Dr. Hobart Reimann, then working at the American University in Beirut, had long been collecting information on clinical phenomena of intermittent and periodic character, which seemed to be more common in the Middle East. He found many examples of what Siegal had described, as well as instances of many other conditions, such as cyclic neutropenia, periodic paralysis, and intermittent hydrarthrosis [2]. It was clear from his descriptions, however, that what would later be called familial Mediterranean fever clustered among Arabs, Armenians, and Jews in the Levant. The creation of the state of Israel and the subsequent influx of Jews fleeing or expelled from Arab countries led to the recognition that the syndrome occurred predominantly in Middle Eastern peoples, with only sporadic cases in other groups [3]. Although Siegal's paper failed to detail the ethnic background of his patients, they probably were Ashkenazi Jews.

Ashkenazi Jews-those chiefly from the Pale of Poland, Russia, and central European countries-seem to be genetically different from their Sephardic coreligionists, who mainly stem from the Mediterranean countries of Africa and Europe. Familial Mediterranean fever is rare among Ashkenazi Jews but common among Sephardim. This accounts for its further elucidation in Israel, where the late Professor Harry Heller and his team gave the disease its current name, solidified its clinical description, and suggested that it was an autosomal recessive disorder. These investigators also discovered that amyloidosis was part of the disease picture and was responsible for early deaths among afflicted persons [4].

By the early 1960s, Heller's group noted that joint manifestations played a prominent role in the clinical presentation of familial Mediterranean fever. In 1964, I was sent by the U.S. Department of Health, Education and Welfare to help further investigate this clinical enigma [5]. Only palliative treatment of symptoms was then available; Mamoud and Cattan had earlier tried colchicine for the acute attacks, having seen parallels with gouty attacks, but had been largely unsuccessful [6]. Regular administration of colchicine, however, not only reduced the frequency, duration, and severity of attacks [7] but also delayed or prevented amyloidosis [8], suggesting a major role of inflammatory mechanisms.

The study by Eisenberg and colleagues in this issue [9] documents a breakthrough by identifying the genetic mutations responsible for familial Mediterranean fever and offering a rapid, accurate, and cost-effective method for detecting these genetic abnormalities (and confirming the diagnosis in affected persons and, perhaps, in those at risk). This is of more than passing interest to patients. When physicians can confirm a diagnosis of familial Mediterranean fever, unnecessary surgical interventions can be avoided.

The discovery of the three missense mutations carries both anthropologic and historical implications. Mutation M694V was found predominantly in Sephardic Jews; M6801 in persons of Armenian ancestry; and V726A in Armenians, Iraqi Jews, and relatively few Ashkenazi Jews. These findings further the debate over the origins of various peoples. In the case of Jews, almost two millennia may not be long enough to account for the genetic differences between the Ashkenazi and Sephardic Jews in their inherited disease propensities (such as diabetes mellitus and Tay-Sachs disease in eastern Ashkenazi Jews and familial Mediterranean fever in Sephardim).

Professor Heller was among those who believed that Ashkenazi and Sephardic Jews have different origins. Some speculate that Ashkenazi Jews descended from the Khazars, an early medieval empire that straddled the Volga River and dominated the eastern Black Sea and the Caspian Sea. Their rulers and many of their subjects converted to Judaism, probably in the eighth century, and the Khazars were gradually forced westward after successive losses to Muslim armies from the south, Mongols from the east, and the Rus (Scandinavians who gave Russia its name) from the north [10]. The genetic distribution of the missense mutations reported by Eisenberg and colleagues [9] adds further detail to the argument: It distinguishes between the Sephardic (M693V) and Ashkenazi (V726A) Jews, grouping the latter with Iraqi Jews and some Armenians and suggesting that all three groups originated in an area contiguous to or encompassing the Khazar empire (which probably incorporated many of the Jews remaining in that area after the Babylonian captivity). In fact, the Khazars were a Turkic people, and it would be of interest to look for this genetic mutation in contemporary Turks with the clinical signs and symptoms of familial Mediterranean fever. While anthropologists argue, the new technology bids fair to solve many puzzles in health and disease.

I had assumed some years ago that genetics would ultimately replace most contemporary treatments with more rational ones [11], and the pace of discovery promises this denouement sooner than even the most optimistic projections had indicated, providing not only the nidus for therapy but increasingly aiding in diagnosis and in the understanding of history. That the tracks of our ancestors should be found through the molecular biology of our cells implies a new role for medicine in understanding the origins and migrations of peoples and the propensities for and distributions of disease. In the case of familial Mediterranean fever, it has taken a mere 50 years to move from the description of a clinical syndrome by a perspicacious physician to a deep understanding of its pathogenesis and, it is hoped, more rational and effective treatment.