Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A)

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Treatment of monogenic disorders with viral transduced haematopoietic stem cells

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Impaired lipolysis in propionic acidemia: A new metabolic myopathy?

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Matthias Zielonka
  • Sven F Garbade
  • Florian Gleich
  • Jürgen G Okun
  • Sandesh C S Nagamani
  • Andrea L Gropman
  • Georg F Hoffmann
  • Stefan Kölker
  • Roland Posset
  • Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
  • Allan Meldgaard Lund (Medlem af forfattergruppering)
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftHuman Mutation
Vol/bind41
Udgave nummer5
Sider (fra-til)946-960
Antal sider15
ISSN1059-7794
DOI
StatusUdgivet - maj 2020

Bibliografisk note

© 2020 Wiley Periodicals, Inc.

ID: 62401883