Nehardea Magazine

Journal of the Babylonian Jewry Heritage Center
No.14, Autumn 2003

THE THIRD INTERNATIONAL CONGRESS

FMF: FAMILIAL MEDITERRANEAN FEVER

a hereditary disease widespread among Iraqi and North African Jews

Prof. Mordechai Pras

Dispersion Locales: FMF patients may be found worldwide, but almost all of them belong to 3-4 ethnic groups: Jews, Armenians, Turks and Arabs. The Disease is more widespread in the Middle East and along the Mediterranean shoreline, hence the name Mediterranean fever. Even though the disease has been in existence for thousands of years, it was only in 1945 that it was described by Siegal who suffered from the disease. In Israel it was actually discovered and recognized in 1948-1949, when a wave of Iraqi and North African Jews arrived here. Ashkenazi immigrants also arrived, but the disease is more widespread among Iraqi and North African immigrants.

Inauguration of a new wing at Meir Elias Hospital, Baghdad, 1924

After having developed the symptoms of the disease, those patients who started arriving were admitted to various hospitals in Israel, especially Tel-Hashomer, since the immigrants, then, were concentrated in Sakiyah and Khayriya transit camps in the ma’abarot area, which today is called Or-Yehuda.

Prof. Harry Heller of Tel-Hashomer, who was also my instructor, started researching the disease, and together with his interns, Ezra Sohar and Yosef Gaffni, documented the disease in numerous articles.

The disease is hereditary and is passed on by a recessive gene, (i.e. hidden) unlike breast cancer where the disease is passed on from generation to generation.

In cases of FMF, as in Cystic Fibrosis, both parents are carriers who pass on the disease to a number of their offspring. Another element frequently seen in a recessive disease is the existences of inter-marriage between family relatives, usually first cousins, among the patients’ parents. It is well known that marriages between family relatives were quite common among Iraqi Jews. In his initial research, Heller found that 17% of the parents of those patients were, at that time, first cousins.

If two patients marry, as is the case among patients from three families, all their children are stricken by the disease.

The initial symptom of the disease usually starts at a very young age and most patients begin to suffer from the first decade of their lives.

Prior to the age of 10, more than 60% suffer from the disease. By the age of 20, 90% already suffer from the disease, but sometimes the disease starts later. Usually the disease is diagnosed when infants start talking, but in many cases, it starts even earlier. One of the youngest diagnosed, was an infant named Abe. He was 8 days old: A few hours after the circumcision ceremony he ran a high fever, cried all the time and was very restless. His mother who had experienced the disease in her previous two children, recognised the disease at the age of 8 days. This was the case of the earliest diagnosis ever made. In contrast, one of the patients was diagnosed at the age of 65. He showed symptoms of the disease, high fever and abdominal pain, at the age of 28 and was operated on several times. Surgeons looked for abscesses and performed cholecystectomy, but he continued to suffer from abdominal pains. One of the surgeons told him: "If you were not an Ashkenazi Jew, I would have had readily pronounced a clear diagnosis, but since you are an Ashkenazi Jew, this is not the case". This, of course was incorrect. When he was 65 years old, his wife read an article published in "La Isha" magazine, emphasizing that Ashkenazi Jews can be born with FMF. The pair arrived at Tel-Hashomer Hospital where the man was correctly diagnosed and finally got effective treatment for this ailment.

The disease starts suddenly and is characterized by a rapidly rising fever which may cause shivering, accompanied by inflammation of one of the serous membranes, the abdominal and the thoracic membranes or the synovia of the joints.

The inflammation of the abdominal membrane is the most common site of inflammation and can be diagnosed in 95% of all FMF cases. The pain is excruciating and most FMF patients underwent surgery. However, during the surgical procedure nothing can be found except the inflammation with very little abdominal fluid, which is actually sterile, (free of germs). If the patient does not undergo surgery, the attack lasts from one to three days and is over without leaving any traces, until the onset of the next attack.

If X-rays are taken during an abdominal attack, they show the existence of fluid levels, which indicate intestinal obstruction. Consequently many FMF patients have undergone surgery more than once. In one case, a young woman had eight operations before the correct diagnosis was made.

Attacks of chest pains are similar to attacks of abdominal pain, except that the pain is localized at one side of the thorax. X-rays show very little fluid, which disappears by the end of the attack, and which usually lasts two or three days. Inflammation of the joints occurs only in the large joints, of the lower extremities i.e., knees hips and ankles, lasting for about three to five days, but again the inflammation vanishes without trace.

Some FMF patients may suffer from prolonged inflammation of the hip joint, knee or ankle, which may last weeks and sometimes, even months. A prolonged inflammation in the hip joint may cause distortions. These patients suffer pain and limping, a situation which needs orthopedic intervention to replace the hip joint, a procedure that usually returns the patient to lead a normal life.

All the above described symptoms may be uncomfortable, but untreated FMF patients may be in danger of developing Amyloidosis which mainly affect the kidneys where accumulation of the protein Amyloid causes the appearance of the protein in the urine in high concentration leading to kidney failure.

Prior to treatment, many FMF patients suffered kidney failure and died, or had to get chronic dialysis treatment or to undergo a kidney transplantation.

The situation was quite gloomy. In 1972, before treatment was started, 90% of the living FMF patients were under the aged 40, and only 10% were aged over 40. The reason was that most FMF patients at that time died at a young age before reaching the age of 40.

In 1972, Goldfinger, a Jewish physician from Boston, suggested treatment with Cholchicin, a herbal medicine which has been in use for thousands of years, by the Ancient Greeks to treat gout.

Cholchicin is extracted from the meadow saffron (family of the autumn crocus), which grows in Israel and the middle east. It must be prescribed for life; 1 to 2 milligrams a day. This dose will prevent most attacks of pain, fever, and inflammation of the abdomen chest and joints and also prevent the deposition of Amyloidosis, which ruins the kidneys. 65% of the patients who regularly receive this treatment will be free of the above attacks, a further 30% will rarely suffer very light attacks but 5% continue to suffer the usual attacks. However, all FMF patients who take Colchicin have not developed Amyloidosis.

A research conducted among 960 patients reveals that only 0.5% of those who received Colchicine had protein in their urine, probably not caused by Amyloidosis. Compared to 54 patients who, for various reasons, did not take the Colchicine (partly because doctors in the community were deterred from prescribing it to children of tender age) 16 patients (30%) developed Amyloidosis. This unplanned control group that did not get Colchicine treatment proved the effectiveness of the medicine.

13 years ago we decided to locate and find the gene that causes this disease. Using the methods and techniques available then, it took 10 years to find the gene. First, the chromosomes had to be found. There are 22 pairs of them and are arrayed in order of their size. It took two and a half years to find the location of the gene on chromosome 16. At this stage we were nearing the end of the road. But in fact we needed another 8 years to isolate the Gene itself. Finding the Gene gave us a diagnostic technique. Diagnosis of FMF was made by demonstrating mutations in the FMF gene (which was nominated MEFV) in patients. For the time being, we have made no significant progress as to how the disease is caused, but this remains only a matter of time. Right now, we have no alternative medicine apart from Colchicine yet, possibly because it is quite an effective one almost without side effects and not expensive compared to other drugs. Further more, we also found explanations of trails of migrations of Jews, in the Diaspora.

Today, we know about over thirty mutations in the FMF Gene, which is a medium sized Gene, but among Jews, there are only three main mutations located in codons 148, 694 & 726 of the MEFV gene. In order to get the disease a patient needs two mutations. Each parent must pass on one mutation.

In addition to causing the disease, these mutations indicate and dictate the severity of the disease. It is most severe in the presence of mutation 694, which is very common among North African Jews. Mutation 726, is rare among North African Jews, but is quite common among Iraqi and Ashkenazi Jews. However, the difficult mutation 694 does exist among Iraqi Jews. Mutation 148 is responsible for the mild type of the disease, and is common among Ashkenazi Jews.

In Israel there are over 7,000 FMF patients and about 100,000 carriers of one of the FMF gene mutations, 148, 694 and 726.

In conclusion, I want to tell this story: about 8 years ago, at the FMF clinic, a young lady entered my room. She was English and arrived in Israel in order to embrace Judaism. She told me that since the age of 15, she suffered from abdominal pain and fevers. She was hospitalized several times in London, once in a hospital for tropical diseases. They looked for malaria but found nothing, and even thought that she had an abdominal infection. In Israel, she resided in Kfar Giladi Ulpan and traveled to Safad for religious lessons and there she had an attack. The Kibbutz physician there immediately suspected FMF. He waited till the next attack happened and had her hospitalized in Safad. She was examined by doctors, who claimed that she could not possibly be suffering from FMF.

However, the attacks continued. After the third or fourth attack she was referred to Tel-Hashomer, and even though she was English, we suspected FMF. We wondered where she could have contracted the disease. Her family had seven children, and one of her sisters, suffered the same attacks of fever and abdominal pains. That meant that each of their parents must be a carrier. Investigations revealed that the mother was English, the father Irish, but when asked about grandparents, it was found out that the maternal grandmother was not English. The grandfatherís surname was Zelig while the grandmotherís surname was Chechik, both typical Jewish family names. The grandmother passed on the Gene to the mother, who in turn passed it on to her daughter. But what about the father? True he was Irish, but the Irish, unlike the English, do have FMF. So what is the difference between the English and Irish that makes the Irish susceptible to FMF?

In 1588, during the reign of Queen Elizabeth the First, daughter of Henry the Eighth, who was head of the Anglican Church, the Spanish King Philip the Second declared war by the Catholics against the Anglicans and sent his Armada to occupy England. The war resulted in the rout of the Spanish Armada whose remnants retreated towards the English West coast, sailed around England and foundered on the Irish coast during stormy weather. The Spanish sailors, being Catholic, were received with open arms. At that time, 15% of the Spanish people were of Jewish origin. This may explain why the Irish have FMF, which bring us back to the English young woman who wished to accept a Jewish fate.

Prof. Mordechai Pras is the Director of Heller Institute for Medical Research, Sheba Medical Center Tel-Hashomer.

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Table of Contents

THE THIRD INTERNATIONAL CONGRESS
FMF: FAMILIAL MEDITERRANEAN FEVER a hereditary disease widespread among Iraqi and North African Jews Prof. Mordechai Pras
Dispersion Locales: FMF patients may be found worldwide, but almost all of them belong to 3-4 ethnic groups: Jews, Armenians, Turks and Arabs. The Disease is more widespread in the Middle East and along the Mediterranean shoreline, hence the name Mediterranean fever. Even though the disease has been in existence for thousands of years, it was only in 1945 that it was described by Siegal who suffered from the disease. In Israel it was actually discovered and recognized in 1948-1949, when a wave of Iraqi and North African Jews arrived here. Ashkenazi immigrants also arrived, but the disease is more widespread among Iraqi and North African immigrants. Inauguration of a new wing at Meir Elias Hospital, Baghdad, 1924 After having developed the symptoms of the disease, those patients who started arriving were admitted to various hospitals in Israel, especially Tel-Hashomer, since the immigrants, then, were concentrated in Sakiyah and Khayriya transit camps in the ma’abarot area, which today is called Or-Yehuda. Prof. Harry Heller of Tel-Hashomer, who was also my instructor, started researching the disease, and together with his interns, Ezra Sohar and Yosef Gaffni, documented the disease in numerous articles. The disease is hereditary and is passed on by a recessive gene, (i.e. hidden) unlike breast cancer where the disease is passed on from generation to generation. In cases of FMF, as in Cystic Fibrosis, both parents are carriers who pass on the disease to a number of their offspring. Another element frequently seen in a recessive disease is the existences of inter-marriage between family relatives, usually first cousins, among the patients’ parents. It is well known that marriages between family relatives were quite common among Iraqi Jews. In his initial research, Heller found that 17% of the parents of those patients were, at that time, first cousins. If two patients marry, as is the case among patients from three families, all their children are stricken by the disease. The initial symptom of the disease usually starts at a very young age and most patients begin to suffer from the first decade of their lives. Prior to the age of 10, more than 60% suffer from the disease. By the age of 20, 90% already suffer from the disease, but sometimes the disease starts later. Usually the disease is diagnosed when infants start talking, but in many cases, it starts even earlier. One of the youngest diagnosed, was an infant named Abe. He was 8 days old: A few hours after the circumcision ceremony he ran a high fever, cried all the time and was very restless. His mother who had experienced the disease in her previous two children, recognised the disease at the age of 8 days. This was the case of the earliest diagnosis ever made. In contrast, one of the patients was diagnosed at the age of 65. He showed symptoms of the disease, high fever and abdominal pain, at the age of 28 and was operated on several times. Surgeons looked for abscesses and performed cholecystectomy, but he continued to suffer from abdominal pains. One of the surgeons told him: "If you were not an Ashkenazi Jew, I would have had readily pronounced a clear diagnosis, but since you are an Ashkenazi Jew, this is not the case". This, of course was incorrect. When he was 65 years old, his wife read an article published in "La Isha" magazine, emphasizing that Ashkenazi Jews can be born with FMF. The pair arrived at Tel-Hashomer Hospital where the man was correctly diagnosed and finally got effective treatment for this ailment. The disease starts suddenly and is characterized by a rapidly rising fever which may cause shivering, accompanied by inflammation of one of the serous membranes, the abdominal and the thoracic membranes or the synovia of the joints. The inflammation of the abdominal membrane is the most common site of inflammation and can be diagnosed in 95% of all FMF cases. The pain is excruciating and most FMF patients underwent surgery. However, during the surgical procedure nothing can be found except the inflammation with very little abdominal fluid, which is actually sterile, (free of germs). If the patient does not undergo surgery, the attack lasts from one to three days and is over without leaving any traces, until the onset of the next attack. If X-rays are taken during an abdominal attack, they show the existence of fluid levels, which indicate intestinal obstruction. Consequently many FMF patients have undergone surgery more than once. In one case, a young woman had eight operations before the correct diagnosis was made. Attacks of chest pains are similar to attacks of abdominal pain, except that the pain is localized at one side of the thorax. X-rays show very little fluid, which disappears by the end of the attack, and which usually lasts two or three days. Inflammation of the joints occurs only in the large joints, of the lower extremities i.e., knees hips and ankles, lasting for about three to five days, but again the inflammation vanishes without trace. Some FMF patients may suffer from prolonged inflammation of the hip joint, knee or ankle, which may last weeks and sometimes, even months. A prolonged inflammation in the hip joint may cause distortions. These patients suffer pain and limping, a situation which needs orthopedic intervention to replace the hip joint, a procedure that usually returns the patient to lead a normal life. All the above described symptoms may be uncomfortable, but untreated FMF patients may be in danger of developing Amyloidosis which mainly affect the kidneys where accumulation of the protein Amyloid causes the appearance of the protein in the urine in high concentration leading to kidney failure. Prior to treatment, many FMF patients suffered kidney failure and died, or had to get chronic dialysis treatment or to undergo a kidney transplantation. The situation was quite gloomy. In 1972, before treatment was started, 90% of the living FMF patients were under the aged 40, and only 10% were aged over 40. The reason was that most FMF patients at that time died at a young age before reaching the age of 40. In 1972, Goldfinger, a Jewish physician from Boston, suggested treatment with Cholchicin, a herbal medicine which has been in use for thousands of years, by the Ancient Greeks to treat gout. Cholchicin is extracted from the meadow saffron (family of the autumn crocus), which grows in Israel and the middle east. It must be prescribed for life; 1 to 2 milligrams a day. This dose will prevent most attacks of pain, fever, and inflammation of the abdomen chest and joints and also prevent the deposition of Amyloidosis, which ruins the kidneys. 65% of the patients who regularly receive this treatment will be free of the above attacks, a further 30% will rarely suffer very light attacks but 5% continue to suffer the usual attacks. However, all FMF patients who take Colchicin have not developed Amyloidosis. A research conducted among 960 patients reveals that only 0.5% of those who received Colchicine had protein in their urine, probably not caused by Amyloidosis. Compared to 54 patients who, for various reasons, did not take the Colchicine (partly because doctors in the community were deterred from prescribing it to children of tender age) 16 patients (30%) developed Amyloidosis. This unplanned control group that did not get Colchicine treatment proved the effectiveness of the medicine. 13 years ago we decided to locate and find the gene that causes this disease. Using the methods and techniques available then, it took 10 years to find the gene. First, the chromosomes had to be found. There are 22 pairs of them and are arrayed in order of their size. It took two and a half years to find the location of the gene on chromosome 16. At this stage we were nearing the end of the road. But in fact we needed another 8 years to isolate the Gene itself. Finding the Gene gave us a diagnostic technique. Diagnosis of FMF was made by demonstrating mutations in the FMF gene (which was nominated MEFV) in patients. For the time being, we have made no significant progress as to how the disease is caused, but this remains only a matter of time. Right now, we have no alternative medicine apart from Colchicine yet, possibly because it is quite an effective one almost without side effects and not expensive compared to other drugs. Further more, we also found explanations of trails of migrations of Jews, in the Diaspora. Today, we know about over thirty mutations in the FMF Gene, which is a medium sized Gene, but among Jews, there are only three main mutations located in codons 148, 694 & 726 of the MEFV gene. In order to get the disease a patient needs two mutations. Each parent must pass on one mutation. In addition to causing the disease, these mutations indicate and dictate the severity of the disease. It is most severe in the presence of mutation 694, which is very common among North African Jews. Mutation 726, is rare among North African Jews, but is quite common among Iraqi and Ashkenazi Jews. However, the difficult mutation 694 does exist among Iraqi Jews. Mutation 148 is responsible for the mild type of the disease, and is common among Ashkenazi Jews. In Israel there are over 7,000 FMF patients and about 100,000 carriers of one of the FMF gene mutations, 148, 694 and 726. In conclusion, I want to tell this story: about 8 years ago, at the FMF clinic, a young lady entered my room. She was English and arrived in Israel in order to embrace Judaism. She told me that since the age of 15, she suffered from abdominal pain and fevers. She was hospitalized several times in London, once in a hospital for tropical diseases. They looked for malaria but found nothing, and even thought that she had an abdominal infection. In Israel, she resided in Kfar Giladi Ulpan and traveled to Safad for religious lessons and there she had an attack. The Kibbutz physician there immediately suspected FMF. He waited till the next attack happened and had her hospitalized in Safad. She was examined by doctors, who claimed that she could not possibly be suffering from FMF. However, the attacks continued. After the third or fourth attack she was referred to Tel-Hashomer, and even though she was English, we suspected FMF. We wondered where she could have contracted the disease. Her family had seven children, and one of her sisters, suffered the same attacks of fever and abdominal pains. That meant that each of their parents must be a carrier. Investigations revealed that the mother was English, the father Irish, but when asked about grandparents, it was found out that the maternal grandmother was not English. The grandfatherís surname was Zelig while the grandmotherís surname was Chechik, both typical Jewish family names. The grandmother passed on the Gene to the mother, who in turn passed it on to her daughter. But what about the father? True he was Irish, but the Irish, unlike the English, do have FMF. So what is the difference between the English and Irish that makes the Irish susceptible to FMF? In 1588, during the reign of Queen Elizabeth the First, daughter of Henry the Eighth, who was head of the Anglican Church, the Spanish King Philip the Second declared war by the Catholics against the Anglicans and sent his Armada to occupy England. The war resulted in the rout of the Spanish Armada whose remnants retreated towards the English West coast, sailed around England and foundered on the Irish coast during stormy weather. The Spanish sailors, being Catholic, were received with open arms. At that time, 15% of the Spanish people were of Jewish origin. This may explain why the Irish have FMF, which bring us back to the English young woman who wished to accept a Jewish fate. Prof. Mordechai Pras is the Director of Heller Institute for Medical Research, Sheba Medical Center Tel-Hashomer.
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