Jewish Genetic Diseases

As researchers decode DNA, new findings and procedures bring hope to sufferers.

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Reprinted with permission from Hadassah Magazine, January 2001 (82:5).

Twenty‑five years ago, the best Dr. Gideon Bach could offer patients was statistical probabilities. “I’d tell a couple who already had a sick child they had a one‑in‑four chance of having another,” says Dr. Bach, head of the Department of Human Genetics at the Hadassah‑Hebrew University Medical Center at Ein Karem. “It was difficult working with patients because we had so little to give them.” Today, tens of thousands of research hours later, geneticists the world over are heading toward a major payoff.

“We now know that most if not all human disorders have a genetic background, and we’re acquiring the tools to study, treat and eventu­ally prevent or cure them,” says Dr. Bach, part of the team that recently identified the mutant gene respon­sible for mucolipidosis IV, a devas­tating disease carried largely by Ashkenazim (Jews of European origin). “Israel, with its many inbred ethnic groups, has proven a rich human laboratory for genetic detectives. It’s far easier to trace genetic anomalies in groups with homogenous pedigrees.”

Worldwide, more than 4,000 genetic diseases have been identified, most fortunately very rare. Almost all began with a mutation in the DNA which, because of inbreeding, was passed on rather than selected out. In Israel’s Arab population, in which consanguinity (blood relationship) is very high, every village, almost every family, carries its own disorders.

Jews are afflicted with their own particular disorders. Ashkenazim, who until some 40 years ago largely married within the group, carry a dozen recessive genetic anomalies in a relatively high frequency. The most widely known is Tay‑Sachs, a fatal neurodegenerative affliction that causes blindness, mental retardation and death, usually around age five.

One in 40 Ashkenazim carries the mutation that causes Canavan’s disease, which ravages its victims with failed mental development, weakened muscles and inability to speak, and victims usually die by age 10. About one in 100 Ashkenazim carry type A or B Niemann‑Pick disease, a crippling neurological disintegration that ends life well before the teens.

Familial dysautonomia, which leaves people unable to control their autonomic (involuntary) and sensory nervous systems, is carried by an estimated one in 30 Ashkenazim. One in 15 carries the mutation for Type 1 Gaucher, which is debilitating but not fatal. Mucolipidosis IV, cystic fibrosis, torsion dystonia, Fanconi anemia, Bloom syndrome and Von Gierke disease, all rare but utterly devastating, also appear more frequently among Ashkenazim than any other ethnic group.

The genetic disorders carried by Sephardim (Jews of Spanish and Middle Eastern origin) differ from those of the Ashkenazim, but the situation is generally far less clear‑cut.

“The high‑frequency genetic disorders specific to Ashkenazim are different from those of the surrounding populations [Poles, Germans],” Dr. Bach explains. “Sephardim, however, tend to share hereditary diseases with their host population. This is believed to result not from intermarriage, but from natural selection. Kurds and Kurdish Jews, for example, have a genetic predisposition toward thalassemia, an inherited blood disorder. Crippling though thalassemia can be, it protects healthy carriers against a severe form of malaria, and may thus have been genetically selected.”

All these diseases are autosomal recessive disorders, which means that for a child to inherit any one of them, parents must each carry a copy of the affected gene—though they are not themselves affected—and they must pass that gene on. When both parents are carriers, there is one in four chance they will have an affected child and a 50‑percent chance their child will be a carrier.

Until recently, the best help doctors could give was to identify carriers as the appropriate blood tests were developed and test the unborn babies [fetuses] of couples at risk. With termination of affected pregnancies problematic for many couples, an Orthodox nonprofit group was established in 1983 in New York to test Jewish teenagers for the most common recessive Ashkenazic diseases, and help avoid marriages between matched carriers. Known as Dor Yeshorim, with Hadassah as its Israel testing center, the group’s strategy, it claims, has eliminated Tay-Sachs by 90 percent.

“We test well over 10,000 people a year,” asserts Dr. Bach. “Despite that, hundreds of families with affected members, usually children, attend our clinic.”

There is growing hope for families the screening failed to protect. With massive impetus from the international Human Genome Project and new technologies, researchers are finally moving to track down the culprit genes.

“The search area is unimaginably vast,” Dr. Bach explains. “Each of our 100,000 genes comprises four chemical sub‑units or nucleic acids, with each of these combined in an almost limitless variety of sequences.”

There are an estimated three billion of these chemical sequences in the human genome. It is from among them that Dr. Bach and his team identified the genetic misprint that triggers mucolipidosis IV (ML4). The disorder, which impairs crawling, walking, talking and learning basic skills, was first described by Hadassah physicians 26 years ago. Discovery of the mutant gene will lead the way, he believes, to treatment, either as protein replacement or gene therapy.

“The more we know about a disorder, the closer we come to treating it successfully,” he says. “We know, for example, that Tay‑Sachs, Canavanas, Niemann‑Pick type A and Thatcher result from missing enzymes and the fatal accumulation of substances they’re designed to break down.”

The first therapeutic protocols are now being developed. “At Hadassah, we’ve started treating patients with the hereditary kidney disorder, Fahey’s disease,” says Dr. Bach. “It, too, is caused by an enzyme deficiency. By injecting our patients with the missing enzyme, we’re solving many of the disease’s problems.”

Which brings Dr. Bach full circle: As a medical student at Hadassah 25 years ago, he identified the defective enzyme in Hunter’s disease, where malfunction causes a damaging accumulation of sugars in brain and other tissues.

“It was because I found the Hunter’s enzyme that I decided to specialize in genetics,” says Dr. Bach. “To me, it was a very exciting field. I had no idea, of course, what lay ahead.”

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