jueves, 15 de marzo de 2018

What is Severe Combined Immunodeficiency (SCID)?

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By Rebecca Woolley, BSc

Severe Combined Immune Deficiency (SCID) is characterized by a severely impaired immune response.

Credit: Andrey_Popov/Shutterstock.com

The activity of their specialized white blood cells (T and B lymphocytes, and, occasionally, natural killer cells) is so low that the body lacks its primary defense response, leaving it vulnerable to infection by viruses, bacteria and fungi. Without effective protection or treatment, SCID is usually fatal within the patients’ early years.

Symptoms

Newborns with SCID struggle to thrive. Within their first few months’, they tend to contract life-threatening infections that do not cause such sickness in infants with well-functioning immune systems.

Particularly dangerous organisms include the viruses responsible for pneumonia and chicken pox, which spread easily throughout the body and are often fatal in immunocompromised patients. Children with SCID can also contract infections from immunizations with live vaccines (e.g. chicken pox, measles, mumps and rubella).

Unlike healthy children, children with SCID suffer:

Ongoing common fungal infections of the mouth or skin (e.g. thrush) that do not resolve spontaneously
Irritation of the intestinal tract by normal gut bacteria
Common infections that prove difficult to treat
Serious infections, as well as persistent diarrhea, are the hallmarks that usually spark deeper medical investigation.

Diagnosis

SCID is generally diagnosed by determining the total number of lymphocytes in the blood (by counting the peripheral or cord blood lymphocytes). Normally, T cells make up 70% of the 4,000 lymphocytes per cubic millimeter. Therefore, infants with SCID (who lack T cells) have a much lower white blood cell (WBC) count, generally around 1,500. To rule out other conditions that affect WBC, the activity of T cells is also tested, measured by their ability to divide in response to various stimuli.

It is possible to detect SCID before birth. Fetal cells taken by chorionic villous sampling (CVS) or amniocentesis can be tested for molecular abnormalities or the known genetic defect (if an older sibling has been previously diagnosed). However, as these procedures pose a risk to the fetus, the diagnosis is often best made at birth.

Causes

SCID is inherited, with at least thirteen genetic mutations known to affect the activity of white blood cells. Almost half of these are linked to a recessive mutation on the X chromosome and are, therefore, passed on from mother to son. In this form of the disease, a genetic mutation in a component of T-cell receptors reduces their ability to detect foreign invaders (the common gamma chain of the T-cell growth factor receptor). Other types of genetic defects that lead to SCID include mutations to:

WBC receptors, e.g. in the alpha chain of the interleukin-7 receptor gene (in 11% of cases)
Signaling molecules, interrupting the flow of information between immune cells, e.g. the Janus Kinase 3 gene (in less than 10% of cases)
Enzymes that break down toxic substances, leading to a build-up that damages WBCs from within, e.g. in the adenosine deaminase gene (in 15% of cases)

Management

Before the first successful bone marrow transplant (BMT) in 1968, SCID was always fatal. David Vetter, probably the most-well documented of SCID patients, was born in 1971 with no matched donor. Affectionately known as “Bubble Boy”, he lived in a protected, germ-free environment until finally receiving a BMT at 12 years of age.

Nowadays, the immune systems of infants with SCID can be effectively repaired through early intervention, such as bone marrow transplant, enzyme replacement or gene therapy. However, if left until serious disease develops, therapy may come too late for these vulnerable patients.

Screening

Routine newborn screening can identify SCID early, before any infections establish, making life-saving intervention possible. A small amount of blood collected from the prick of an infant’s heel can be tested for markers that indicate the number of T cells developing in the thymus (T-cell receptor excision circles).

Several US states have included SCID detection in their newborn screening programs, and early therapeutic intervention has enabled affected infants to live without further complications. Nearly 50% of babies are screened for SCID currently. Rapid diagnosis leads to early intervention (transplantation or gene therapy), and a greater likelihood of treatment success for all patients.

Reviewed by Kate Anderton, BSc