Abstract
Mevalonate kinase-associated diseases (MKAD) are caused by pathogenic mutations in the mevalonate kinase gene (MVK) and encompass several phenotypically different rare and hereditary autoinflammatory conditions. The most serious is a recessive systemic metabolic disease called mevalonic aciduria, and the most recently recognized is disseminated superficial actinic porokeratosis, a dominant disease limited to the skin. To evaluate a possible correlation between genotypes and (1) the different MKAD clinical subtypes or (2) the occurrence of severe manifestations, data were reviewed for all patients with MVK variants described in the literature (N = 346), as well as those referred to our center (N = 51). The genotypes including p.(Val377Ile) (homozygous or compound heterozygous) were more frequent in mild systemic forms but were also sometimes encountered with severe disease. We confirmed that amyloidosis was more prevalent in patients compound heterozygous for p.(Ile268Thr) and p.(Val377Ile) than in others and revealed new associations. Patients homozygous for p.(Leu264Phe), p.(Ala334Thr) or compound heterozygous for p.(His20Pro) and p.(Ala334Thr) had increased risk of severe neurological or ocular symptoms. All patients homozygous for p.(Leu264Phe) had a cataract. The variants associated with porokeratosis were relatively specific and more frequently caused a frameshift than in patients with other clinical forms (26% vs. 6%). We provide practical recommendations focusing on phenotype–genotype correlation in MKAD that could be helpful for prophylactic management.
Highlights
Monogenic autoinflammatory diseases are a group of rare and heterogeneous conditions that display abnormal regulation of innate immunity resulting from one or two pathogenic variants in a single gene [1].Among them are diseases associated with the mevalonate kinase gene (MVK)
mevalonate kinase deficiency (MKD) encompasses a continuum of conditions ranging from a serious metabolic disease called mevalonic aciduria (MA, OMIM—Online Mendelian Inheritance in Men, 610377) [2,9] to a milder disease coined “hyper IgD (Immunoglobulin D) syndrome with periodic fever” (HIDS, OMIM 260920) because high amounts of IgD were found in the serum of most patients [7,10]
Three resources were queried for this study: (1) references extracted from PubMed with the following string of keywords: (MVK or mevalonate kinase or mevalonic aciduria or hyperIgD syndrome or HIDS), (2) records of patients referred to our laboratory for genetic analysis, and (3) Infevers, the registry of autoinflammatory mutations, which was updated with the two other resources if necessary
Summary
Monogenic autoinflammatory diseases are a group of rare and heterogeneous conditions that display abnormal regulation of innate immunity resulting from one (dominant transmission) or two (recessive transmission) pathogenic variants in a single gene [1]. Defective protein prenylation underlies the inflammation seen in mevalonate kinase-associated diseases (MKAD) [2,3,4] These include several very different phenotypic subtypes with either systemic [5] or localized [6] heterogeneous manifestations. MKD encompasses a continuum of conditions ranging from a serious metabolic disease called mevalonic aciduria (MA, OMIM—Online Mendelian Inheritance in Men, 610377) [2,9] to a milder disease coined “hyper IgD (Immunoglobulin D) syndrome with periodic fever” (HIDS, OMIM 260920) because high amounts of IgD were found in the serum of most patients [7,10] This IgD measurement should be abandoned in daily practice because elevated IgD level is neither specific nor constant [11] and does not correlate with disease severity, mevalonate kinase enzyme activity, or genotype [12]. This observation prompted us to design a study on the largest possible series of patients with all MKAD subtypes to try to identify clearer genotype–phenotype correlations after the integration of newer patients
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