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Severe combined immune system deficiency


Clinical signs

Severe combined immune system deficiency is the name given to a group of hereditary diseases that mainly affect the immune system. In this group of diseases there is a lack of 2 major types of immune response cells:
  1. B cells - these are responsible for the secretion of antibodies (materials called immunoglobulins, which recognize bacteria and other infectious organisms). This type of immunity is called humoral immunity.
  2. T cells - these recognize and treat infectious organisms. This type of immunity is called cellular immunity.

In severe combined immune system deficiency both the T-cells and B-cells are deficient, and as a result the patient will suffer from life-threatening severe infections. Life expectancy is markedly decreased (infancy or childhood).

There are several types of severe combined immune system deficiency:

  • Some are part of a syndrome that affects other organs (for example Omenn syndrome).
    .
  • Some are transmitted by autosomal recessive inheritance (for example Adenosine deaminase deficiency, SCID, which is common among Athabaskan-speaking Native Americans, etc.)
    .
  • Some are transmitted by X-linked inheritance.

There is a uniquely high frequency of severe combined immune system deficiency (SCID) associated with deficiency of both T-cell and B-cell immunity among Athabaskan-speaking Native Americans -this form of the disorder is termed SCIDA. It has been reported in the Navajo and Apache tribes and among the Dene Indians, a small tribe of Athabascan speakers living in the Northwest Territories of Canada.

The incidence of SCIDA is said to be approximately 1 in 2,000 live births among Navajo Indians. Clinically, affected children present with oral/genital ulcers and life-threatening infections within the first 3 months of life. Without a bone marrow transplant, most die by 6 months of age.

Inheritance pattern


  • Some are part of a syndrome such as Omenn syndrome, Adenosine deaminase deficiency, and SCID - these are transmitted by autosomal recessive inheritance,which means that when both parents are carriers, the child will only be affected if he or she inherits two abnormal genes - one from the mother and one from the father.

  • Some cases of SCID are transmitted by X-linked inheritance - in these conditions only males are affected.

Penetrance

Complete.

As described above, the disease is relatively frequent among Navajo and Apache Native Americans. In these groups the carrier rate is 1:20 among individuals with no family history.

Associated features that can be demonstrated in tests performed during pregnancy

In most types of SCID there are no definitive signs that are detectable during the pregnancy, and only DNA tests can confirm the diagnosis.

In all these cases it is important to refer the couple for genetic counseling, to which they should bring all data, including the results of other tests performed during the pregnancy such as alpha-fetoprotein, nuchal translucency, etc.

What is the risk of recurrence in a subsequent pregnancy?

In SCIDA, the type that is common among the Navajo and Apache peoples, and in the other SCIDs that are transmitted by autosomal recessive inheritance:

  • For a couple who has already had an affected child, the risk is 25% in every subsequent pregnancy. When only one parent carries the abnormal gene, there is no risk that any of their offspring will have the disease; however, in such families there is a 50% chance that the infant will be a carrier, but he himself will be healthy, like the carrier parent.

  • The risk for more distant relatives depends on the degree of relationship between the relatives and the affected individuals, the ethnic groups of their partners, affected relatives of partners, consanguinity between the parents, if present, etc., and is established within genetic counseling.

In the type of SCID that is transmitted by X-linked inheritance:

  • For a couple who has already had an affected child, the risk is 50% in every subsequent pregnancy with a male fetus.

  • The risk for more distant relatives on the maternal side depends on the degree of relationship between the relatives and the affected individuals, and is established within genetic counseling. Carrier females can be identified by genetic tests.


Immune System - Natural Killer Cell


Molecular genetic information

The gene for the disease



In SCIDA (the type that is common among the Navajo and Apache peoples): the DCLRE1C gene, which produces the Artemis protein and is situated on chromosome 10p.

Genetic testing

Diagnostic testing

Among the Navajo and Apache peoples, a direct test can be performed to identify the mutation in the gene by testing for the common mutations. See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal recessive diseases.

In the other types, testing of other genes that may be involved is required.

Carrier testing

The mutation Y192TER (C-to-A transversion in exon 8 of the DCLRE1C gene) is the one that is common in the Navajo and Apache peoples. The carrier rate varies between 1:10 in healthy individuals of Navajo and Apache origin to 1:100 in other ethnic groups. In other ethnic groups, carriers cannot be identified.

In view of this, it is very important to ascertain the ethnic origins of the couple, and it is advisable to examine (carrier DNA testing) those couples where both partners are fully or even partially of Navajo or Apache origin.

See also: Introduction to population DNA screening for autosomal recessive diseases such as Cystic fibrosis and others.

Carrier status testing in relatives of patients with severe combined immune system deficiency

It is important that relatives of patients with severe combined immune system deficiency clarify which mutations are present in the patient or parents in their family in order to ascertain that they are included in the battery of mutations routinely tested for - otherwise it will be necessary to expand the list of mutations tested for and/or examine the partner. This will be discussed in genetic counseling.

Fetal testing

Same as the diagnostic test.

Prenatal diagnosis can also be offered to each couple who has had an affected child. The best way is after identifying the mutations in the parents, but if these are not found, indirect linkage analysis can be performed. See: Indirect testing for genetic markers in a family that has one or more patients - when there is only one gene that can cause the disease - autosomal recessive diseases.

Preimplantation diagnosis (before the embryonic cells implant in the uterine wall) can also be offered for this disease - this is performed in special centers, and in special cases this can be considered within genetic counseling.
 
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Comments (2)


Monday, March 16, 2015 5:55 AM
(1) Mehmet  says:


Clinical signs

Very good article. I like it Thanks.


Tuesday, March 31, 2015 1:49 AM
(2) asad  says:


Calculatoare Second Hand

This knowledge.Excellently written article, if only all bloggers offered the same level of content as you, the internet would be a much better place. Please keep it up.





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