The link between isoprenoid metabolism and periodic fever, inflammation and dysregulation of apoptosis

At the core of this program grant application is the hyper-IgD and periodic fever syndrome (HIDS), a familial periodic fever syndrome or autoinflammatory disorder. This syndrome was originally described by Van der Meer in 1984 as a syndrome of recurrent incapacitating attacks of fever and a number of accompanying inflammatory symptoms, an acute phase response and elevated serum immunoglobulin D and A. A few years ago, the groups of Wanders, Poll-Thé and Kuis and those of Van der Meer and Delpech identified the defect in HIDS as a deficiency of mevalonate kinase (MK), due to mutations in the MVK gene. MK is a key enzyme of isoprenoid biosynthesis. Phenotypically HIDS can be distinguished from mevalonic aciduria (MVA), a rare inborn error of metabolism that is also due to defects in the MVK gene. The surprising discovery of a metabolic defect as a causative factor of a syndrome consisting of periodic fever, inflammation and immunodysregulation is a great challenge. The overall aim of this program grant is to resolve the unexpected link between isoprenoid biosynthesis and the pathophysiology of HIDS.Key objectives of the program that will be carried out by the two collaborative groups are: I] To obtain insight into the pathophysiological mechanisms that lead to periodic fever, inflammation and immunodysregulation. II] To use the insights obtained to design a therapy for patients with HIDS and other inflammatory disorders.