A multinational team headed by medical geneticists at Jerusalem’s Shaare Zedek Medical Center has discovered a gene responsible for a serious and even life-threatening inherited disorder.
The gene causes inflammation of blood vessels and damage to the immune system.
The discovery, just published in the New England Journal of Medicine, was made when doctors recognized symptoms in the children of Jews of Georgian (of the former Soviet Union) origin, but it has since been found in Arabs and even in non-Jewish residents of Germany and Turkey.
The disorder is called polyarteritis nodosa (PAN), a form of vasculitis (disorders that destroy blood vessels by inflammation), and it is caused by adenosine deaminase (ADA) deficiency.
At least one in 100 couples of Georgian origin are both carriers of the disease, and since there are at least 100,000 Israelis of Georgian origin, there would be some 200 cases here alone, said Prof. Ephrat Levy-Lahad, head of medical genetics at the Jerusalem hospital who led and coordinated the international team over several years.
“We tried to look for other families with the same disease and other ethnicities with mutations in the same place in their genome,” she told The Jerusalem Post. Each ethnic group, she explained, has different mutations for same disease. Some of the children with PAN “even had strokes, along with skin ulcers, rashes and neurological problems with peripheral nerve damage.”
As a result of the team’s discovery, families will be referred for genetic counseling, and preimplantation genetic diagnosis can be performed to select unaffected, healthy embryos to be implanted for a pregnancy.
One woman whose child was affected by the disease was afraid to get pregnant again, Levy-Lahad said.
“Now she can be tested at Shaare Zedek or Sheba Medical Center, and eventually the test will be available elsewhere.” In the future, it could be possible that patients get fresh-frozen plasma as a replacement therapy for the disease.
Prof. Mary-Claire King, the eminent geneticist at the University of Washington who was the first to identify a breast cancer mutation and who sequenced genes to help Shaare Zedek with its research, commented: “This is lovely and important work and a real coup for Israeli genetics. It was a great pleasure to be a small part of it.”
The discovery is important, said King, because “it provides immediate clues to treatment of an entire class of vasculitis problems. The vast majority of gene discoveries are important for the insights they provide into biology and for the possibilities they provide for disease prevention – for example, quite drastic surgery as for breast and ovarian cancer or for pre-implantation diagnosis for congenital defects. The discovery of the gene responsible for PAN offers a far more immediate practical benefit: a simple approach to treatment for patients, based on the presence of the ADA protein in the blood. To go from gene to treatment in one step is almost unheard of in genomic medicine,” the American geneticist said.
“The second remarkable contribution of this discovery is the opportunity to approach the diagnosis of vasculitis in a new way,” she continued.
“Vasculitis disorders are collectively very common, but terribly difficult to distinguish from one another, because the presenting symptoms of different forms overlap so much.
The discovery of mutations as responsible for an entire class of vascultis problems offers a new dimension to their diagnosis and to their treatment,” she said.
Dr. Paulina Navon-Elkan, who was for years head of Shaare Zedek’s pediatric rheumatology clinic but is now semi-retired, was involved in the early stages of the research. She saw a toddler of Georgian origin who suffered from inflammatory disease. A sibling was more seriously affected, and then a cousin of theirs was also diagnosed. Later, similar patients were found in Germany, as well as an Arab girl, now 19, who lives in a village near Nazareth.
Treatment until now has included cytotoxic drugs ordinarily used for cancers, but they are very aggressive, said the rheumatologist. “But now that we understand the disease’s genetic origin, we have more options.
When a two-year-old child with disease was in such a bad state that we felt we had nothing to lose, we tried the biological drug Remicade (infliximab) used to treat autoimmune diseases,” she continued. “To our surprise, within 24 hours, he had left intensive care. He gets it now every six weeks, goes to school, is a very good pupil at school and had a bar mitzva.”