Submission Details

MVK was first reported in relation to autosomal recessive Mevalonate Aciduria (MA) in 1997 in three families (Hinson et al., PMID: 9334262). In 1999 MVK variants were also implicated in a milder recessive condition, called Hyper-IgD Syndrome with periodic fever (HIDS) (Houten et al 1999). Collectively these conditions are known as Mevalonate Kinase Deficiency (MKD) and are characterized by episodes of recurrent fever lasting 3-6 days, which begin early in childhood. In addition to fevers, symptoms can include abdominal pain, hepatosplenomegaly, serositis, lymphadenopathy, skin lesions/rash, aphthous ulcers, arthralgia/arthritis. In more severe forms of MA there may also be growth delay, congenital anomalies (cataracts, shortened limbs and dysmorphic features), failure to thrive and neurological symptoms (PMID:27142780). Fetal ascites as well as oligohydramnios and polyhydramnios are other related prenatal phenotypes (PMID: 23146290, 27012807). There are many severe, neonatal-onset cases, which can be lethal (PMID: 14711867, PMID: 23146290)

In both conditions there is decreased MVK enzyme activity which leads to the accumulation of mevalonic acid, defective prenylation, and ultimately constitutive activation of the pyrin inflammasome. This activation leads to excess production of IL-1 causing many of the inflammatory features of the disease. It is hypothesized that excess MA accumulation may lead to the ocular and neurologic symptoms which are seen in both forms of the disease, but more commonly in the more severe form of mevalonate aciduria (PMID:35685471). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism as both lead to varying levels of mevalonate kinase deficiency, and both follow the same inheritance pattern. Therefore, the following disease entities have been lumped into one disease entities, Hyper-IgD Syndrome (OMIM:260920) and Mevalonic Aciduria (OMIM:610377). The split curation for Porokeratosis, which is also caused by variants in MVK, but which is inherited in an autosomal dominant mechanism with localized post-zygotic mutation will be curated separately. 179 pathogenic or likely pathogenic variants have been reported in the Infevers database to date (https://infevers.umai-montpellier.fr/web/) and 132 have been reported in ClinVar. 19 probands in 2 publications (PMIDs: PMID:1036926 and PMID:11371670) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The gene disease relationship is supported by experimental evidence. The mechanism of pathogenicity is reported to be loss of function. Several studies have shown decreased MVK activity in patient cells (PMIDs: 10369261, 11313769) and an upregulation of IL-1β and other cytokines (PMID:12384940, PMID:25173351). Mouse models with heterozygous MVK deletions (MVK +/-) have also shown decreased mevalonate kinase activity, immune dysfunction, and similar clinical features to individuals with HIDS included hepatosplenomegaly, abnormal thermoregulation and general malaise (PMID:18008182) In summary, there is definitive evidence supporting the relationship between MVK autosomal recessive Mevalonate Kinase Deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Autoinflammatory GCEP on the meeting date 05/15/2024 (SOP Version 10).