Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria
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Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria. / Brennenstuhl, Heiko; Nashawi, Mohammed; Schröter, Julian; Baronio, Federico; Beedgen, Lars; Gleich, Florian; Jeltsch, Kathrin; von Landenberg, Christina; Martini, Silvia; Simon, Anna; Thiel, Christian; Tsiakas, Konstantinos; Opladen, Thomas; Kölker, Stefan; Hoffmann, Georg F; Haas, Dorothea; Unified Registry for Inherited Metabolic Disorders (U-IMD) Consortium and the European Registry for Hereditary Metabolic Disorders (MetabERN).
in: J INHERIT METAB DIS, Jahrgang 44, Nr. 5, 09.2021, S. 1272-1287.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria
AU - Brennenstuhl, Heiko
AU - Nashawi, Mohammed
AU - Schröter, Julian
AU - Baronio, Federico
AU - Beedgen, Lars
AU - Gleich, Florian
AU - Jeltsch, Kathrin
AU - von Landenberg, Christina
AU - Martini, Silvia
AU - Simon, Anna
AU - Thiel, Christian
AU - Tsiakas, Konstantinos
AU - Opladen, Thomas
AU - Kölker, Stefan
AU - Hoffmann, Georg F
AU - Haas, Dorothea
AU - Unified Registry for Inherited Metabolic Disorders (U-IMD) Consortium and the European Registry for Hereditary Metabolic Disorders (MetabERN)
N1 - © 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Disease Progression
KW - Female
KW - Humans
KW - Male
KW - Mevalonate Kinase Deficiency/metabolism
KW - Mevalonic Acid/metabolism
KW - Mutation, Missense
KW - Phosphotransferases (Alcohol Group Acceptor)/genetics
KW - Young Adult
U2 - 10.1002/jimd.12412
DO - 10.1002/jimd.12412
M3 - SCORING: Journal article
C2 - 34145613
VL - 44
SP - 1272
EP - 1287
JO - J INHERIT METAB DIS
JF - J INHERIT METAB DIS
SN - 0141-8955
IS - 5
ER -