Skip to main content
SpringerLink
Log in

Mevalonate Kinase Deficiency

  • Chapter
  • First Online:
Textbook of Autoinflammation

Abstract

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease caused by loss of function mutations in both alleles of MVK, the gene encoding the enzyme mevalonate kinase. Deficiency of this enzyme results in impaired isoprenoid biosynthesis. The inflammatory attacks in MKD are characterized by fever, lymphadenopathy, gastrointestinal symptoms, aphthous ulcers, rash, arthralgias and/or arthritis. Severely affected patients may in addition have neurological involvement, cataract, uveitis, and failure to thrive, often dying in early childhood. This severe end of the phenotypic spectrum is called mevalonic aciduria (MA) as opposed to the milder phenotype also known as hyperimmunoglobulinemia D periodic fever syndrome (HIDS). In this chapter, we detail clinical phenotype and pathophysiological background as well as treatment options.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CAPS:

Cryopyrin-associated periodic syndrome

CRP:

C-reactive protein

DSAP:

Disseminated superficial actinic porokeratosis

EMA:

European Medicines Agency

FDA:

Food and Drug Administration (FDA)

FDPS:

Farnesyl diphosphate synthase

FMF:

Familial Mediterranean fever

GC-MS:

Gas chromatography-mass spectrometry

HIDS:

Hyperimmunoglobulinemia D syndrome

HMG-CoA:

Hydroxymethylglutaryl-coenzyme A

IgD:

Immunoglobulin D

IL-1:

Interleukin-1

MA:

Mevalonic aciduria

MK:

Mevalonate kinase

MKD:

Mevalonate kinase deficiency

MVD:

Mevalonate decarboxylase

MVK :

Mevalonate kinase gene

NSAIDs:

Non-steroidal anti-inflammatory drugs

PBMC:

Peripheral blood mononuclear cells

PFAPA:

Periodic fever, aphthous stomatitis, pharyngitis, adenitis

PMVK:

Phosphomevalonate kinase

SAA:

Serum amyloid A

TNF:

Tumor necrosis factor

TRAPS:

TNF receptor-associated periodic syndrome

References

  1. Ter Haar NM, Jeyaratnam J, Lachmann HJ, et al. The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever Registry. Arthritis Rheumatol. 2016;68(11):2795–805.

    Article  PubMed  CAS  Google Scholar 

  2. van der Hilst JC, 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(6):301–10.

    Article  CAS  Google Scholar 

  3. Lainka E, Neudorf U, Lohse P, et al. Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children. Rheumatol Int. 2012;32(10):3253–60.

    Article  CAS  PubMed  Google Scholar 

  4. Simon A, Mariman EC, van der Meer JW, Drenth JP. A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am J Med. 2003;114(2):148–52.

    Article  CAS  PubMed  Google Scholar 

  5. Houten SM, van Woerden CS, Wijburg FA, Wanders RJ, Waterham HR. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet. 2003;11(2):196–200.

    Article  CAS  PubMed  Google Scholar 

  6. Bader-Meunier B, Florkin B, Sibilia J, et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 2011;128(1):e152–9.

    Article  PubMed  Google Scholar 

  7. 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(2):178–81.

    Article  CAS  PubMed  Google Scholar 

  8. 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(2):175–7.

    Article  CAS  PubMed  Google Scholar 

  9. Houten SM, Koster J, Romeijn GJ, et al. Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome. Eur J Hum Genet. 2001;9(4):253–9.

    Article  CAS  PubMed  Google Scholar 

  10. 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. 2001;9(4):260–6.

    Article  CAS  PubMed  Google Scholar 

  11. Mandey SH, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat. 2006;27(8):796–802.

    Article  CAS  PubMed  Google Scholar 

  12. Houten SM, Frenkel J, Waterham HR. Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation. Cell Mol Life Sci. 2003;60(6):1118–34.

    Article  CAS  PubMed  Google Scholar 

  13. Munoz MA, Jurczyluk J, Mehr S, et al. Defective protein prenylation is a diagnostic biomarker of mevalonate kinase deficiency. J Allergy Clin Immunol. 2017;140(3):873–5.e6.

    Article  CAS  PubMed  Google Scholar 

  14. Jurczyluk J, Munoz MA, Skinner OP, et al. Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases. Immunol Cell Biol. 2016;94(10):994–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jeyaratnam J, Ter Haar NM, de Sain-van der Velden MG, Waterham HR, van Gijn ME, Frenkel J. Diagnostic value of urinary mevalonic acid excretion in patients with a clinical suspicion of mevalonate kinase deficiency (MKD). JIMD Rep. 2016;27:33–8.

    Article  PubMed  Google Scholar 

  16. De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the treatment of auto-inflammatory recurrent fever syndromes: results from the CLUSTER trial. N Engl J Med. 2018;378:1908–19.

    Article  PubMed  Google Scholar 

  17. Drenth JP, Powell RJ, Brown NS, Van der Meer JW. Interferon-gamma and urine neopterin in attacks of the hyperimmunoglobulinaemia D and periodic fever syndrome. Eur J Clin Invest. 1995;25(9):683–6.

    Article  CAS  PubMed  Google Scholar 

  18. Drenth JP, van Deuren M, van der Ven-Jongekrijg J, Schalkwijk CG, van der Meer JW. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood. 1995;85(12):3586–93.

    CAS  PubMed  Google Scholar 

  19. Drenth JP, van der Meer JW, Kushner I. 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. J Immunol. 1996;157(1):400–4.

    CAS  PubMed  Google Scholar 

  20. Mandey SH, Kuijk LM, Frenkel J, Waterham HR. A role for geranylgeranylation in interleukin-1beta secretion. Arthritis Rheum. 2006;54(11):3690–5.

    Article  CAS  PubMed  Google Scholar 

  21. Kuijk LM, Beekman JM, Koster J, Waterham HR, Frenkel J, Coffer PJ. HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood. 2008;112(9):3563–73.

    Article  CAS  PubMed  Google Scholar 

  22. Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol. 2016;17(8):914–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Akula MK, Shi M, Jiang Z, et al. Control of the innate immune response by the mevalonate pathway. Nat Immunol. 2016;17(8):922–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science. 2014;345(6197):679–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Simon A. Cholesterol metabolism and immunity. N Engl J Med. 2014;371(20):1933–5.

    Article  PubMed  CAS  Google Scholar 

  26. Bekkering S, Arts RJW, Novakovic B, et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell. 2018;172(1–2):135–46.e9.

    Article  CAS  PubMed  Google Scholar 

  27. Durel CA, Aouba A, Bienvenu B, et al. Observational study of a French and Belgian Multicenter Cohort of 23 patients diagnosed in adulthood with mevalonate kinase deficiency. Medicine (Baltimore). 2016;95(11):e3027.

    Article  CAS  Google Scholar 

  28. Levy M, Arion A, Berrebi D, et al. Severe early-onset colitis revealing mevalonate kinase deficiency. Pediatrics. 2013;132(3):e779–83.

    Article  PubMed  Google Scholar 

  29. Damian LO, Fufezan O, Farcău M, Tătar S, Lazăr C, Farcău DI. Ultrasonographic findings in hyperimmunoglobulin D syndrome: a case report. Med Ultrason. 2017;19(2):224–7.

    Article  PubMed  Google Scholar 

  30. Wilker SC, Dagnelie G, Goldberg MF. Retinitis pigmentosa and punctate cataracts in mevalonic aciduria. Retin Cases Brief Rep. 2010;4(1):34–6.

    Article  PubMed  Google Scholar 

  31. Hoffmann GF, Charpentier C, Mayatepek E, et al. Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics. 1993;91(5):915–21.

    CAS  PubMed  Google Scholar 

  32. 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(5):408–12.

    Article  CAS  PubMed  Google Scholar 

  33. Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare Dis. 2006;1:13.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Siemiatkowska AM, van den Born LI, van Hagen PM, et al. Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa. Ophthalmology. 2013;120(12):2697–705.

    Article  PubMed  Google Scholar 

  35. Zhang SQ, Jiang T, Li M, et al. Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nat Genet. 2012;44(10):1156–60.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Z, Li C, Wu F, et al. Correction: genomic variations of the mevalonate pathway in porokeratosis. Elife. 2016;5:e14383.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu Y, Wang J, Qin Y, et al. Identification of three mutations in the MVK gene in six patients associated with disseminated superficial actinic porokeratosis. Clin Chim Acta. 2016;454:124–9.

    Article  CAS  PubMed  Google Scholar 

  38. Zeng K, Zhang QG, Li L, Duan Y, Liang YH. Splicing mutation in MVK is a cause of porokeratosis of Mibelli. Arch Dermatol Res. 2014;306(8):749–55.

    Article  CAS  PubMed  Google Scholar 

  39. Hiemstra I, Vossen JM, van der Meer JW, Weemaes CM, Out TA, Zegers BJ. Clinical and immunological studies in patients with an increased serum IgD level. J Clin Immunol. 1989;9(5):393–400.

    Article  CAS  PubMed  Google Scholar 

  40. Klasen IS, Göertz JH, van de Wiel GA, Weemaes CM, van der Meer JW, Drenth JP. Hyper-immunoglobulin A in the hyperimmunoglobulinemia D syndrome. Clin Diagn Lab Immunol. 2001;8(1):58–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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. Rheumatology (Oxford). 2007;46(10):1597–600.

    Article  CAS  Google Scholar 

  42. Simon A, Bijzet J, Voorbij HA, Mantovani A, van der Meer JW, Drenth JP. Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response. J Intern Med. 2004;256(3):247–53.

    Article  CAS  PubMed  Google Scholar 

  43. Steichen O, van der Hilst J, Simon A, Cuisset L, Grateau G. A clinical criterion to exclude the hyperimmunoglobulin D syndrome (mild mevalonate kinase deficiency) in patients with recurrent fever. J Rheumatol. 2009;36(8):1677–81.

    Article  PubMed  Google Scholar 

  44. Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74(5):799–805.

    Article  PubMed  Google Scholar 

  45. Poll-The BT, Frenkel J, Houten SM, et al. Mevalonic aciduria in 12 unrelated patients with hyperimmunoglobulinaemia D and periodic fever syndrome. J Inherit Metab Dis. 2000;23(4):363–6.

    Article  CAS  PubMed  Google Scholar 

  46. Simon A, Drewe E, van der Meer JW, et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther. 2004;75(5):476–83.

    Article  CAS  PubMed  Google Scholar 

  47. van der Burgh R, Ter Haar NM, Boes ML, Frenkel J. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol. 2013;147(3):197–206.

    Article  PubMed  CAS  Google Scholar 

  48. ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636–44.

    Article  PubMed  CAS  Google Scholar 

  49. Galeotti C, Meinzer U, Quartier P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford). 2012;51(10):1855–9.

    Article  CAS  Google Scholar 

  50. Bodar EJ, van der Hilst JC, Drenth JP, van der Meer JW, Simon A. Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth J Med. 2005;63(7):260–4.

    CAS  PubMed  Google Scholar 

  51. Tsitsami E, Papadopoulou C, Speletas M. A case of hyperimmunoglobulinemia d syndrome successfully treated with canakinumab. Case Rep Rheumatol. 2013;2013:795027.

    PubMed  PubMed Central  Google Scholar 

  52. Curtis CD, Fox CC. Treatment of adult hyper-IgD syndrome with canakinumab. J Allergy Clin Immunol Pract. 2015;3(5):817–8.

    Article  PubMed  Google Scholar 

  53. Arostegui JI, Anton J, Calvo I, et al. Open-label, phase II study to assess the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheumatol. 2017;69(8):1679–88.

    Article  CAS  PubMed  Google Scholar 

  54. Demirkaya E, Caglar MK, Waterham HR, Topaloglu R, Ozen S. A patient with hyper-IgD syndrome responding to anti-TNF treatment. Clin Rheumatol. 2007;26(10):1757–9.

    Article  PubMed  Google Scholar 

  55. Topaloglu R, Ayaz NA, Waterham HR, Yüce A, Gumruk F, Sanal O. Hyperimmunoglobulinemia D and periodic fever syndrome; treatment with etanercept and follow-up. Clin Rheumatol. 2008;27(10):1317–20.

    Article  PubMed  Google Scholar 

  56. Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014;20(2):103–5.

    Article  PubMed  Google Scholar 

  57. Di Gangi M, Amato G, Converso G, et al. Long-term efficacy of adalimumab in hyperimmunoglobulin D and periodic fever syndrome. Isr Med Assoc J. 2014;16(10):605–7.

    PubMed  Google Scholar 

  58. Drenth JP, Vonk AG, Simon A, Powell R, van der Meer JW. Limited efficacy of thalidomide in the treatment of febrile attacks of the hyper-IgD and periodic fever syndrome: a randomized, double-blind, placebo-controlled trial. J Pharmacol Exp Ther. 2001;298(3):1221–6.

    CAS  PubMed  Google Scholar 

  59. Cantarini L, Vitale A, Magnotti F, et al. Weekly oral alendronate in mevalonate kinase deficiency. Orphanet J Rare Dis. 2013;8:196.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Schulert GS, Bove K, McMasters R, Campbell K, Leslie N, Grom AA. 11-month-old infant with periodic fevers, recurrent liver dysfunction, and perforin gene polymorphism. Arthritis Care Res (Hoboken). 2015;67(8):1173–9.

    Article  Google Scholar 

  61. Arkwright PD, Abinun M, Cant AJ. Mevalonic aciduria cured by bone marrow transplantation. N Engl J Med. 2007;357(13):1350.

    Article  CAS  PubMed  Google Scholar 

  62. Neven B, Valayannopoulos V, Quartier P, et al. Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med. 2007;356(26):2700–3.

    Article  CAS  PubMed  Google Scholar 

  63. Chaudhury S, Hormaza L, Mohammad S, et al. Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria. Am J Transplant. 2012;12(6):1627–31.

    Article  CAS  PubMed  Google Scholar 

  64. Giardino S, Lanino E, Morreale G, et al. Long-term outcome of a successful cord blood stem cell transplant in mevalonate kinase deficiency. Pediatrics. 2015;135(1):e211–5.

    Article  PubMed  Google Scholar 

  65. Erdol S, Cekic S, Kılıc SC, Saglam H, Kılıc SS. Massive ascites in a canakinumab resistant case with MVA leading to bone marrow transplantation. Rheumatol Int. 2016;36(7):1011–3.

    Article  PubMed  Google Scholar 

  66. Li Cavoli G, Passantino D, Tortorici C, et al. Renal amyloidosis due to hyper-IgD syndrome. Nefrologia. 2012;32(6):865–6.

    PubMed  Google Scholar 

  67. Lane T, Loeffler JM, Rowczenio DM, et al. AA amyloidosis complicating the hereditary periodic fever syndromes. Arthritis Rheum. 2013;65(4):1116–21.

    Article  CAS  PubMed  Google Scholar 

  68. Yel S, Gunduz Z, Bastug F, et al. Amyloidosis in a child with hyperimmunoglobulinemia D syndrome. Iran J Kidney Dis. 2013;7(1):70–2.

    PubMed  Google Scholar 

  69. Kallianidis AF, Ray A, Goudkade D, de Fijter JW. Amyloid A amyloidosis secondary to hyper IgD syndrome and response to IL-1 blockage therapy. Neth J Med. 2016;74(1):43–6.

    CAS  PubMed  Google Scholar 

  70. van der Hilst JC, Drenth JP, Bodar EJ, et al. Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD syndrome. Amyloid. 2005;12(2):115–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Wilhelmina’s Children’s Hospital, University Medical Center, Utrecht, The Netherlands

    Joost Frenkel

  2. Department of Internal Medicine, Radboudumc Expertisecenter for Immunodeficiency and Autoinflammation, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna Simon

Authors
  1. Joost Frenkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Simon .

Editor information

Editors and Affiliations

  1. Pediatric Rheumatology Unit, Shaare Zedek Medical Center and Hebrew University, Jerusalem, Israel

    Philip J. Hashkes

  2. Department Paediatrics, Division of Rheumatology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Ronald M. Laxer

  3. Department of Internal Medicine, Radboudumc Expertisecenter for Immunodeficiency and Autoinflammation, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna Simon

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Frenkel, J., Simon, A. (2019). Mevalonate Kinase Deficiency. In: Hashkes, P., Laxer, R., Simon, A. (eds) Textbook of Autoinflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-98605-0_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-98605-0_17

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-98604-3

  • Online ISBN: 978-3-319-98605-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation