Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD/HIDS) are disorders of cholesterol biosynthesis caused by variants in the MVK gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in-depth analysis of the phenotypic spectrum of MVA and provide an in-silico pathogenicity model analysis of MVK missense variants. The phenotypic spectrum of 11 MVA patients (age range 0-51 years) registered in the Unified European Registry for Inherited Metabolic Disorders database was systematically analyzed using terms of the Human Phenotype Ontology. Biochemical, radiological as well as genetic characteristics were investigated. Six of eleven patients have reached adulthood and four have reached adolescence. One of the adolescent patients died at the age of 16 years and one patient died shortly after birth. Symptoms started within the first year of life, including episodic fever, developmental delay, ataxia, and ocular involvement. We also describe a case with absence of symptoms despite massive excretion of mevalonic acid. Pathogenic variants causing MVA cluster within highly conserved regions, which are involved in mevalonate and ATP binding. The phenotype of adult and adolescent MVA patients is more heterogeneous than previously assumed. Outcome varies from an asymptomatic course to early death. MVK variants cluster in functionally important and highly conserved protein domains and show high concordance regarding their expected pathogenicity.

中文翻译：

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MVK错义变异在甲羟戊酸尿症中的表型多样性、疾病进展和致病性

甲羟戊酸尿症 (MVA) 和高免疫球蛋白血症 D 综合征 (MKD/HIDS) 是由MVK基因变异引起的胆固醇生物合成障碍，其特征是尿中甲羟戊酸排泄增加。迄今为止，已有 30 名 MVA 患者报告出现反复发热危象和神经功能障碍。在这里，我们对 MVA 的表型谱进行了深入分析，并提供了MVK错义变异的计算机内致病性模型分析。使用人类表型本体论的术语系统地分析了在欧洲统一登记处遗传代谢疾病数据库中注册的 11 名 MVA 患者（年龄范围 0-51 岁）的表型谱. 研究了生化、放射学和遗传特征。11 名患者中有 6 名已成年，4 名已进入青春期。其中一名青少年患者在 16 岁时死亡，一名患者在出生后不久死亡。症状在出生后的第一年内开始出现，包括发作性发热、发育迟缓、共济失调和眼部受累。我们还描述了一个尽管有大量甲羟戊酸排泄但没有症状的病例。导致高度保守区域内的 MVA 簇的致病变异，这些区域与甲羟戊酸和 ATP 结合有关。成人和青少年 MVA 患者的表型比以前假设的更异质。结果从无症状病程到过早死亡不等。