Mevalonate kinase deficiency syndrome: Single center experience

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).

Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.

Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in the MVK gene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.

1. Kozlova AL, Burlakov VI, Shcherbina AYu. Autoinflammatory diseases. Pediatria. 2019;98(3):227-234 (In Russ.).

2. Fietta P. Autoinflammatory diseases: the hereditary periodic fever syndromes. Acta Biomed. 2004;75(2):92-99.

3. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, CunninghamRundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24-64. doi: 10.1007/s10875-019-00737-x

4. Kozlova AL, Varlamova TV, Zimin SB, Novichkova GA, Shcherbina AYu. Experience in the management of patients with hyper IgD syndrome (mevalonate kinase deficiency syndrome). Pediatric Hematology/Oncology and Immunopathology = Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2016;15(1):46-53 (In Russ.).

5. van der Burgh R, Ter Haar NM, Boes ML, Frenkel J. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol. 2013;147:197-206. doi: 10.1016/j.clim.2012.09.011

6. Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, et al. Mevalonate kinase deficiency: A survey of 50 patients. Pediatrics. 2011;128:e152-e159. doi: 10.1542/peds.2010-3639

7. Federici S, Vanoni F, Ben-Chetrit E, Cantarini L, Frenkel J, Goldbach-Mansky R, et al.; Eurofever and the Pediatric Rheumatology International Trials Organization (PRINTO). An international Delphi survey for the definition of new classification criteria for familial mediterranean fever, mevalonate kinase deficiency, TNF receptor-associated periodic fever syndromes, and cryopyrin-associated periodic syndrome. J Rheumatol. 2019;46(4):429-436. doi: 10.3899/jrheum.180056

8. Jeyaratnam J, Ter Haar N, Lachmann H, Simon A, Brogan P, Doglio M, et al. Genetic and phenotypic characteristics of 114 patients with mevalonate kinase deficiency. Pediatr Rheumatol. 2015;13(Suppl 1):25. doi: 10.1186/1546-0096-13-S1-P25

9. Ben-Chetrit E, Gattorno M, Gul A, Kastner DL, Lachmann HJ, Touitou I, et al.; Paediatric Rheumatology International Trials Organisation (PRINTO) and the AIDs Delphi study participants. Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): A Delphi study. Ann Rheum Dis. 2018;77(11):1558-1565. doi: 10.1136/annrheumdis-2017-212515

10. Stoffels M, Jongekrijg J, Remijn T, Kok N, van der Meer JW, Simon A. TLR2/TLR4-dependent exaggerated cytokine production in hyperimmunoglobulinaemia D and periodic fever syndrome. Rheumatology (Oxford). 2015;54(2):363-368. doi: 10.1093/rheumatology/keu341

11. Kuijk LM, Mandey SH, Schellens I, Waterham HR, Rijkers GT, Coffer PJ, et al. Statin synergizes with LPS to induce IL-1beta release by THP-1 cells through activation of caspase-1. Mol Immunol. 2008;45(8):2158-2165.

12. Frenkel J, Rijkers GT, Mandey SH, Buurman SW, Houten SM, Wanders RJ, et al. Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum. 2002;46(10):2794-2803.

13. Favier LA, Schulert GS. Mevalonate kinase deficiency: Current perspectives. Appl Clin Genet. 2016;9:101-110.

14. Ter Haar NM, Jeyaratnam J, Lachmann HJ, Simon A, Brogan PA, Doglio M, et al.; Paediatric Rheumatology International Trials Organisation and Eurofever Project. The phenotype and genotype of mevalonate kinase deficiency: A series of 114 cases from the Eurofever Registry. Arthritis Rheumatol. 2016;68(11):2795-2805. doi: 10.1002/art.39763

15. van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, 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. doi: 10.1097/MD.0b013e318190cfb7

16. Tanaka T, Yoshioka K, Nishikomori R, Sakai H, Abe J, Yamashita Y, et al. National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics. Mod Rheumatol. 2019;29(1):181-187. doi: 10.1080/14397595.2018.1442639

17. International molecular genetic registry of hereditary autoinflammatory diseases (In Russ.). URL: https://infevers.umai-montpellier.fr/web/index.php (Дата доступа: 04.11.2020).

18. Piram M, Koné-Paut I, Lachmann HJ, Frenkel J, Ozen S, Kuemmerle-Deschner J, et al. Validation of the auto-inflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis. 2014;73(12):2168-2173.

19. Celsi F, Tommasini A, Crovella S. “Hyper-IgD syndrome” or “mevalonate kinase deficiency”: An old syndrome needing a new name? Rheumatol Int. 2014;34:423-424.

20. Cekin N, Akyurek ME, Pinarbasi E, Ozen F. MEFV mutations and their relation to major clinical symptoms of familial mediterranean fever gene. 2017;626:9-13. doi: 10.1016/j.gene.2017.05.013

21. Ruiz-Ortiz E, Iglesias E, Soriano A, Buján-Rivas S, EspañolRego M, Castellanos-Moreira R, et al. Disease phenotype and outcome depending on the age at disease onset in patients carrying the R92Q low-penetrance variant in TNFRSF1A gene. Front Immunol. 2017;8:299. doi: 10.3389/fimmu.2017.00299

22. Naselli A, Penco F, Cantarini L, Insalaco A, Alessio M, Tommasini A, et al. Clinical characteristics of patients carrying the Q703K variant of the NLRP3 gene: A 10-year multicentric national study. J Rheumatol. 2016;43(6):1093-1100. doi: 10.3899/jrheum.150962

23. Sornsakrin M, Wenner K, Ganschow R. B cell cytopenia in two brothers with hyper-IgD and periodic fever syndrome. Eur J Pediatr. 2009;168(7):825-831. doi: 10.1007/s00431-008-0843-6

24. Siavoshian S, Simoneau C, Maugeais P, Marks L, Rodary L, Gardette J, et al. Measurement of mevalonic acid in human urine by bench top gas chromatography-mass spectrometry. Clin Chim Acta. 1995;243(2):129-136.

25. Rodrigues AV, Maggs JL, McWilliam SJ, Pirmohamed M, Coen M, Wilson ID, et al. Quantification of urinary mevalonic acid as a biomarker of HMG-CoA reductase activity by a novel translational LC-MS/MS method. Bioanalysis. 2014;6(7):919-933.

26. Gibson KM, Lohr JL, Broock RL, Hoffmann G, Nyhan WL, Sweetman L, et al. Mevalonate kinase in lysates of cultured human fibroblasts and lymphoblasts: Kinetic properties, assay conditions, carrier detection and measurement of residual activity in a patient with mevalonic aciduria. Enzyme. 1989;41(1):47-55.

27. Ammouri W, Cuisset L, Rouaghe S, Rolland MO, Delpech M, Grateau G, 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. doi: 10.1093/rheumatology/kem200

28. Ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, et al. Paediatric Rheumatology International Trials O, The Eurofever/Eurotraps Project Treatment of autoinflammatory diseases: Results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72(5):678-685.

29. Di Gangi M, Amato G, Converso G, Benenati A, Leonetti C, Borella E, et al. Long-term efficacy of adalimumab in hyperimmunoglobulin D and periodic fever syndrome. Isr Med Assoc J. 2014;16(10):605-607.

30. Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2014;20(2):103-105.

31. Instructions for medical use of the medicinal product ILARIS® (In Russ.) URL: https://www.novartis.ru/sites/www.novartis.ru/files/2017-11-16-ilaris-lyo-npi-v3-2-full-version.pdf (Дата доступа: 04.11.2020).

32. Bodar EJ, Kuijk LM, Drenth JP, van der Meer JW, Simon A, Frenkel J. On-demand anakinra treatment is effective in mevalonate kinase deficiency. Ann Rheum Dis. 2011;70(12):2155-2158.

33. Arostegui JI, Anton J, Calvo I, Robles A, Iglesias E, LópezMontesinos B, 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;69:1679-1688.

34. De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med. 2018;378(20):1908-1919.

35. Moiseev SV, Rameev VV. Canakinumab in the treatment of periodic illness and other autoinflammatory diseases – The CLUSTER Study. Clinical Pharmacology and Therapy. 2018;4:59-64 (In Russ.).

36. 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):260-264.

37. Erdol S, Cekic S, Cakı Kılıc S, Saglam H, Sebnem Kılıc S. Massive ascites in a canakinumab resistant case with MVA leading to bone marrow transplantation. Rheumatol Int. (2016) 36:1011-1013

38. Giardino S, Lanino E, Morreale G, Madeo A, Di Rocco M, Gattorno M, et al. Long-term outcome of a successful cord blood stem cell transplant in mevalonate kinase deficiency. Pediatrics. 2015;135(1):e211-e215.

39. Neven B, Valayannopoulos V, Quartier P, Blanche S, Prieur AM, Debré M, et al. Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med. 2007;356:2700-2703.

40. Szymanski AM, Dávila Saldaña B, Ferreira CR, Loechelt B, Jung L. Mevalonic aciduria: Does stem cell transplant fully cure disease? Pediatr Transplant. 2020;24(1):e13604. doi: 10.1111/petr.13604.