma; IL2RG - 308380
- Online Mendelian Inheritance in Man (OMIM): Severe Combined Immunodeficiency, X-Linked; SCIDX1 - 300400