Genetic clues to understanding periodic fevers, and possible therapies

Significant breakthroughs in our understanding of the molecular basis of the inflammatory response have been achieved in the past five years, with the successive identification of the genetic basis of all known hereditary periodic-fever syndromes. Impaired cytokine recognition and defective signalling molecules have been implicated in the inception of recurrent attacks of fever with acute-phase protein response. Disorders of interleukin-1 processing and of regulation of nuclear factor kappaB transcription factor, and possibly defective apoptosis, might be involved in the pathogenesis of all but one of these disorders. Mutations in genes of both the pyrin and tumour-necrosis-factor-receptor superfamilies are postulated to lead to the survival of leukocytes that would ordinarily undergo apoptosis, and ultimately to a prolonged inflammatory response. Improved therapies have reduced the incidence of systemic amyloidosis, but this complication remains the most frequent cause of death.