SCID Genes - Page 3 of 7

Severe combined immune deficiency, or SCID, is the name given to several inherited syndromes, each with a different cause, that block normal immune function. In the late 1970s, doctors identified severe immune deficiency as the most likely cause of a mysterious illness that struck some Navajo and Apache newborns. The babies were highly susceptible to infections, fevers and ulcerating sores on their bodies. Most died within a few months after birth.

Worldwide, SCID is extremely rare -- only one of 100,000 U.S. newborns is born with any form of the disorder. However, this particular type of SCID occurs in one out of 2,000 births in some parts of the Navajo reservation. In comparison, a different disorder, cystic fibrosis (CF), occurs in about one in 2,000 babies of northern European ancestry. These are among the highest incidences of any inherited disease. Yet like CF and other rare inborn conditions, SCID was rarely diagnosed until recently because it is not easy to tell the symptoms apart from ordinary infections.

Over generations, some families have lost many babies without knowing why.

The genetic reason was discovered by Lanying Li, a research geneticist in Cowan's lab. With the cooperation of Navajo families, Li and Cowan compared the gene sequences of people affected by SCID and those who are not affected. They found a gene on chromosome 10 with a mistake written into its coding sequence. The miscoded gene is unable to make a complete version of a protein called Artemis, which is necessary for the normal development of disease-fighting T cells and B cells.

The miscode is unique to the Navajo and Apache. Because their languages share Athabascan roots, the UCSF team dubbed this version of the gene SCIDA, for Athabascan SCID. Some children in Europe have also been found with miscodes in different parts of the Artemis gene. Like the SCIDA children, they have one of the most severe forms of the disease.

Anthropologists surmise that Athabascan-speaking peoples migrated from the Canadian Northwest Territories to the Southwestern United States between 700 and 1300, and that Navajo and Apache have been separate communities since the 17th century. Thus SCIDA may be a "founder mutation" that occurred long before that separation.

An autosomal recessive gene, it can be passed from one generation to the next without causing harm. However, when two people who carry the gene have children together, each child has a one in four chance to be born with SCIDA.

Over the years since it was understood that SCIDA can affect multiple offspring within a family, NAIHS doctors and counselors have worked with those affected families to help them understand and cope with this information. A few years ago, Cowan and his team organized an explanatory workshop for parents and their relatives, including a support session to allow people to express their emotions.

One grandmother, hearing the explanation for SCIDA translated into Navajo, began to recall a newborn of her own who lived only a short time, and mothers she knew long ago who suffered the same loss. It was the first time others in her family had heard about those babies.

With the gene isolated, it would be feasible for the Navajo and Apache Nations to offer genetic testing and counseling services. But genetics experts recognize that information about the genes a person carries has powerful emotional impact on the individual, the family and their community. Decisions about how to use this information are personal and cultural.

The UCSF group has concentrated on ways that discoveries about the gene can help families who already know they could be affected by SCIDA. For example, it originally was difficult to diagnose a child before birth. A blood sample from the fetus had to be drawn from the umbilical cord. Cowan and Li developed a less invasive test based on amniotic fluid or chorionic villus sampling, as soon as they discovered markers for the gene.

With the gene itself identified, Li and Cowan refined their method of detecting it in blood or amniotic fluid. Prenatal diagnosis now takes only an amniocentesis test that can be done in a day. The rapid test also helps speed doctors' decisions about treatment for an infant with suspected SCIDA. And it increases the accuracy of diagnosis to better than 99 percent.

As soon as it was discovered that defects in Artemis might also hamper DNA repair, Cowan refined the treatment of babies with SCIDA. Without robust DNA repair mechanisms, the children may be more susceptible to the standard chemotherapy and radiation therapy regimens typically used in BMT procedures. Whenever possible, in the conditioning phase before bone marrow transplants for these patients, Cowan avoids chemotherapy and radiation.

In fact, Cowan's group currently is evaluating a novel approach to transplantation that it has developed for these children. This BMT method avoids conditioning entirely and may benefit children with all types of SCID.

"The most rewarding value of discovering the gene is that we get a chance to improve treatments by tailoring them to these particular patients," Cowan says.

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