Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria

Abstract

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.

Neuroinflammation Associated With Inborn Errors of Immunity

“…MVA and HIDS represent opposite ends of a clinical spectrum associated with absent to subnormal enzyme activity, respectively ( 64 ). The exact pathogenesis is elusive but involves build-up of mevalonate and loss of pyrin inhibition resulting in inflammasome activation and excess IL-1β production ( 65 ). The mevalonate pathway produces the substrate for a form of post-translational modification, prenylation, which is involved in the regulation of TLR-induced phosphoinositide 3-kinase (PI3K) activation ( 66 ).…”

“…Loss of prenylation in MKD thus contributes to pyrin activation and the hyperinflammatory phenotype. MVA is associated with severe developmental delay, ataxia, epilepsy, and shortened lifespan ( 65 ). HIDS is an autoinflammatory periodic fever syndrome associated with persistently elevated IgD and increased mevalonic acid in the urine during attacks ( 13 ).…”

“…Common clinical manifestations of HIDS include rash, hepatosplenomegaly, and lymphadenopathy. The most common neurological manifestation is headache (10-40%), which may be present independent of the fever episodes ( 65 ). Sporadic reports of seizures, transverse myelitis, cerebellar syndrome, and aseptic meningitis exist ( 13 , 14 ).…”

Autoinflammation – Unterschiede bei Kindern und Erwachsenen

“…Die monogen vererbte Mevalonatkinasedefizienz (MKD) umfasst zwei Krankheitsbilder mit z. T. überlappenden Symptomen: die extrem seltene, schwer verlaufende Stoffwechselerkrankung Mevalonazidurie (MEVA; [30]) sowie das ursprünglich als Hyperimmunglobulin-D-Syndrom (HIDS) bezeichnete hereditäre Fiebersyndrom [31]. Da sich im weiteren Verlauf der Erkrankung jedoch herausstellte, dass bei Weitem nicht bei allen Patient*innen mit dieser Erkrankung erhöhte Immunglobulin-D-Spiegel nachweisbar sind, wird heute häufig für diesen Phänotyp der Begriff "Mevalonatkinasedefizienz" verwandt.…”

Increased core body temperature exacerbates defective protein prenylation in mouse avatars of mevalonate kinase deficiency

“…The most striking example of this is the genetic autoinflammatory disorder mevalonate kinase deficiency (MKD). MKD is an inborn error of metabolism caused by autosomal recessive inheritance of mutations in the MVK gene (Drenth et al, 1999; Houten et al, 1999) encoding mevalonate kinase (MK; ATP:(R)-mevalonate 5-phosphotransferase, EC 2.7.1.36), a proximal enzyme in the mevalonate pathway (Brennenstuhl et al, 2021; Houten et al, 2000). Understanding of the molecular mechanisms underpinning MKD pathogenesis remain largely unknown due to the lack of appropriate genetic tools to study this disease.…”