Guan Chenchen, Wang Wenjie, Zhou Qinhua, Sun Jinqiao, Liu Lipin, Liu Luyao, Sun Bijun, Hou Jia, Wang Xiaochuan
Department of Clinical Immunology and Allergy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
Pediatr Rheumatol Online J. 2025 Jul 27;23(1):78. doi: 10.1186/s12969-025-01131-1.
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.
甲羟戊酸激酶缺乏症（MKD）是一种罕见的自身炎症性疾病，而甲羟戊酸尿症（MA）是MKD的一种严重表型。本研究报告了中国队列中MKD的特征以及甲羟戊酸激酶（MVK）基因的四个新突变。
对2013年7月至2024年12月期间诊断为MKD的患者进行回顾性研究。从电子病历中收集临床、免疫学和随访数据。进行下一代测序和桑格测序以鉴定基因突变。对MKD患者进行文献综述，以进一步研究基因型与表型之间的关联。
从中国一组不明原因长期反复发热的队列中纳入了11例MKD患者。10例患者被归类为高免疫球蛋白D综合征（HIDS），1例患者被归类为MA。中位随访时间为5年（四分位间距：1.5 - 6年）。反复发热和胃肠道症状是最常见的症状。11例患者中有8例出现贫血，其中1例有严重血液学并发症。还观察到生长受限（5/11例患者）和发育迟缓（4/11例患者）。对10例患者进行了IgD水平检测，中位IgD水平为85.23µg/ml（四分位间距：18.74 - 385.19µg/ml）。在MVK基因中发现了四个新的突变位点：c.78G＞A、c.463G＞A、c.1076C＞T和c.1088G＞A。依那西普是经测试有效的生物制剂，6例患者中有5例实现了完全或部分缓解。对20例MA患者的文献综述表明，MVK基因纯合突变与MA的关联更为常见。此外，具有纯合A334T突变的MA患者表现出较轻的表型，而具有I268T纯合突变的患者表现出更严重的表型。
本研究是中国最大的MKD儿科患者病例系列。鉴定出MVK中的四个新突变位点，进一步扩大了MKD的表型和基因型谱，并强调了MVK突变模式对影响疾病严重程度的重要性。
