Nienke M Ter Haar1, Jerold Jeyaratnam1, Helen J Lachmann2, Anna Simon3, Paul A Brogan4, Matteo Doglio5, Marco Cattalini6, Jordi Anton7, Consuelo Modesto8, Pierre Quartier9, Esther Hoppenreijs3, Silvana Martino10, Antonella Insalaco11, Luca Cantarini12, Loredana Lepore13, Maria Alessio14, Inmaculada Calvo Penades15, Christina Boros16, Rita Consolini17, Donato Rigante18, Ricardo Russo19, Jana Pachlopnik Schmid20, Thirusha Lane2, Alberto Martini21, Nicolino Ruperto5, Joost Frenkel22, Marco Gattorno5. 1. University Medical Center Utrecht, Utrecht, The Netherlands. 2. University College London Medical School, London, UK. 3. Radboud University Medical Center, Nijmegen, The Netherlands. 4. University College London and Great Ormond Street Hospital NHS Foundation Trust, London, UK. 5. Istituto Giannina Gaslini, Genoa, Italy. 6. University of Brescia and Spedali Civili di Brescia, Brescia, Italy. 7. Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain. 8. Hospital Valle de Hebron, Barcelona, Spain. 9. Université Paris-Descartes, Hôpital Necker-Enfants Malades, Paris, France. 10. Clinica Pediatrica Università di Torino, Day-Hospital Immuno-reumatologia, Turin, Italy. 11. Ospedale Pediatrico Bambino Gesù, Rome, Italy. 12. University of Siena, Siena, Italy. 13. Università degli Studi di Trieste, Trieste, Italy. 14. Università di Napoli Federico II, Naples, Italy. 15. University Hospital La Fe, Valencia, Spain. 16. Women's and Children's Hospital, University of Adelaide, North Adelaide, South Australia, Australia. 17. Ospedale Santa Chiara, Università di Pisa, Pisa, Italy. 18. Università Cattolica Sacro Cuore, Rome, Italy. 19. Hospital de Pediatria Juan P. Garrahan, Buenos Aires, Argentina. 20. University Childrens Hospital Zurich, Zurich, Switzerland. 21. Istituto Giannina Gaslini and Università degli Studi di Genova, Genoa, Italy. 22. University Medical Center Utrecht, Utrecht, The Netherlands. j.frenkel@umcutrecht.nl.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
OBJECTIVE: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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.