Abstract
Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
Highlights
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive metabolic disorder, which is characterized by life-long recurring febrile and inflammatory episodes [1]
The mevalonate kinase (MK) and hydroxy-3-methylglutarylCoA reductase (HMGR) activities showed a clear inversed correlation when measured in peripheral blood mononuclear cells (PBMCs) drawn from patients with the HIDS presentation during or between fever episodes: during fever, the MK activity is decreased and the HGMR activity increased when compared to the activities between a fever episode [16]. These observations combined with what is known about the regulation of the isoprenoid biosynthesis pathway, have led to the following hypothesis for the pathogenesis underlying the episodic inflammatory symptoms in MKD [16, 20]: under normal conditions, the increased HMGR activity in cells from MKD patients results in an elevated mevalonate level, which compensates for the decreased MK activity in the cells and assures a normal flux through the pathway
Treatment options aimed at increasing the residual MK activity and/or bypassing the enzyme defect in the isoprenoid biosynthesis pathway to assure the synthesis of geranylgeranyl pyrophosphate (GGPP) in principle could be beneficial in controlling or even preventing the inflammatory episodes
Summary
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive metabolic disorder, which is characterized by life-long recurring febrile and inflammatory episodes [1]. These observations combined with what is known about the regulation of the isoprenoid biosynthesis pathway, have led to the following hypothesis for the pathogenesis underlying the episodic inflammatory symptoms in MKD [16, 20]: under normal conditions, the increased HMGR activity in cells from MKD patients results in an elevated mevalonate level, which compensates for the decreased MK activity in the cells and assures a normal flux through the pathway.
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