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Early prediction of phenotypic severity in Citrullinemia Type 1
OBJECTIVE: Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐modera...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764635/ https://www.ncbi.nlm.nih.gov/pubmed/31469252 http://dx.doi.org/10.1002/acn3.50886 |
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author | Zielonka, Matthias Kölker, Stefan Gleich, Florian Stützenberger, Nicolas Nagamani, Sandesh C. S. Gropman, Andrea L. Hoffmann, Georg F. Garbade, Sven F. Posset, Roland |
author_facet | Zielonka, Matthias Kölker, Stefan Gleich, Florian Stützenberger, Nicolas Nagamani, Sandesh C. S. Gropman, Andrea L. Hoffmann, Georg F. Garbade, Sven F. Posset, Roland |
author_sort | Zielonka, Matthias |
collection | PubMed |
description | OBJECTIVE: Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model. METHODS: We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E‐IMD databases. RESULTS: Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L‐citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification‐based guidance of therapeutic decision‐making based on residual enzymatic ASS1 activity in the future. INTERPRETATION: Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity‐adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system. |
format | Online Article Text |
id | pubmed-6764635 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-67646352019-09-30 Early prediction of phenotypic severity in Citrullinemia Type 1 Zielonka, Matthias Kölker, Stefan Gleich, Florian Stützenberger, Nicolas Nagamani, Sandesh C. S. Gropman, Andrea L. Hoffmann, Georg F. Garbade, Sven F. Posset, Roland Ann Clin Transl Neurol Research Articles OBJECTIVE: Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model. METHODS: We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E‐IMD databases. RESULTS: Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L‐citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification‐based guidance of therapeutic decision‐making based on residual enzymatic ASS1 activity in the future. INTERPRETATION: Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity‐adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system. John Wiley and Sons Inc. 2019-08-30 /pmc/articles/PMC6764635/ /pubmed/31469252 http://dx.doi.org/10.1002/acn3.50886 Text en © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Zielonka, Matthias Kölker, Stefan Gleich, Florian Stützenberger, Nicolas Nagamani, Sandesh C. S. Gropman, Andrea L. Hoffmann, Georg F. Garbade, Sven F. Posset, Roland Early prediction of phenotypic severity in Citrullinemia Type 1 |
title | Early prediction of phenotypic severity in Citrullinemia Type 1 |
title_full | Early prediction of phenotypic severity in Citrullinemia Type 1 |
title_fullStr | Early prediction of phenotypic severity in Citrullinemia Type 1 |
title_full_unstemmed | Early prediction of phenotypic severity in Citrullinemia Type 1 |
title_short | Early prediction of phenotypic severity in Citrullinemia Type 1 |
title_sort | early prediction of phenotypic severity in citrullinemia type 1 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764635/ https://www.ncbi.nlm.nih.gov/pubmed/31469252 http://dx.doi.org/10.1002/acn3.50886 |
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