Key result
MVK missense variants in mevalonic aciduria are associated with a highly heterogeneous phenotype, ranging from an asymptomatic course to early death, and cluster in highly conserved protein domains.
Why the study?
Mevalonic aciduria is a rare disorder of cholesterol biosynthesis with only 30 patients previously reported, warranting an in-depth analysis of its phenotypic spectrum and the pathogenicity of MVK missense variants.
Observational (n=11)
Yes
The phenotypic spectrum of mevalonic aciduria is more heterogeneous than previously assumed, ranging from asymptomatic to early death.
Broad MVA phenotypic heterogeneity warrants inclusive diagnostic consideration in adolescents/adults; leaves open validation of conserved-region variant effects.
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.
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Brennenstuhl et al. (2021) conducted an observational in Mevalonic aciduria (n=11). MVK missense variants was evaluated on Phenotypic spectrum and pathogenicity. MVK missense variants in mevalonic aciduria are associated with a highly heterogeneous phenotype, ranging from an asymptomatic course to early death, and cluster in highly conserved protein domains.
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