From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria. Issue 5 (30th January 2020)

• Record Type: Journal Article
• Authors: Zielonka, Matthias; Garbade, Sven F.; Gleich, Florian; Okun, Jürgen G.; Nagamani, Sandesh C. S.; Gropman, Andrea L.; Hoffmann, Georg F.; Kölker, Stefan; Posset, Roland
• Other Names: Ah Mew Nicholas investigator.; Burrage Lindsay C. investigator.; Schulze Andreas investigator.; Berry Susan A. investigator.; Baumgartner Matthias R. investigator.; Diaz George A. investigator.; Merritt J. Lawrence investigator.; Bedoyan Jirair K. investigator.; Wong Derek investigator.; Harding Cary O. investigator.; Yudkoff Marc investigator.; Garcia‐Cazorla Angeles investigator.; Cortès‐Saladelafont Elisenda investigator.; Lund Allan M. investigator.; Dionisi‐Vici Carlo investigator.; Burlina Alberto B. investigator.; Morris Andrew A. investigator.; Freisinger Peter investigator.; Walter Magdalena E. investigator.; Jalan Anil investigator.; Schiff Manuel investigator.; Dobbelaere Dries investigator.; Bosch Annet M. investigator.; Ioannou Harikleia investigator.; Barić Ivo investigator.
• Is Part Of: Human mutation. Volume 41:Issue 5(2020)
• Page Start: 946
• Page End: 960
• Publication Date: 2020-01-30
• Subjects: argininosuccinic aciduria -- clinical outcome -- disease course -- enzymatic ASL activity -- predictive biomarker; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23983
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: 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.