Mevalonate kinase deficiency: therapeutic targets, treatments, and outcomes

Abstract

Introduction: Mevalonate Kinase Deficiency (MKD) is a rare inborn disease caused by the mutation of mevalonate kinase gene. The clinical phenotype encompasses recurrent fever episodes in combination with gastrointestinal,\ud immunological, rheumatological and neurological complaints. No specific treatment is available, apart from the newly approved biologics (canakinumab), but MKD can be still considered an orphan-drug disease, since the identification of a reliable therapeutic target needs an improved knowledge on the pathogenesis of the disease, which is so far controversial.\ud Areas covered: On one hand, shortage of isoprenoid compounds downstream of mevalonate led to a defective geranylgeranylation of RhoA/Rac proteins and increased caspase-1-dependent inflammation. On the other hand, recent studies pointed the attention to the pathogenic role of the mitochondrial dysfunction and to defective production of 25-hydroxycholesterol. These mechanisms are not exclusive of each other, as they can contribute to different pathogenic features of MKD.\ud Expert opinion: Innovative therapeutic approaches to MKD may count upon various medicaments, such as isoprenoid compounds that can enter the metabolic pathway, specific enzyme inhibitors and mitochondria-\ud targeted drugs. Some of these compounds have already passed the clinical phase for other uses and may be repositioned to the treatment of MKD, fostering the development of clinical trials

Mevalonate Kinase Deficiency and Squalene Synthase Inhibitor (TAK-475): The Balance to Extinguish the Inflammation

“…The effect of zaragozic acid is related not only to the blockade of sterol synthesis, but also to a relative accumulation of geranylgeraniol due to both the blocking of its conversion to squalene and the induction The most accredited hypothesis regarding MKD pathogenesis claims that the typical inflammation of the disease is caused by the deficiency of pre-squalenic isoprenoid intermediates, with a reduced prenylation of small GTPases, which, consequently, lose their membrane localization [5,6]. The lack of membrane-bound RhoA reflects on a reduced threshold of activation of the NLR family pyrin domain containing 3 (NLRP3) and pyrin inflammasomes and to the process of pyroptosis with a secretion of the inflammatory cytokines IL-1β, IL-6 and TNF-α [7][8][9]. An altered prenylation of KRAS (an isoform of RAS) is thought to play a role in the activation of PI3K-δ and in the lymphoproliferative phenotype characterizing MKD.…”