A Hunt for Genes That Betrayed a Desert People

March 21, 2006
A Hunt for Genes That Betrayed a Desert People
By DINA KRAFT
HURA, Israel - In a sky blue bedroom they share but rarely leave, a
young sister and brother lie in twin beds that swallow up their small
motionless bodies, victims of a genetic disease so rare it does not
even have a name.

Moshira, 9, and Salame, 8, who began life as apparently healthy babies,
fell into vegetative states after their first birthdays.

Now their dark eyes stare enormous and uncomprehending into the
stillness of their room. The silence is broken only by the boy's
sputtering breaths and the flopping noise his sister's atrophied legs
make when they fall, like those of a rag doll, upon the mattress.

"I cannot bear it," said the children's father, Ismail, 37, turning to
leave the room as his daughter coughs up strawberry yogurt his wife
feeds her through a plastic syringe.

The sick children are Bedouin. Until recently their ancestors were
nomads who roamed the deserts of the Middle East and, as tradition
dictated, often married cousins. Marrying within the family helped
strengthen bonds among extended families struggling to survive the
desert. But after centuries this custom of intermarriage has had
devastating genetic effects.

Bedouins do not carry more genetic mutations than the general
population. But because so many marry relatives - some 65 percent of
Bedouin in Israel's Negev marry first or second cousins - they have a
significantly higher chance of marrying someone who carries the same
mutations, increasing the odds they will have children with genetic
diseases, researchers say. Hundreds have been born with such diseases
among the Negev Bedouin in the last decade.

The plight of the community is being addressed by an unusual scientific
team: Dr. Ohad Birk, a Jewish Israeli geneticist, and two physicians,
Dr. Izzeldin Abuelaish, a Palestinian from the Gaza Strip, and Dr.
Khalil Elbedour, himself a Bedouin from Israel.

They work together in the southern Israeli city of Beersheba at a
genetics center with two neighboring branches, the Genetics Institute
of Soroka Medical Center and the Morris Kahn Human Molecular Genetics
Lab at Ben-Gurion University of the Negev.

Dr. Birk heads both institutions, which work to identify the mutant
genes that cause these diseases. In the last two years, the center has
identified eight mutant genes not previously associated with a disease,
as well as dozens of new mutations in other genes that were already
associated with diseases.

The findings are passed on to interested families who are given
premarital genetic counseling and prenatal testing. More than 20
couples chose to end pregnancies over the past year, after doctors
diagnosed in the fetuses terminal diseases that usually kill within the
first few years of life.

But there are risks. In a small, closed society in which secrets are
hard to keep, there is the danger of stigmatizing carriers and their
families, subsequently lowering their chances for marriage should word
get out that a genetic disease runs in the family.

The researchers try to minimize that risk by approaching families
confidentially through their family doctors and offering them discreet
testing, even in their own homes. Extensive genetic counseling is
provided before and after testing. Results are given only in person by
genetic counselors who walk individuals and families through the
science and emotions of the process.

The researchers are also working closely with local Muslim leaders to
spread a message about the benefits of genetic testing.

Many of the diseases among the Bedouins are not only rare but extremely
severe. One such disease is aplasia cutis, in which babies are born
with no skin on their skull. Some babies are born with
neurological-spastic diseases and die within a few months. Other
inherited conditions are blindness and severe mental retardation.

In a Bedouin tent camp south of Beersheba, Omar, 11, lives with an
especially rare disorder known as "congenital insensitivity to pain
with anhidrosis." Children with this disorder become their own worst
enemies, burning and maiming themselves without feeling a thing.

Omar's body is covered with scrapes and bruises, and his left leg was
amputated below the knee - a result of a septic infection that set in
after he hurt himself. His mother, who like several others interviewed
asked not to be identified for fear of being stigmatized, fears he will
hurt or even kill himself if left alone, so she carries him constantly
around the steep, rock-strewn slopes. But it is exhausting, and she
also has to care for her 11 other children.

"He is glued to me," she said. "I am very supportive of testing so
people won't suffer the way I have suffered."

The Beersheba research team seeks to identify the mutant genes behind
such diseases through genetic linkage analysis, in which the genomes of
affected and non-affected family members are scanned at 10,000 known
points of variation using powerful Affymetrix chips.

Once researchers home in on the area where the defective gene is
housed, the region is sequenced to find the specific mutant gene.

"It's very satisfying to be able to tell families" that the gene
causing a particular illness has been identified, said Dr. Elbedour. Of
course, he cautioned, it is not easy for families to receive the news
that they carry a risky gene, and the knowledge is not a cure. But it
can be a step toward prevention.

Identifying the disease-related genes may help researchers design drug
therapies. The Israeli lab is working to do so. "We are actually
finding pathways and the molecular basis for diseases," Dr. Birk said.

The team is focusing on Mendelian diseases, the relatively rare type
caused by disorder in a single gene. But Dr. Birk said the research
might also help the team members find genes that combine to cause more
common problems like diabetes, epilepsy, asthma and obesity.

The findings on Mendelian disease could be used by the major Bedouin
populations in neighboring Egypt, Jordan and Saudi Arabia with similar
gene mutations. But so far, Dr. Birk said, scientists in those
countries have refused offers to collaborate.

"It's so essential and basic that we should be working together," he
said. "It's funny. The only Middle Eastern people we are collaborating
with are the Palestinians."

The cooperation sometimes falters. On a recent morning an exasperated
Dr. Abuelaish stormed into Dr. Birk's office. He was furious that
Israeli soldiers at the crossing from Gaza into Israel had made him
wait two hours to pass through and then asked him to take off his shirt
to make sure he was not wired with bombs.

Still, Dr. Abuelaish declares, "Medicine does not know borders."

Dr. Abuelaish, who works as an obstetrician and a gynecologist in the
Jabalia refugee camp in Gaza, is one of the few Gaza Palestinians
permitted to enter the country since Israel's recent withdrawal from
Gaza, traveling to Beersheba once a week.

An estimated 140,000 Bedouins live in the Negev desert in the south of
Israel bordering Gaza. Some of the families the researchers are
studying have branches in both the Negev and Gaza.

One of the lab's breakthroughs was solving the genetic puzzle that
caused members of three extended families to be born without eyes. One
of the families was in Gaza, another in the Negev, and one was a Jewish
family of Syrian-descent living in Jerusalem.

One member of the Gaza family is Ramzi Abu Aljidian, 24, who like his
sister has eyelids but no eyes underneath them. He is pleased his
family's participation in the research was fruitful.

"We want to prevent such cases in the future," said Mr. Abu Aljidian,
who added that his condition persuaded him not to marry within the
family. Mr. Abu Aljidian married a woman who is not a relative, and the
couple have two normal, healthy children.

Dr. Abuelaish is the lab's connection to Gaza. A specialist in fetal
medicine, he meets with families who have a history of genetic
diseases, collects blood samples and draws up the detailed family trees
of his patients.

"People need help, and we try to help them," he said. Access to the
modern facilities in Israel is essential for his patients in Gaza
because there are no genetic labs there.

In Beersheba, Dr. Abuelaish shows Dr. Birk a collection of X-rays he
took of a brother and sister from Gaza who suffer from phocomelia, in
which their limbs are short and twisted.

"That's his hand," said Dr. Abuelaish, pointing to a 6-year-old boy who
has three oversized fingers on one hand, two on the other. Like his
older sister, he has legs that are only a few inches long. The two get
around in wheelchairs that they roll down the dusty streets of their
refugee camp.

The children, like many of the Gazans, do not have permission to enter
Israel. Dr. Abuelaish must therefore document the clinical side of the
cases as thoroughly as possible and take that documentation -
together with blood samples and photographs - back to Israel.

The lab was sponsored by Morris Kahn, an Israeli philanthropist, and
was championed by the acting president of Ben-Gurion University, Rivka
Carmi, a genetics professor herself, specifically to research genetic
diseases among the Bedouins. Its research has helped establish Israel
as an important center for the study of genetic diseases among inbred
peoples.

One of the main challenges facing the researchers is how to reach out
to the people affected in a culturally sensitive way.

Bedouins are known for their pride and privacy, and illness is
associated with weakness and a loss of family honor. The stigma of
disease causes some families to balk at the idea of testing.

Muslim religious leaders have been drafted to help educate the members
of the group about genetic problems, speaking out about the dangers of
marrying relatives and increasing awareness of genetic testing and
counseling. The imams also let families know that under Islam a woman
can abort a fetus up to four months for health reasons.

"We are trying to convince people that to do a test is in their best
interest," said Jomah al-Zodeah, 36, an imam in the Bedouin town Rahat.
He and his two wives, cousins from either side of his family, recently
had their blood tested by Dr. Elbedour.

Mr. Zodeah knows the toll of genetic disease; several children in his
own extended family have died young.

Among the genes the Israeli genetics lab has identified is the one that
caused Moshira and Salame's devastating disease. For years the
children's parents, cousins who are both carriers of the gene that
causes the illness, struggled over the decision of whether or not to
have more children.

Just over two years ago they decided to take a chance. They had a baby
girl who is free of the disease. Now pregnant again, their mother,
Gazia, 30, was able for the first time to receive a prenatal test that
determined the fetus she is carrying is indeed healthy. In her modern
and immaculate home, Gazia has just finished feeding Moshira and Salame
a liquid lunch through a plastic syringe. She muses on the better lives
genetic research might bring.

"I hope everyone will have healthy children," she said.

.

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