From genotype to phenotype: early prediction ...
Type de document :
Article dans une revue scientifique: Article original
DOI :
PMID :
URL permanente :
Titre :
From genotype to phenotype: early prediction of disease severity in argininosuccinic aciduria
Auteur(s) :
Zielonka, Matthias [Auteur]
Garbade, Sven F. [Auteur]
Gleich, Florian [Auteur]
Okun, Jurgen G. [Auteur]
Nagamani, Sandesh C. S. [Auteur]
Gropman, Andrea L. [Auteur]
Hoffmann, Georg F. [Auteur]
Kolker, Stefan [Auteur]
Posset, Roland [Auteur]
Garbade, Sven F. [Auteur]
Gleich, Florian [Auteur]
Okun, Jurgen G. [Auteur]
Nagamani, Sandesh C. S. [Auteur]
Gropman, Andrea L. [Auteur]
Hoffmann, Georg F. [Auteur]
Kolker, Stefan [Auteur]
Posset, Roland [Auteur]
Titre de la revue :
Human mutation
Nom court de la revue :
Hum. Mutat.
Date de publication :
2020-01-15
ISSN :
1098-1004
Mot(s)-clé(s) :
disease course
argininosuccinic aciduria
clinical outcome
predictive biomarker
enzymatic ASL activity
argininosuccinic aciduria
clinical outcome
predictive biomarker
enzymatic ASL activity
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Argininosuccinic aciduria (ASA) is an inherited urea cycle disorder and has a highly variable phenotypic spectrum ranging from individuals with lethal hyperammonemic encephalopathy, liver dysfunction, and cognitive ...
Lire la suite >Argininosuccinic aciduria (ASA) is an inherited urea cycle disorder and has a highly variable phenotypic spectrum ranging from individuals with lethal hyperammonemic encephalopathy, liver dysfunction, and cognitive deterioration, to individuals with a mild disease course. As it is difficult to predict the phenotypic severity, we aimed at identifying a reliable disease prediction model. We applied a biallelic expression system to assess the functional impact of pathogenic argininosuccinate lyase (ASL) variants and to determine the enzymatic activity of ASL in 58 individuals with ASA. This cohort represented 42 ASL gene variants and 42 combinations in total. Enzymatic ASL activity was compared with biochemical and clinical endpoints from the UCDC and E-IMD databases. Enzymatic ASL activity correlated with peak plasma ammonium concentration at initial presentation and with the number of hyperammonemic events (HAEs) per year of observation. Individuals with ≤9% of enzymatic activity had more severe initial decompensations and a higher annual frequency of HAEs than individuals above this threshold. Enzymatic ASL activity also correlated with the cognitive outcome and the severity of the liver disease, enabling a reliable severity prediction for individuals with ASA. Thus, enzymatic activity measured by this novel expression system can serve as an important marker of phenotypic severity.Lire moins >
Lire la suite >Argininosuccinic aciduria (ASA) is an inherited urea cycle disorder and has a highly variable phenotypic spectrum ranging from individuals with lethal hyperammonemic encephalopathy, liver dysfunction, and cognitive deterioration, to individuals with a mild disease course. As it is difficult to predict the phenotypic severity, we aimed at identifying a reliable disease prediction model. We applied a biallelic expression system to assess the functional impact of pathogenic argininosuccinate lyase (ASL) variants and to determine the enzymatic activity of ASL in 58 individuals with ASA. This cohort represented 42 ASL gene variants and 42 combinations in total. Enzymatic ASL activity was compared with biochemical and clinical endpoints from the UCDC and E-IMD databases. Enzymatic ASL activity correlated with peak plasma ammonium concentration at initial presentation and with the number of hyperammonemic events (HAEs) per year of observation. Individuals with ≤9% of enzymatic activity had more severe initial decompensations and a higher annual frequency of HAEs than individuals above this threshold. Enzymatic ASL activity also correlated with the cognitive outcome and the severity of the liver disease, enabling a reliable severity prediction for individuals with ASA. Thus, enzymatic activity measured by this novel expression system can serve as an important marker of phenotypic severity.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
CHU Lille
Inserm
Université de Lille
Inserm
Université de Lille
Collections :
Date de dépôt :
2021-09-02T07:02:15Z