title: The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry.
abstract: Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients.
  
  
  
  All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases.
  
  
  
  The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10-20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD.
  
  
  
  We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected.
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nienke M
authors.initials: NM
authors.lastname: Ter Haar
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jerold
authors.initials: J
authors.lastname: Jeyaratnam
authors.affiliation: University College London Medical School, London, UK.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Lachmann
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Simon
authors.affiliation: University College London and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brogan
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Doglio
authors.affiliation: University of Brescia and Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cattalini
authors.affiliation: Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Anton
authors.affiliation: Hospital Valle de Hebron, Barcelona, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Modesto
authors.affiliation: Université Paris-Descartes, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Hoppenreijs
authors.affiliation: Clinica Pediatrica Università di Torino, Day-Hospital Immuno-reumatologia, Turin, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.affiliation: Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Insalaco
authors.affiliation: University of Siena, Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cantarini
authors.affiliation: Università degli Studi di Trieste, Trieste, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Lepore
authors.affiliation: Università di Napoli Federico II, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Alessio
authors.affiliation: University Hospital La Fe, Valencia, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Calvo Penades
authors.affiliation: Women's and Children's Hospital, University of Adelaide, North Adelaide, South Australia, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Boros
authors.affiliation: Ospedale Santa Chiara, Università di Pisa, Pisa, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Consolini
authors.affiliation: Università Cattolica Sacro Cuore, Rome, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Rigante
authors.affiliation: Hospital de Pediatria Juan P. Garrahan, Buenos Aires, Argentina.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Russo
authors.affiliation: University Childrens Hospital Zurich, Zurich, Switzerland.
authors.forename: Jana
authors.initials: J
authors.lastname: Pachlopnik Schmid
authors.affiliation: University College London Medical School, London, UK.
authors.forename: Thirusha
authors.initials: T
authors.lastname: Lane
authors.affiliation: Istituto Giannina Gaslini and Università degli Studi di Genova, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Nicolino
authors.initials: N
authors.lastname: Ruperto
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands. j.frenkel@umcutrecht.nl.
authors.forename: Joost
authors.initials: J
authors.lastname: Frenkel
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
mesh_terms: D015746:Abdominal Pain / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D000293:Adolescent; D017668:Age of Onset; D000686:Amyloidosis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D018771:Arthralgia / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D001168:Arthritis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D002526:Cerebellar Diseases / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D003231:Conjunctivitis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D003967:Diarrhea / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005838:Genotype; D006261:Headache / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D000072281:Lymphadenopathy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D054078:Mevalonate Kinase Deficiency / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D063806:Myalgia / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D010612:Pharyngitis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D012042:Registries; D012189:Retrospective Studies; D012871:Skin Diseases / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D013281:Stomatitis, Aphthous / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D014605:Uveitis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D014839:Vomiting / Q000209:etiology / Q000235:genetics / Q000503:physiopathology
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase