Mevalonate kinase deficiency: genetic and clinical characteristics of a Chinese pediatric cohort

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease, and mevalonic aciduria (MA) is a severe phenotype of MKD. The present study reports the characteristics of MKD and four novel mutations in the mevalonate kinase (MVK) gene in a Chinese cohort.

A retrospective study was conducted on patients diagnosed with MKD from July 2013 to December 2024. The clinical, immunological, and follow-up data were collected from electronic medical records. Next-generation sequencing and Sanger sequencing were performed to identify gene mutations. A literature review was performed on MKD patients to further investigate the associations between genotype and phenotype.

Eleven MKD patients were enrolled from a Chinese cohort of prolonged and recurrent fever of unknown origin. Ten patients were classified as having hyperimmunoglobulin D syndrome (HIDS), and one patient was classified as having MA. The median follow-up duration was 5 years (IQR: 1.5-6 years). Recurrent fever and gastrointestinal symptoms were the most common symptoms. Anemia was observed in 8 of the 11 patients, including one patient with severe hematological complications. Growth restriction (5/11 patients) and developmental delay (4/11 patients) were also observed. IgD levels were measured in ten patients, and the median IgD level was 85.23 µg/ml (IQR: 18.74-385.19 µg/ml). Four novel mutation sites in the MVK gene were discovered: c.78G > A, c.463G > A, c.1076C > T and c.1088G > A. Etanercept was the effective biological agent tested, leading to complete or partial remission in 5 of the 6 patients. A literature review of 20 MA patients suggested that homozygous MVK gene mutations are more frequently associated with MA. Moreover, MA patients with the homozygous A334T mutation present a milder phenotype, and those with the I268T homozygous mutation present a more severe phenotype.

This study is the largest case series of MKD pediatric patients from China. Four new mutation sites in MVK were identified, further expanding the phenotypic and genotypic spectrum of MKD and emphasizing the significance of MVK mutation patterns in influencing disease severity.