Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene.

Familial Mediterranean fever (FMF) is a genetic disorder, restricted to peoples originating in the Middle East. The clinical syndrome is characterized by shortlived febrile episodes, accompanied by inflammation in one of the serous membranes, resulting in peritonitis pleuritis or synovitis. In many untreated FMF patients, systemic amyloidosis developed. The clinical presentation of amyloidosis in FMF is nephropathic, progressing from proteinuria, nephrosis to renal failure and end stage renal disease. Continuous colchicine treatment, which was introduced in 1972, prevents most febrile-inflammatory attacks of FMF, and inhibits the development of amyloidosis in this otherwise fatal disease. Recently, the gene that causes FMF was cloned. It is called the pyrin gene and encodes the pyrin protein. Five missense mutations were found so far in the gene. These give rise to 5 amino acid substitutions, all of them in the carboxyterminal part of the pyrin protein. The pyrin protein is expressed solely in neutrophiles white blood cells which are found in large numbers in the inflammatory sites during FMF attacks. It seems that the role of the wild type of the pyrin protein is to inhibit inflammation that can be provoked by a minor insult. The mutated pyrin protein in FMF is probably unable to inhibit these unnecessary inflammatory events. Preliminary studies of phenotype genotype correlation are reported.