Temperature and Drug Treatments in Mevalonate Kinase Deficiency: AnEx VivoStudy

Paola Maura Tricarico,Annalisa Marcuzzi,Valentina Zanin,Elisa Piscianz,Giulio Kleiner,Lorenzo Monasta,Sergio Crovella

doi:10.1155/2013/715465

Paola Maura Tricarico, Annalisa Marcuzzi + Show 5 more

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https://doi.org/10.1155/2013/715465

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Abstract

Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused by mutations in the mevalonate kinase (MK) gene, leading to MK enzyme decreased activity. The consequent shortage of mevalonate-derived isoprenoid compounds results in an inflammatory phenotype, caused by the activation of the NALP3 inflammasome that determines an increased caspase-1 activation and IL-1β release. In MKD, febrile temperature can further decrease the residual MK activity, leading to mevalonate pathway modulation and to possible disease worsening. We previously demonstrated that the administration of exogenous isoprenoids such as geraniol or the modulation of the enzymatic pathway with drugs, such as Tipifarnib, partially rescues the inflammatory phenotype associated with the defective mevalonic pathway. However, it has not been investigated yet how temperature can affect the success of these treatments. Thus, we investigated the effect of temperature on primary human monocytes from MKD patients. Furthermore the ability of geraniol and Tipifarnib to reduce the abnormal inflammatory response, already described at physiological temperature in MKD, was studied in a febrile condition. We evidenced the role of temperature in the modulation of the inflammatory events and suggested strongly considering this variable in future researches aimed at finding a treatment for MKD.

Highlights

Mevalonate Kinase Deficiency (MKD), a rare autoinflammatory disease (OMIM no. 251170), is caused by mutations in the second enzyme of the mevalonate pathway (mevalonate kinase (MK)) resulting in reduced enzymatic activity and in the consequent shortage of downstream compounds [1].MKD has an early onset usually in infancy and affects both sexes
Different degrees of MKD severity were observed depending on MK residual activity, ranging from an autoinflammatory phenotype characterized by recurrent inflammatory episodes (Hyper-IgD Syndrome (HIDS), OMIM no. 260920) to a more severe clinical presentation, including neurological and psychomotor impairment (mevalonic aciduria (MA), OMIM no. 610377)
NALP3 inflammasome seems to be involved in the pathogenesis of MKD: inflammasome activation causes the increased secretion of IL-1β [8] and the pyroptosis or caspase1 dependent cell death [9]

Summary

Introduction

Mevalonate Kinase Deficiency (MKD), a rare autoinflammatory disease (OMIM no. 251170), is caused by mutations in the second enzyme of the mevalonate pathway (mevalonate kinase (MK)) resulting in reduced enzymatic activity and in the consequent shortage of downstream compounds [1].MKD has an early onset usually in infancy and affects both sexes . Mevalonate Kinase Deficiency (MKD), a rare autoinflammatory disease 251170), is caused by mutations in the second enzyme of the mevalonate pathway (mevalonate kinase (MK)) resulting in reduced enzymatic activity and in the consequent shortage of downstream compounds [1]. Different degrees of MKD severity were observed depending on MK residual activity, ranging from an autoinflammatory phenotype characterized by recurrent inflammatory episodes (Hyper-IgD Syndrome (HIDS), OMIM no. The lack of the mevalonate intermediate compound geranylgeranyl pyrophosphate, resulting in the increased caspase-1 activation and IL-1β release, has been recently reported as the main pathogenic mechanism in MKD [5, 6]. NALP3 inflammasome seems to be involved in the pathogenesis of MKD: inflammasome activation causes the increased secretion of IL-1β [8] and the pyroptosis or caspase dependent cell death [9]

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