Abstract
Mevalonic aciduria, a rare autosomal recessive disease, represents the most severe form of the periodic fever, known as Mevalonate Kinase Deficiency. This disease is caused by the mutation of the MVK gene, which codes for the enzyme mevalonate kinase, along the cholesterol pathway. Mevalonic aciduria patients show recurrent fever episodes with associated inflammatory symptoms, severe neurologic impairments, or death, in early childhood. The typical neurodegeneration occurring in mevalonic aciduria is linked both to the intrinsic apoptosis pathway (caspase-3 and -9), which is triggered by mitochondrial damage, and to pyroptosis (caspase-1). These cell death mechanisms seem to be also related to the assembly of the inflammasome, which may, in turn, activate pro-inflammatory cytokines and chemokines. Thus, this particular molecular platform may play a crucial role in neuroinflammation mechanisms. Nowadays, a specific therapy is still lacking and the pathogenic mechanisms involving neuroinflammation and neuronal dysfunction have not yet been completely understood, making mevalonic aciduria an orphan drug disease. This review aims to analyze the relationship among neuroinflammation, mitochondrial damage, programmed cell death, and neurodegeneration. Targeting inflammation and degeneration in the central nervous system might help identify promising treatment approaches for mevalonic aciduria or other diseases in which these mechanisms are involved.
Highlights
IntroductionMevalonate Kinase Deficiency (MKD) is a rare, autosomic recessive, metabolic disease, caused by mutations in the MVK gene (12q24.11, NM_000431) coding for the enzyme mevalonate kinase (MK)
Mevalonate Kinase Deficiency (MKD) is a rare, autosomic recessive, metabolic disease, caused by mutations in the MVK gene (12q24.11, NM_000431) coding for the enzyme mevalonate kinase (MK)(E.C. 2.7.1.36), the second enzyme of the mevalonate pathway, the route to cholesterol (Figure 1a) [1,2].The severity of the disease is linked with the residual activity of MK; a residual activity between1%–8% leads to a mild autoinflammatory phenotype, called hyper immunoglobulinemia D syndrome (HIDS, OMIM #260920), the symptoms of which are recurrent episodes of fever and associated inflammatory events
Even if the findings presented in these MKD models should be considered as preliminary, due to the adoption of a biochemical model of MKD, they should be taken as a first step in research aimed at better disclosing the MKD pathogenesis
Summary
Mevalonate Kinase Deficiency (MKD) is a rare, autosomic recessive, metabolic disease, caused by mutations in the MVK gene (12q24.11, NM_000431) coding for the enzyme mevalonate kinase (MK). A residual activity below the level of detection leads to the most severe form of this pathology, known as mevalonic aciduria (MA, OMIM #610377), which, in addition, shows developmental delay, dysmorphic features, ataxia, cerebellar atrophy, psychomotor retardation, and sometimes death occurs in early childhood [3]. The most accredited pathogenic hypothesis is that the inflammatory phenotype is caused by shortage of isoprenoid compounds [4,5,6]. Far, this condition has been reproduced in biochemical experimental models obtained using drugs able to block the mevalonate pathway [7]. The attainment of new pharmacological treatments is of fundamental importance especially for the most severe forms of MKD, in which even the nervous system is involved
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