{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T16:42:30Z","timestamp":1784133750619,"version":"3.55.0"},"reference-count":55,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["777259"],"award-info":[{"award-number":["777259"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD\/HIDS) are disorders of cholesterol biosynthesis caused by variants in the <jats:italic>MVK<\/jats:italic> gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in\u2010depth analysis of the phenotypic spectrum of MVA and provide an in\u2010silico pathogenicity model analysis of <jats:italic>MVK<\/jats:italic> missense variants. The phenotypic spectrum of 11 MVA patients (age range 0\u201051\u2009years) registered in the <jats:italic>Unified European Registry for Inherited Metabolic Disorders<\/jats:italic> database was systematically analyzed using terms of the <jats:italic>Human Phenotype Ontology<\/jats:italic>. Biochemical, radiological as well as genetic characteristics were investigated. Six of eleven patients have reached adulthood and four have reached adolescence. One of the adolescent patients died at the age of 16\u2009years and one patient died shortly after birth. Symptoms started within the first year of life, including episodic fever, developmental delay, ataxia, and ocular involvement. We also describe a case with absence of symptoms despite massive excretion of mevalonic acid. Pathogenic variants causing MVA cluster within highly conserved regions, which are involved in mevalonate and ATP binding. The phenotype of adult and adolescent MVA patients is more heterogeneous than previously assumed. Outcome varies from an asymptomatic course to early death. MVK variants cluster in functionally important and highly conserved protein domains and show high concordance regarding their expected pathogenicity.<\/jats:p>","DOI":"10.1002\/jimd.12412","type":"journal-article","created":{"date-parts":[[2021,6,19]],"date-time":"2021-06-19T04:23:15Z","timestamp":1624076595000},"page":"1272-1287","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Phenotypic diversity, disease progression, and pathogenicity of <scp><i>MVK<\/i><\/scp> missense variants in mevalonic aciduria"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-0003","authenticated-orcid":false,"given":"Heiko","family":"Brennenstuhl","sequence":"first","affiliation":[{"name":"Division of Neuropaediatrics and Paediatric Metabolic Medicine Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Nashawi","sequence":"additional","affiliation":[{"name":"Division of Neuropaediatrics and Paediatric Metabolic Medicine Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg  Heidelberg Germany"},{"name":"Department of Pediatrics King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Schr\u00f6ter","sequence":"additional","affiliation":[{"name":"Division of Pediatric Epileptology Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Baronio","sequence":"additional","affiliation":[{"name":"Paediatric Unit, Department of Medical and Surgical Sciences S. Orsola\u2010Malpighi University Hospital  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Beedgen","sequence":"additional","affiliation":[{"name":"Division of Neuropaediatrics and Paediatric Metabolic Medicine Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Gleich","sequence":"additional","affiliation":[{"name":"Division of Neuropaediatrics and Paediatric Metabolic Medicine Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Jeltsch","sequence":"additional","affiliation":[{"name":"Division of Neuropaediatrics and Paediatric Metabolic Medicine Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"von Landenberg","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Martini","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences S. Orsola\u2010Malpighi University Hospital  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Radboudumc Expertise Centre for Immunodeficiency and Autoinflammation (REIA), Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Thiel","sequence":"additional","affiliation":[{"name":"Division of Neuropaediatrics and Paediatric Metabolic Medicine Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Tsiakas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf  Hamburg 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