Seeing Red Over Childhood Blindness

“We followed the clue that Tunisian Jews with the disorder had red hair, so we began looking in the vicinity of the gene that causes redheadedness,” says Moshe Frydman, one of the lead researchers at Sheba Medical Center.

“We followed the clue that Tunisian Jews with the disorder had red hair, so we began looking in the vicinity of the gene that causes redheadedness,” says Moshe Frydman, one of the lead researchers at Sheba Medical Center.

by Michele Chabin
Israel Correspondent

Jerusalem — What do redheadedness and childhood
blindness have in common? That was the question scientists at Tel Hashomer Hospital IN RAMAT GAN asked themselves four decades ago
when they examined a tiny group of redheaded Jews from Tunisia who had developed blindness and a host of other medical problems at
a young very age.
In the 1960s Professor Richard Stein, head of ophthalmology at Tel Hashomer, along with two of his colleagues, reported on a new disorder they dubbed Brittle Corneal Syndrome (BCS). The handful of patients they identified with the disorder were all Tunisian Jews with red hair — a highly unusual combination.
Over the years about 60 patients with the syndrome, a connective tissue disease, were identified, but the disease remained

obscure and largely unexamined until recently.
Two years ago, a patient with the condition asked genetic researchers at Sheba Medical Center to try to locate the gene for BCS. The goal was to develop a prenatal test that could identify affected fetuses and thus enable expectant parents to make informed decisions.
According to an article on this groundbreaking research in the May 1, 2008 issue of the American Journal of Human Genetics, Brittle Cornea Syndrome is a disorder characterized by a thin cornea that tends to perforate, causing progressive visual loss and blindness.
Even a small blow to the eye, such as the type caused by a minor fall or a jab from a sibling, can cause trauma, even when the eye is covered by special protective glasses. Affected children begin losing their sight by the age of 2 or 3 and are usually blind by age 10.
Additional systemic symptoms include hypermotility (extreme flexibility of joints), very lax skin and spinal curvature. Patients also suffer from progressive though relatively minor hearing loss, according to one of the researchers.
The disease is autosomal recessive. In other words, for a child to be born with BCS, both parents must be carriers.
Scientists from Sheba, Bar-Ilan University, Tel Aviv University and Assaf Harofeh Hospital worked together to identify the gene.
“We followed the clue that Tunisian Jews with the disorder had red hair, so we began looking in the vicinity of the gene that causes red headedness,” said Professor Moshe Frydman, one of the lead researchers at Sheba. “As expected, all the Tunisian Jews we tested with the problem had the same genetic condition in the red head gene.”
Almogit Abu, the Bar Ilan grad student whose name tops the list of researchers in the journal article, says the mutated BCS gene “was linked to the redhead, but we will never know whether the first person who had the gene was himself a redhead.”
The mutation likely occurred between 200 and 300 years ago, said Frydman, an associate professor of pediatrics and medical genetics at Tel Aviv University and director of clinical service at Sheba’s Human Genetics Institute.
The scientists looked at all the genes in the area of the gene for red hair and identified the ones expressed in the cornea. They systematically sequenced them and identified a “novel gene” — a gene that, by its structure, interacts with and regulates other genes and proteins.
“We think it interacts with connective tissue structures,” Frydman said.
The team was hot on the trail but still needed to identify other individuals with the disease.
“We sent 1,500 letters via the Ministry of Welfare, to people all over Israel who are legally blind with corneal diseases, and we got one hit,” Frydman said, sounding like a detective. To everyone’s surprise, the “hit” wasn’t a Jew of Tunisian descent. It was a Muslim family from East Jerusalem with six affected family members.
“They’re a very fine, very smart family,” Frydman said, adding that the family was grateful for the scientists’ interest in their medical condition. Until then, they had felt isolated from a medical perspective.
It didn’t take long for the researchers to isolate the mutation in the Arab family’s gene, but it turned out to be different from the gene isolated from the Tunisian Jews.
Finding two disease-causing variations in a single gene “was our proof that we had found the correct gene,” Frydman explained.
Professor Elon Pras, director of the Human Genetics Institute at Sheba Medical Center and one of the BCS researchers, said locating the gene was extremely important “because we can now offer prenatal testing to families where the disease has already occurred. Perhaps more importantly, in the future we may be able to add BCS screening to all Jewish couples of Tunisian origin.”
Abu says patients with BCS “were very emotional when we discovered the gene. They hope for a cure one day, and locating the gene is half the battle.”
“It’s wonderful, says Mustafa Zin, who has two sisters and four children with BCS, referring to the gene’s discovery. We live with this disease every day and know the suffering. We won’t be expanding our family — we have enough on our plate — but the prenatal test could help my siblings and others.”

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