Periodic fever and mevalonate kinase deficiency

Mevalonate kinase (MK) deficiency is an autosomal recessive disorder, caused by mutations in the MVK-gene on chromosome 12q24. The affected enzyme catalyzes an early step in isoprenoid biosynthesis, the pathway that produces cholesterol and several non-sterol isoprenoids. The clinical spectrum includes hyper IgD and periodic fever syndrome (HIDS) and mevalonic aciduria. Both phenotypes are characterized by recurrent generalized inflammation and fever attacks from infancy,. accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgias, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. In addition, the mevalonic aciduria phenotype is characterized by mental retardation and facial malformation. The severe phenotype reflects a more profound enzyme deficiency due to distinct mutations in the MVK gene. Urinary excretion of the accumulating substrate of MK, mevalonic acid is about a thousand fold higher in MA than in HIDS. By definition, serum IgD is elevated in HIDS. However, 20% of clinically diagnosed HIDS patients have normal MK activity and IgD may be normal in MK deficiency. Ex vivo, mononuclear cells from MK deficiency patients secrete more IL-1beta. We could demonstrate that this was due to decreased generation of isoprenoid products and not to accumulation of the substrate of MK, mevalonate, linking the metabolic defect directly to inflammation. The enzyme activity in HIDS proved to be discontinuous, dropping with increasing temperature, both in vitro and in vivo. This finding provides a possible explanation for he episodic nature of inflammation in HIDS. Despite the raised serum IgD, the affected leukocyte populations were not lymphocytes, but phagocytes, as judged by the surface expression of cellular activation markers. .This was further supported by the increased urinary excretion of leukotriene E4, a product of activated monocytes and macrophages, during febrile crises. In summary, distinct mutations in MVK, lead to varying degrees of MK deficiency. This is reflected in a variable phenotype of episodic generalized inflammation with (MA) or without (HIDS) neurological and facial abnormalities. Due to the shortage of an as yet unidentified isoprenoid product, activated mononuclear phagocytes secrete more IL-1beta, a potent primary pro-inflammatory cytokine, giving rise to realized inflammation. Thisinflammation is episodic due to the increased temperature sensitivity of mutant MK.