National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics

Abstract

Objectives: Mevalonate kinase deficiency (MKD), a rare autosomal recessive autoinflammatory syndrome, is caused by disease-causing variants of the mevalonate kinase (MVK) gene. A national survey was undertaken to investigate clinical and genetic features of MKD patients in Japan.

Methods: The survey identified ten patients with MKD. Clinical information and laboratory data were collected from medical records and by direct interviews with patients, their families, and their attending physicians. Genetic analysis and measurement of MVK activity and urinary excretion of mevalonic acid were performed.

Results: None of the 10 patients harbored MVK disease-causing variants that are common in European patients. However, overall symptoms were in line with previous European reports. Continuous fever was observed in half of the patients. Elevated transaminase was observed in four of the 10 patients, two of whom fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. About half of the patients responded to temporary administration of glucocorticoids and NSAIDs; the others required biologics such as anti-IL-1 drugs.

Conclusion: This is the first national survey of MKD patients in a non-European country. Although clinical symptoms were similar to those reported in Europe, the incidence of continuous fever and elevated transaminase was higher, probably due to differences in disease-causing variants.

Keywords:

• Canakinumab
• genotype-phenotype relationship
• mevalonate kinase deficiency
• national survey

Acknowledgments

We thank Y. Takaoka (Kyoto University) for technical assistance and Dr. Hans R. Waterham (Laboratory of Genetic Metabolic Diseases, Amsterdam) for measurement of mevalonate kinase activity. We also thank all participating patients, their families, and the referring physicians for their generous cooperation. Patients 1 and 4 were enrolled in the clinical trial, which was sponsored by Novartis Pharma AG and registered at www.clinicaltrials.gov (NCT0259291). Canakinumab for Patient 8 was provided by Novartis Pharma AG for clinical research purposes.

Conflict of interest

RN received consultancy and speaker fees from Novartis. TK, TY, and TH received speaker fees from Novartis. The other authors have no conflicts of interest to declare.

Additional information

Funding

This work was supported by a Grant-in-Aid for Young Scientists (15K19610) from the Japan Society for the Promotion of Science (JSPS), a Grant-in-Aid for Scientific Research (15H04876) from the JSPS, and a Health Labor Sciences Research Grant for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (H26-Nanchi-Ippan-070). RN received an institutional grant from Novartis to undertake an open-label trial of canakinumab in children with MKD.