Genetics of Mevalonate Kinase Deficiency


Mevalonate kinase deficiency (MKD) represents a spectrum of clinical phenotypes that result from genetic variants in the MVK gene encoding mevalonate kinase. This spectrum ranges from the autoinflammatory disorder hyper‐IgD and periodic fever syndrome (HIDS) on the mild to the severe metabolic disorder mevalonic aciduria (MA). Homozygous variants in MVK lead to loss of enzyme function, and severity of clinical phenotype is linked to degree of residual enzyme activity. However, the disease has variable genotype/phenotype correlation, and additional modifier genes may exist to alter the clinical presentation. In addition, MVK variants have recently been associated with expanded phenotypes including retinitis pigmentosa, disseminated superficial actinic porokeratosis and inflammatory bowel disease. Further genetic and pathophysiological understanding of MKD is needed to better predict clinical course and direct management.

Key Concepts

  • MKD is a metabolic autoinflammatory disorder linked to variants in MVK, encoding mevalonate kinase.
  • MKD is an autosomal recessive condition with variants leading to loss of enzyme function.
  • Severely affected MKD patients have minimal mevalonate kinase activity and present with MA.
  • Patients with some residual enzyme activity lack metabolic and central nervous system features and manifest HIDS.
  • While there is significant genotype–phenotype association in MKD, there is a broad range of clinical features.
  • In addition, there are reports of asymptomatic patients despite biallelic variants and patients with heterozygous variants and HIDS.
  • There may exist modifier genes which impact the clinical features of MKD such as risk for complications including macrophage activation syndrome.
  • MVK variants have recently been linked to additional disorders including retinitis pigmentosa (RP) and disseminated superficial actinic porokeratosis (DSAP).
  • Further genetic and pathophysiologic understanding of MKD is needed to improve patient diagnosis and management.

Keywords: autoinflammatory; periodic fever syndrome; hyperimmunoglobulin D and periodic fever syndrome; mevalonic aciduria; pediatric rheumatology

Figure 1. Overview of the mevalonate pathway. Cells convert HMG‐CoA into mevalonate, which is then converted into 5‐phosphomevalonic acid by mevalonate kinase. In patients with MKD (mevalonate kinase deficiency), the pathway is blocked at this step, leading to build‐up of mevalonic acid and depletion of downstream products. 5‐Phosphomevalonic acid is converted to geranyl pyrophosphate, which serves as precursor for the isoprenoids FPP (farnesyl pyrophosphate) and GGPP (geranylgeranyl pyrophosphate), which are the substrates for protein prenylation.
Figure 2. Genetic structure of MVK and mevalonate kinase along with key variants implicated in MKD. The gene‐encoding mevalonate kinase has 11 exons, and the protein has 4 conserved functional domains including a putative ATP (adenosine triphosphate)‐binding domain and peroxisomal targeting domain. Stars denote key amino acids in mevalonate kinase function. Several well‐described genetic variants are shown: variants linked to severe MA (mevalonic aciduria) phenotype are in bold, and splice‐site variants shown to lead to exon skipping or reduced enzyme function are in italics.
Figure 3. Genotype–phenotype association in MKD. Patients with homozygous variants in MVK typically have very low enzyme activity, particularly variants associated with more severe structural consequences. Patients with significant loss of enzyme activity display markedly increased levels of urine mevalonic acid and have clinical features consistent with MA phenotype including some with RP (retinitis pigmentosa), while those with more mild defects typically manifest the HIDS (hyperimmunoglobulinemia D and periodic fever syndrome) phenotype. In contrast, patients who are carriers of heterozygous MVK variants, as well as even some with homozygous variants, have clinically silent or mild phenotypes such as DSAP (disseminated superficial actinic porokeratosis). However, there is some overlap in these categories, and even siblings with identical MVK genotypes have different clinical phenotypes.


Akula MK, Shi M, Jiang Z, et al. (2016) Control of the innate immune response by the mevalonate pathway. Nature Immunology 17 (8): 922–929.

Bader‐Meunier B, Florkin B, Sibilia J, et al. (2011) Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics 128 (1): e152–e159.

Berger R, Smit GP, Schierbeek H, et al. (1985) Mevalonic aciduria: an inborn error of cholesterol biosynthesis? Clinica Chimica Acta 152 (1–2): 219–222.

Bianco AM, Girardelli M, Vozzi D, et al. (2014) Mevalonate kinase deficiency and IBD: shared genetic background. Gut 63 (8): 1367–1368.

Browne C and Timson DJ (2015) In silico prediction of the effects of mutations in the human mevalonate kinase gene: towards a predictive framework for mevalonate kinase deficiency. Annals of Human Genetics 79 (6): 451–459.

van der Burgh R, Ter Haar NM, Boes ML, et al. (2013) Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clinical Immunology 147 (3): 197–206.

Celsi F, Tommasini A and Crovella S (2014) “Hyper‐IgD syndrome” or “mevalonate kinase deficiency”: an old syndrome needing a new name? Rheumatology International 34 (3): 423–424.

Cuisset L, Drenth JP, Simon A, et al. (2001) Molecular analysis of MVK mutations and enzymatic activity in hyper‐IgD and periodic fever syndrome. European Journal of Human Genetics 9 (4): 260–266.

Drenth JP, Deuren M, Ven‐Jongekrijg J, et al. (1995) Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood 85 (12): 3586–3593.

Drenth JP, van der Meer JW and Kushner I (1996) Unstimulated peripheral blood mononuclear cells from patients with the hyper‐IgD syndrome produce cytokines capable of potent induction of C‐reactive protein and serum amyloid A in Hep3B cells. Journal of Immunology (Baltimore, Md. : 1950) 157 (1): 400–404.

Drenth JP, Cuisset L, Grateau G, et al. (1999) Mutations in the gene encoding mevalonate kinase cause hyper‐IgD and periodic fever syndrome. International Hyper‐IgD Study Group. Nature Genetics 22 (2): 178–181.

Filipovich AH (2009) Hemophagocytic Lymphohistiocytosis (HLH) and Related Disorders. Hematology/The Education Program of the American Society of Hematology. American Society of Hematology. Education Program, pp. 127–131.

Frenkel J, Gijkers GT, Mandey SH, et al. (2002) Lack of isoprenoid products raises ex vivo interleukin‐1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis and Rheumatism 46 (10): 2794–2803.

Haas D and Hoffmann GF (2006) Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet Journal of Rare Diseases 1: 13.

van der Hilst JC, Bodar EJ, Barron KS, et al. (2008) Long‐term follow‐up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 87 (6): 301–310.

Hinson DD, Rogers ZR, Hoffmann GF, et al. (1998) Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency. American Journal of Medical Genetics 78 (5): 408–412.

Houten SM, Kuis W, Duran M, et al. (1999) Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nature Genetics 22 (2): 175–177.

Houten SM, Woerden CS, Wijburg F, et al. (2001) Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome. European Journal of Human Genetics 9 (4): 253–259.

Houten SM, Koster J, Romeijn GJ, et al. (2003) Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper‐IgD and periodic fever syndrome, in the Netherlands. European Journal of Human Genetics 11 (2): 196–200.

Koné‐Paut I, Sanchez E, Quellec A, et al. (2007) Autoinflammatory gene mutations in Behçet's disease. Annals of the Rheumatic Diseases 66 (6): 832–834.

Lainka E, Neudoft U, Lohse P, et al. (2012) Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children. Rheumatology International 32 (10): 3253–3260.

Levy M, Arion A, Berrebi D, et al. (2013) Severe early‐onset colitis revealing mevalonate kinase deficiency. Pediatrics 132 (3): e779–e783.

Mandey SH, Kuijk LM, Frenkel J, et al. (2006a) A role for geranylgeranylation in interleukin‐1beta secretion. Arthritis and Rheumatism 54 (11): 3690–3695.

Mandey SHL, Schneiders MS, Koster JA, et al. (2006b) Mutational spectrum and genotype – phenotype correlations in mevalonate kinase deficiency. Human Mutation 27 (July): 796–802.

Marcuzzi A, Vozzi D, Girardelli M, et al. (2016) Putative modifier genes in mevalonate kinase deficiency. Molecular Medicine Reports 13 (4): 3181–3189.

Masters SL, Simon A, Aksentijevich I, et al. (2009) Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annual Review of Immunology 27: 621–668.

McTaggart SJ (2006) Isoprenylated proteins. Cellular and Molecular Life Sciences 63 (3): 255–267.

van der Meer JW, Vossen JM, Radl J, et al. (1984) Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet (London, England) 1 (8386): 1087–1090.

Messer L, Alsaleh G, Georgel P, et al. (2016) Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS). RMD Open 2 (1): e000196.

Miziorko HM (2011) Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Archives of Biochemistry and Biophysics 505 (2): 131–143.

Mizuno T, Sakai H, Nishikomori R, et al. (2012) Novel mutations of MVK gene in Japanese family members affected with hyperimmunoglobulinemia D and periodic fever syndrome. Rheumatology International 32 (12): 3761–3764.

Moura R, Aladbe B, Taha RZ, et al. (2015) GRID2 a novel gene possibly associated with mevalonate kinase deficiency. Rheumatology International 35 (4): 657–659.

Moussa T et al. (2015) Overlap of familial Mediterranean fever and hyper‐IgD syndrome in an Arabic kindred. Journal of Clinical Immunology 35 (3): 249–253.

Park YH, Wood G, Kastner DL, et al. (2016) Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nature Immunology 17 (8): 914–921.

Poll‐The BT, Frenkel J, Houten SM, et al. (2000) Mevalonic aciduria in 12 unrelated patients with hyperimmunoglobulinaemia D and periodic fever syndrome. Journal of Inherited Metabolic Disease 23 (4): 363–366.

Prietsch V, Mayatepek E, Krastel H, et al. (2003) Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum. Pediatrics 111 (2): 258–261.

Ravelli A, Grom AA, Behrens EM, et al. (2012) Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes and Immunity 13 (4): 289–298.

Rigante D, Capoluongo E, Bertoni B, et al. (2007) First report of macrophage activation syndrome in hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis and Rheumatism 56 (2): 658–661.

Rigante D, Emi G, Fastiggi M, et al. (2015) Macrophage activation syndrome in the course of monogenic autoinflammatory disorders. Clinical Rheumatology 34 (8): 1333–1339.

Schulert GS, Bove K, McMasters R, et al. (2014) Mevalonate kinase deficiency associated with recurrent liver dysfunction, macrophage activation syndrome and perforin gene polymorphism. Arthritis Care & Research 67 (8): 1173–1179.

Siemiatkowska AM, Born LI, Hagen PM, et al. (2013) Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa. Ophthalmology 120 (12): 2697–2705.

Simon A, Cuisset L, Vincent MF, et al. (2001) Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper‐igd and periodic fever syndrome: its application as a diagnostic tool. Annals of Internal Medicine 135 (5): 338–343.

Simon A, Kremer HP, Wevers RA, et al. (2004) Mevalonate kinase deficiency: evidence for a phenotypic continuum. Neurology 62 (6): 994–997.

Sinha A, Waterham HR, Sreedhar KV, et al. (2012) Novel mutations causing hyperimmunoglobulin D and periodic fever syndrome. Indian Pediatrics 49 (7): 583–585.

Stabile A, Compagnone A, Napodano S, et al. (2013) Mevalonate kinase genotype in children with recurrent fevers and high serum IgD level. Rheumatology International 33 (12): 3039–3042.

Ter Haar NM, Jeyaratnam F, Lachmann HJ, et al. (2016) The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever Registry. Arthritis & Rheumatology (Hoboken, N.J.) 68 (11): 2795–2805.

Touitou I (2016) Infevers: An Online Database for Autoinflammatory Mutations (04 Aug 2016). Available at:

Uhlig HH (2013) Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 62 (12): 1795–1805.

Zhang S‐Q, Jiang T, Li M, et al. (2012) Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nature Genetics 44 (10): 1156–1160.

Zhang M, Behrens EM, Atkinson TP, et al. (2014) Genetic defects in cytolysis in macrophage activation syndrome. Current Rheumatology Reports 16 (9): 439.

Further Reading

Durel C‐A, Aouba A, Bienvenu B, et al. (2016) Observational study of a French and Belgian Multicenter Cohort of 23 patients diagnosed in adulthood with Mevalonate Kinase Deficiency Medicine ® OBSERVATIONAL STUDY. Medicine (Baltimore) 95: 1–7.

Favier LA and Schulert GS (2016) Mevalonate kinase deficiency: current perspectives. The Application of Clinical Genetics 9: 101–110.

Federici S, Sormani MP, Ozen S, et al. (2015) Evidence‐based provisional clinical classification criteria for autoinflammatory periodic fevers. Annals of the Rheumatic Diseases 74: 799–805.

Galeotti C, Meinzer U, Quartier P, et al. (2012) Efficacy of interleukin‐1‐targeting drugs in mevalonate kinase deficiency. Rheumatology 51: 1855–1859.

Jeyaratnam J, Ter Haar NM, de Sain‐van der Velden MGM, et al. (2015) Diagnostic value of urinary mevalonic acid excretion in patients with a clinical suspicion of mevalonate kinase deficiency (MKD). JIMD Reports 27: 33–38.

Shinar Y, Obici L, Aksentijevich I, et al. (2012) Guidelines for the genetic diagnosis of hereditary recurrent fevers. Annals of the Rheumatic Diseases 71: 1599–1605.

Ter Haar NM, Oswald M, Jeyaratnam J, et al. (2015) Recommendations for the management of autoinflammatory diseases. Annals of the Rheumatic Diseases 74: 1636–1644.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Schulert, Grant S(Jul 2017) Genetics of Mevalonate Kinase Deficiency. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027246]