[en] The aim of this study was to describe the clinical and biological features of Mevalonate kinase deficiency (MKD) in patients diagnosed in adulthood. This is a French and Belgian observational retrospective study from 2000 to 2014. To constitute the cohort, we cross-check the genetic and biochemical databases. The clinical, enzymatic, and genetic data were gathered from medical records. Twenty-three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission. MKD diagnosed in adulthood shared clinical and genetic features with classical pediatric disease. An elevated IgD concentration is a good marker for MKD in adults. Despite a decrease of severity and frequency of attacks with age, only one-third of patients achieved spontaneous remission.
Disciplines :
General & internal medicine
Author, co-author :
Durel, Cecile-Audrey
Aouba, Achille
Bienvenu, Boris
Deshayes, Samuel
Coppere, Brigitte
Gombert, Bruno
Acquaviva-Bourdain, Cecile
Hachulla, Eric
Lecomte, Frederic
Touitou, Isabelle
Ninet, Jacques
Philit, Jean-Baptiste
Messer, Laurent
Brouillard, Marc
Girard-Madoux, Marie-Helene
Moutschen, Michel ; Université de Liège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén.
Prieur AM, Griscelli C. Nosologic aspects of systemic forms of very early onset juvenile arthritis. Apropos of 17 cases. Ann Pédiatrie. 1983;30:565-569.
Drenth JP, van der Meer JW. Hereditary periodic fever. N Engl J Med. 2001;345:1748-1757.
Houten SM, Kuis W, Duran M, et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999;22:175-177.
Drenth JP, Cuisset L, Grateau G, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet. 1999;22:178-181.
Henneman L, Schneiders MS, Turkenburg M, et al. Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency. J Inherit Metab Dis. 2010;33:625-632.
Simon A, Kremer HPH, Wevers RA, et al. Mevalonate kinase deficiency: evidence for a phenotypic continuum. Neurology. 2004;62:994-997.
Van der Meer JW, Vossen JM, Radl J, et al. Hyperimmunoglobuli-naemia D and periodic fever: a new syndrome. Lancet. 1984;1:1087-1090.
Berger R, Smit GP, Schierbeek H, et al. Mevalonic aciduria: an inborn error of cholesterol biosynthesis? Clin Chim Acta Int J Clin Chem. 1985;152:219-222.
Cuisset L, Drenth JP, Simon A, et al. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet EJHG. 2001;9:260-266.
Houten SM, van Woerden CS, Wijburg FA, et al. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet EJHG. 2003;11:196-200.
Van der Hilst JCH, Simon A, Drenth JPH. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med. 2005;5:87-98.
Van der Hilst JCH, Bodar EJ, Barron KS, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008;87:301-310.
Ammouri W, Cuisset L, Rouaghe S, et al. Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatol Oxf Engl. 2007;46:1597-1600.
Bader-Meunier B, Florkin B, Sibilia J, et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 2011;128:e152-e159.
Lequerré T, Vittecoq O, Pouplin S, et al. Mevalonate kinase deficiency syndrome with structural damage responsive to anakinra. Rheumatol Oxf Engl. 2007;46:1860-1862.
Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobuline-mia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore). 1994;73:133-144.
Bodar EJ, van der Hilst JCH, van Heerde W, et al. Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome. Blood. 2007;109:2416-2418.
Van der Burgh R, Ter Haar NM, Boes ML, et al. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol Orlando Fla. 2013;147:197-206.
Nevyjel M, Pontillo A, Calligaris L, et al. Diagnostics and therapeutic insights in a severe case of mevalonate kinase deficiency. Pediatrics. 2007;119:e523-e527.
Cailliez M, Garaix F, Rousset-Rouvière C, et al. Crescentic glomerulonephritis is part of hyperimmunoglobulinemia D syndrome. Pediatr Nephrol Berl Ger. 2006;21:1917-1918.
Hinson DD, Rogers ZR, Hoffmann GF, et al. Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency. Am J Med Genet. 1998;78:408-412.
D'Osualdo A, Picco P, Caroli F, et al. MVK mutations and associated clinical features in Italian patients affected with autoin-flammatory disorders and recurrent fever. Eur J Hum Genet EJHG. 2005;13:314-320.
Raupp P, Varady E, Duran M, et al. Novel genotype of mevalonic aciduria with fatalities in premature siblings. Arch Dis Child Fetal Neonatal Ed. 2004;89:F90-F91.
Sornsakrin M, Wenner K, Ganschow R. B cell cytopenia in two brothers with hyper-IgD and periodic fever syndrome. Eur J Pediatr. 2009;168:825-831.
Saulsbury FT. Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) in a child with normal serum IgD, but increased serum IgA concentration. J Pediatr. 2003;143:127-129.
Di Rocco M, Caruso U, Waterham HR, et al. Mevalonate kinase deficiency in a child with periodic fever and without hyperimmu-noglobulinaemia D. J Inherit Metab Dis. 2001;24:411-412.
Livneh A, Drenth JP, Klasen IS, et al. Familial Mediterranean fever and hyperimmunoglobulinemia D syndrome: two diseases with distinct clinical, serologic, and genetic features. J Rheumatol. 1997;24:1558-1563.
Medlej-Hashim M, Petit I, Adib S, et al. Familial Mediterranean Fever: association of elevated IgD plasma levels with specific MEFV mutations. Eur J Hum Genet EJHG. 2001;9:849-854.
Dodé C, André M, Bienvenu T, et al. French Heraditary Recurrent Inflammatory Disorder Study Group. The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2002;46:2181-2188.
Milhavet F, Cuisset L, Hoffman HM, et al. The infevers autoin-flammatory mutation online registry: update with new genes and functions. Hum Mutat. 2008;29:803-808.
Mandey SHL, Schneiders MS, Koster J, et al. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat. 2006;27:796-802.
Fu Z, Wang M, Potter D, et al. The structure of a binary complex between a mammalian mevalonate kinase and ATP: insights into the reaction mechanism and human inherited disease. J Biol Chem. 2002;277:18134-18142.
Houten SM, Frenkel J, Rijkers GT, et al. Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome. Hum Mol Genet. 2002;11:3115-3124.
Kostjukovits S, Kalliokoski L, Antila K, et al. Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. Eur J Pediatr. 2015;74:707-714.
Ter Haar N, Lachmann H, Ozen S, et al. Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever/Euro-traps Projects. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72:678-685.
Galeotti C, Meinzer U, Quartier P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatol Oxf Engl. 2012;51:1855-1859.
Bodar EJ, Kuijk LM, Drenth JPH, et al. On-demand anakinra treatment is effective in mevalonate kinase deficiency. Ann Rheum Dis. 2011;70:2155-2158.
Normand S, Massonnet B, Delwail A, et al. Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation. Eur Cytokine Netw. 2009;20:101-107.
Stoffels M, Jongekrijg J, Remijn T, et al. TLR2/TLR4-dependent exaggerated cytokine production in hyperimmunoglobulinaemia D and periodic fever syndrome. Rheumatol Oxf Engl. 2015;54:363-368.
Bilginer Y, Akpolat T, Ozen S. Renal amyloidosis in children. Pediatr Nephrol Berl Ger. 2011;26:1215-1227.
Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol. 2010;22:567-578.
Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001;358:24-29.
Yel S, Gunduz Z, Bastug F, et al. Amyloidosis in a child with hyperimmunoglobulinemia D syndrome. Iran J Kidney Dis. 2013;7:70-72.
Li Cavoli G, Passantino D, Tortorici C, et al. Renal amyloidosis due to hyper-IgD syndrome. Nefrol Publ Of Soc Esp Nefrol. 2012;32:865-866.
Lachmann HJ, Goodman HJB, Andrews PA, et al. AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: a report of two cases. Arthritis Rheum. 2006;54: 2010-2014.
Obici L, Manno C, Muda AO, et al. First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum. 2004;50:2966-2969.
Siewert R, Ferber J, Horstmann RD, et al. Hereditary periodic fever with systemic amyloidosis: is hyper-IgD syndrome really a benign disease? Am J Kidney Dis Off J Natl Kidney Found. 2006;48:e41-e45.
