{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T22:47:43Z","timestamp":1776120463704,"version":"3.50.1"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Mevalonate kinase deficiency (MKD) is an inherited autoinflammatory syndrome resulting from impaired isoprenoid biosynthesis due to biallelic mevalonate kinase (<jats:italic>MVK<\/jats:italic>) mutations. This metabolic defect leads to dysregulated innate immunity, particularly excessive interleukin-1\u03b2 release. While typically presenting in childhood with periodic fevers, expanding evidence links MKD to heterogeneous adult phenotypes with immune-mediated end-organ damage. We report an adult male presenting with leg pain and finger cyanosis followed by acute ischemic stroke, macular rash, and lymphadenopathies. He exhibited classical markers of innate immune activation, including persistent elevation of C-reactive protein. Genetic testing identified compound heterozygosity for the known <jats:italic>MVK<\/jats:italic> pathogenic variant c.1129G&amp;gt;A (V377I) and a novel missense variant, c.1049A&amp;gt;C (Q350P). Structural modeling of Q350P revealed disruption of the GHMP kinase domain, predicted to destabilize mevalonate kinase conformation and impair its function. The measurement of mevalonate kinase activity in lymphocytes was at 55% (normal &amp;gt;60%). Interleukin-1\u03b2 blockade with canakinumab was initiated, and the blood markers of inflammation normalized, further supporting a central role for innate immune dysregulation. This case highlights a novel <jats:italic>MVK<\/jats:italic> missense variant (Q350P) with subnormal mevalonate kinase activity. The patient\u2019s compound heterozygous state with partially preserved mevalonate kinase activity may explain the attenuated systemic features and the delayed clinical onset. Remarkably, ischemic stroke was part of the initial presentation, suggesting that mevalonate kinase deficiency can manifest primarily through thrombo-inflammatory complications in adulthood, even in the absence of recurrent febrile episodes. This expands the phenotypic spectrum of MKD and underscores the need to consider adult-onset autoinflammatory syndromes in the differential diagnosis of cryptogenic ischemic strokes with markers of systemic inflammation. It also supports the utility of cytokine-targeted therapies in such contexts.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1651819","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T05:30:42Z","timestamp":1759469442000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: Mevalonate kinase deficiency: an underdiagnosed cause of ischemic stroke\u2014characterization of a novel genetic variant"],"prefix":"10.3389","volume":"16","author":[{"given":"Lyna-Nour","family":"Hamidi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack Christopher","family":"Drda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meriem","family":"Belhocine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah-Laure","family":"Elfassy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phanie","family":"Ducharme-B\u00e9nard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxime","family":"Chayer-Lanthier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bushra","family":"Sultana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvain","family":"Lanthier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.724991","article-title":"Compromised protein prenylation as pathogenic mechanism in mevalonate kinase deficiency","volume":"12","author":"Politiek","year":"2021","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10081552","article-title":"Mevalonate kinase-associated diseases: hunting for phenotype-genotype correlation","volume":"10","author":"Boursier","year":"2021","journal-title":"J Clin Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2021.05.002","article-title":"Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review","volume":"9","author":"Touitou","year":"2022","journal-title":"Genes Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI160929","article-title":"Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency","volume":"132","author":"Munoz","year":"2022","journal-title":"J Clin Invest"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200614","article-title":"Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome","volume":"9","author":"Cuisset","year":"2001","journal-title":"Eur J Hum Genet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"106780","DOI":"10.1016\/j.jstrokecerebrovasdis.2022.106780","article-title":"Ischemic stroke is a potential complication of uncontrolled inflammation in mevalonate kinase deficiency - A case report","volume":"31","author":"Blais","year":"2022","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky949","article-title":"Protein Data Bank: the single global archive for 3D macromolecular structure data","volume":"47","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1021\/bi7024386","article-title":"Biochemical and structural basis for feedback inhibition of mevalonate kinase and isoprenoid metabolism","volume":"47","author":"Fu","year":"2008","journal-title":"Biochemistry"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1021\/bi048963o","article-title":"Molecular functions of conserved aspects of the GHMP kinase family","volume":"43","author":"Andreassi","year":"2004","journal-title":"Biochemistry"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.0030241","article-title":"Stereochemical criteria for prediction of the effects of proline mutations on protein stability","volume":"3","author":"Bajaj","year":"2007","journal-title":"PloS Comput Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1016\/j.jaci.2019.02.013","article-title":"Lack of protein prenylation promotes NLRP3 inflammasome assembly in human monocytes","volume":"143","author":"Skinner","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2015-000196","article-title":"Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS)","volume":"2","author":"Messer","year":"2016","journal-title":"RMD Open"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2147\/TACG.S93933","article-title":"Mevalonate kinase deficiency: current perspectives","volume":"9","author":"Favier","year":"2016","journal-title":"Appl Clin Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1038\/sj.ejhg.5200933","article-title":"Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands","volume":"11","author":"Houten","year":"2003","journal-title":"Eur J Hum Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s40744-024-00733-7","article-title":"Long-term safety and effectiveness of canakinumab in patients with MKD\/HIDS: interim analysis of the RELIANCE registry","volume":"12","author":"Oommen","year":"2025","journal-title":"Rheumatol Ther"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.14588","article-title":"Acute stroke in familial Mediterranean fever: An analysis of 23 new cases and systematic review of the literature","volume":"26","author":"Topcuoglu","year":"2023","journal-title":"Int J Rheum Dis"},{"key":"B18","doi-asserted-by":"publisher","first-page":"101844","DOI":"10.1016\/j.berh.2023.101844","article-title":"Deficiency of adenosine deaminase 2 (DADA2): Review","volume":"37","author":"Sharma","year":"2023","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-021-00552-1","article-title":"Interplay between inflammation and thrombosis in cardiovascular pathology","volume":"18","author":"Stark","year":"2021","journal-title":"Nat Rev Cardiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1097\/RHU.0b013e318289e06e","article-title":"Cryofibrinogenemia","volume":"19","author":"Michaud","year":"2013","journal-title":"J Clin Rheumatol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.lpm.2012.07.015","article-title":"Cryofibrinogenemia revealed by digital ischemia with stroke","volume":"42","author":"Viot","year":"2013","journal-title":"La Presse m\u00e9dicale (1983)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew379","article-title":"Cryofibrinogenaemia-a neglected disease","volume":"56","author":"Moiseev","year":"2017","journal-title":"Rheumatol (Oxford)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1001\/archderm.1994.01690010063008","article-title":"Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. International Hyper IgD Study Group","volume":"130","author":"Drenth","year":"1994","journal-title":"Arch Dermatol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"480","DOI":"10.3390\/cancers15020480","article-title":"Monoclonal gammopathy of thrombotic significance","volume":"15","author":"Gkalea","year":"2023","journal-title":"Cancers"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izab139","article-title":"Mevalonate kinase deficiency: A cause of severe very-early-onset inflammatory bowel disease","volume":"27","author":"Bader-Meunier","year":"2021","journal-title":"Inflammation Bowel Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1651819\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T05:30:43Z","timestamp":1759469443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1651819\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,3]]},"references-count":25,"alternative-id":["10.3389\/fimmu.2025.1651819"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651819","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,3]]},"article-number":"1651819"}}