Identifying mutations in autoinflammatory diseases: towards novel genetic tests and therapies?

Am J Pharmacogenomics. 2004;4(2):109-18. doi: 10.2165/00129785-200404020-00005.


Autoinflammatory diseases are defined as illnesses caused by primary dysfunction of the innate immune system. This new concept includes a broad number of disorders, but the spotlight has been focused for the past two years on periodic fevers (familial Mediterranean fever [FMF]; mevalonate kinase deficiency [MVK]; tumor necrosis factor [TNF] receptor-associated periodic syndrome [TRAPS]; cryopyrin-associated periodic syndrome [CAPS]), Crohn's disease and Blau syndrome, thanks to the recent understanding of their molecular basis. Indeed, until recently, these conditions were defined only by phenotypical features, the main ones being recurrent attacks of fever, abdominal pain, arthritis, and cutaneous signs, which sometimes overlap, obscuring diagnosis. The search for distinguishing signs such as periorbital edema in TRAPS, and the use of specific functional tests where available, are valuable. Needless to say, molecular screening of the causative genes has dramatically improved patient quality-of-life by providing early and accurate diagnosis, subsequently allowing for the appropriate treatment. Some patients, however, remain hard to manage despite the advent of new genetic tests, and/or due to the lack of effective treatment. The original clinical link between the aforementioned diseases can now be confirmed by a molecular one, following the exciting discovery that most of the altered proteins are related to the death domain fold (DDF) superfamily involved in inflammation and apoptosis. These molecules mediate the regulation of nuclear factor-kappa B (NF-kappa B) activation, cell apoptosis, and interleukin-1 beta secretion through cross-regulated and, sometimes, common signaling pathways. Knowledge of the defective step in autoinflammation has already led to the elucidation of the mechanisms of action of existing drugs and may allow the development of new therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Genetic Testing
  • Genetic Therapy
  • Humans
  • Inflammation / diagnosis*
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Inflammation / therapy
  • Mutation / genetics*