“Hyper-IgD syndrome” or “mevalonate kinase deficiency”: an old syndrome needing a new name?

Abstract

In the recent paper by Stabile et al. [1], the authors evaluate a group of patients suffering from a rare metabolic disease, called mevalonate kinase deficiency (MKD), previously known as Hyper-IgD syndrome (HIDs). The latter name was due to the fact that some patients displayed, among other symptoms, increased levels of circulating IgD during febrile flares. Stabile and colleagues re-evaluated 305 children with recurrent fevers, drawing out 10 patients based on the presence of inflammatory signs and elevated IgD levels. They found that IgD levels did not correlate with disease severity. This is one of the several works showing that IgD levels in this syndrome are not specific as diagnostic marker [2, 3]; the diagnosis of MKD should be based on other, more specific, markers (for a review of a possible diagnostic algorithm, see [4]. Here, we propose to re-evaluate the christening of this syndrome, for both the names HIDs and MKD. As we stated above, IgD levels should not be considered strictly a marker of this specific disease, rather an indication of a generic inflammatory state, due to the fact that around one out of five patients has normal IgD levels [2, 3]. So, we suggest that the use of HIDs name is obsolete, while MKD definition could suit better to the description of the disease. However, the role of mevalonate kinase in the pathogenesis of the disease could be questioned. A critical factor in the diagnosis of MKD is the level of mevalonic acid excreted in urine during fevers as well the presence of mutation in MVK gene (12q24). To our knowledge, there is no robust correlation between MK activity and the severity of the phenotype (see also [5]. To give an example, the more frequent mutation in MVK gene, causing MKD, is the Val377Ile: the phenotype is not constant and some individuals are completely asymptomatic while others are affected but still homozygous for this mutation. Stabile and coauthors found five patients (out of 10) with a novel SNP in heterozygosis, a substitution of a Ser to a Asn at position 52 (S52N). We evaluated ‘‘in silico’’ the potential for damaging effects using PolyPhen2 software [5]: S52N has potentially no effect on MK activity. Based on the literature findings and our own experience in the genetics of MKD, we suggest that the role of MK in MKD should be re-evaluated. Are other novel genes, previously overlooked, involved in the modulation of the clinical phenotype? The hereditary pattern of the disease correlates with the transmission pattern of MK mutations but not in a complete monogenic way. We could hypothesize the presence of other mechanisms, still linked to MVK gene. For example, could MK intronic sequences regulate through miRNA other genes and thus mutations linked to MKD could influences other genes? To answer this question, we performed a ‘‘in silico’’ search (using TargetScan and PolymiRTS softwares) looking for SNPs at 3’UTR of MVK gene able to change the affinity for the miRNA: we identified seven SNPs potential targets for miRNA (Table 1). So, when performing MKD genetic diagnosis, the 3’UTR region containing the potential targets for miRNA should be considered as possibly involved in the regulation mechanisms of MVK expression. This is just an example of different mechanisms possibly overlooked due to the main focus only on MVK gene. The search of novel pathogenic mechanism aimed at better understanding/diagnose this F. Celsi (&) A. Tommasini S. Crovella Institute for Maternal and Child Health, IRCCS ‘‘Burlo Garofolo’’, Trieste, Italy e-mail: celsi@burlo.trieste.it