From genotype to phenotype : early prediction of disease severity in argininosuccinic aciduria
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 predi...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Zielonka, Matthias - 1983- [verfasserIn] Garbade, Sven - 1971- [verfasserIn] Gleich, Florian [verfasserIn] Okun, Jürgen G. - 1968- [verfasserIn] Nagamani, Sandesh C. S. [verfasserIn] Gropman, Andrea L. [verfasserIn] Hoffmann, Georg F. - 1957- [verfasserIn] Kölker, Stefan [verfasserIn] Posset, Roland - 1986- [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
15 January 2020 |
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| Schlagwörter: |
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| Anmerkung: |
Gesehen am 12.08.2021 |
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| Umfang: |
15 |
| Übergeordnetes Werk: |
Enthalten in: Human mutation - London : Hindawi Limited, 1992, 41(2020), 5, Seite 946-960 |
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| Übergeordnetes Werk: |
volume:41 ; year:2020 ; number:5 ; pages:946-960 ; extent:15 |
| Links: |
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| DOI / URN: |
10.1002/humu.23983 |
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| Katalog-ID: |
1766610641 |
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| 245 | 1 | 0 | |a From genotype to phenotype |b early prediction of disease severity in argininosuccinic aciduria |c Matthias Zielonka, Sven F. Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. Hoffmann, Stefan Kölker, Roland Posset for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group |
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| 520 | |a 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. | ||
| 650 | 4 | |a argininosuccinic aciduria | |
| 650 | 4 | |a clinical outcome | |
| 650 | 4 | |a disease course | |
| 650 | 4 | |a enzymatic ASL activity | |
| 650 | 4 | |a predictive biomarker | |
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10.1002/humu.23983 doi (DE-627)1766610641 (DE-599)KXP1766610641 (OCoLC)1295680684 DE-627 ger DE-627 rda eng Zielonka, Matthias 1983- verfasserin (DE-588)1056891297 (DE-627)79418670X (DE-576)412871637 aut From genotype to phenotype early prediction of disease severity in argininosuccinic aciduria Matthias Zielonka, Sven F. Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. Hoffmann, Stefan Kölker, Roland Posset for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group 15 January 2020 15 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 12.08.2021 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. argininosuccinic aciduria clinical outcome disease course enzymatic ASL activity predictive biomarker Garbade, Sven 1971- verfasserin (DE-588)129234362 (DE-627)707186889 (DE-576)297554263 aut Gleich, Florian verfasserin (DE-588)1114740195 (DE-627)86900445X (DE-576)47746100X aut Okun, Jürgen G. 1968- verfasserin (DE-588)121578232 (DE-627)705551415 (DE-576)292781296 aut Nagamani, Sandesh C. S. verfasserin aut Gropman, Andrea L. verfasserin aut Hoffmann, Georg F. 1957- verfasserin (DE-588)115652868 (DE-627)077386116 (DE-576)261230042 aut Kölker, Stefan verfasserin (DE-588)1022937758 (DE-627)717335771 (DE-576)366197568 aut Posset, Roland 1986- verfasserin (DE-588)1058087347 (DE-627)796372160 (DE-576)414059034 aut Enthalten in Human mutation London : Hindawi Limited, 1992 41(2020), 5, Seite 946-960 Online-Ressource (DE-627)306586193 (DE-600)1498165-8 (DE-576)250043572 1098-1004 nnns volume:41 year:2020 number:5 pages:946-960 extent:15 https://doi.org/10.1002/humu.23983 Verlag Resolving-System lizenzpflichtig Volltext https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23983 Verlag lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2011 ISIL_DE-16 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2013 GBV_ILN_2013 ISIL_DE-16-250 AR 41 2020 5 946-960 15 2011 01 DE-16 3969545226 00 --%%-- --%%-- --%%-- --%%-- l01 17-08-21 2013 01 DE-16-250 3966410281 00 --%%-- --%%-- --%%-- --%%-- l01 12-08-21 2013 01 DE-16-250 00 s hd2020 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_9 2013 01 DE-16-250 03 s s_15 2013 01 DE-16-250 04 p (DE-627)1493468650 Zielonka, Matthias 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1529261783 Garbade, Sven 2013 01 DE-16-250 05 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2 2013 01 DE-16-250 06 p (DE-627)1547461748 Gleich, Florian 2013 01 DE-16-250 06 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_3 2013 01 DE-16-250 07 p (DE-627)148007991X Okun, Jürgen G. 2013 01 DE-16-250 07 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 07 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 07 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 07 s pos_4 2013 01 DE-16-250 08 p (DE-627)1436198674 Hoffmann, Georg F. 2013 01 DE-16-250 08 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 08 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 08 s pos_7 2013 01 DE-16-250 09 p (DE-627)1436198933 Kölker, Stefan 2013 01 DE-16-250 09 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 09 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 09 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 09 s pos_8 2013 01 DE-16-250 10 p (DE-627)1493265547 Posset, Roland 2013 01 DE-16-250 10 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 10 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 10 s pos_9 |
| spelling |
10.1002/humu.23983 doi (DE-627)1766610641 (DE-599)KXP1766610641 (OCoLC)1295680684 DE-627 ger DE-627 rda eng Zielonka, Matthias 1983- verfasserin (DE-588)1056891297 (DE-627)79418670X (DE-576)412871637 aut From genotype to phenotype early prediction of disease severity in argininosuccinic aciduria Matthias Zielonka, Sven F. Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. Hoffmann, Stefan Kölker, Roland Posset for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group 15 January 2020 15 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 12.08.2021 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. argininosuccinic aciduria clinical outcome disease course enzymatic ASL activity predictive biomarker Garbade, Sven 1971- verfasserin (DE-588)129234362 (DE-627)707186889 (DE-576)297554263 aut Gleich, Florian verfasserin (DE-588)1114740195 (DE-627)86900445X (DE-576)47746100X aut Okun, Jürgen G. 1968- verfasserin (DE-588)121578232 (DE-627)705551415 (DE-576)292781296 aut Nagamani, Sandesh C. S. verfasserin aut Gropman, Andrea L. verfasserin aut Hoffmann, Georg F. 1957- verfasserin (DE-588)115652868 (DE-627)077386116 (DE-576)261230042 aut Kölker, Stefan verfasserin (DE-588)1022937758 (DE-627)717335771 (DE-576)366197568 aut Posset, Roland 1986- verfasserin (DE-588)1058087347 (DE-627)796372160 (DE-576)414059034 aut Enthalten in Human mutation London : Hindawi Limited, 1992 41(2020), 5, Seite 946-960 Online-Ressource (DE-627)306586193 (DE-600)1498165-8 (DE-576)250043572 1098-1004 nnns volume:41 year:2020 number:5 pages:946-960 extent:15 https://doi.org/10.1002/humu.23983 Verlag Resolving-System lizenzpflichtig Volltext https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23983 Verlag lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2011 ISIL_DE-16 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2013 GBV_ILN_2013 ISIL_DE-16-250 AR 41 2020 5 946-960 15 2011 01 DE-16 3969545226 00 --%%-- --%%-- --%%-- --%%-- l01 17-08-21 2013 01 DE-16-250 3966410281 00 --%%-- --%%-- --%%-- --%%-- l01 12-08-21 2013 01 DE-16-250 00 s hd2020 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_9 2013 01 DE-16-250 03 s s_15 2013 01 DE-16-250 04 p (DE-627)1493468650 Zielonka, Matthias 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1529261783 Garbade, Sven 2013 01 DE-16-250 05 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2 2013 01 DE-16-250 06 p (DE-627)1547461748 Gleich, Florian 2013 01 DE-16-250 06 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_3 2013 01 DE-16-250 07 p (DE-627)148007991X Okun, Jürgen G. 2013 01 DE-16-250 07 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 07 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 07 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 07 s pos_4 2013 01 DE-16-250 08 p (DE-627)1436198674 Hoffmann, Georg F. 2013 01 DE-16-250 08 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 08 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 08 s pos_7 2013 01 DE-16-250 09 p (DE-627)1436198933 Kölker, Stefan 2013 01 DE-16-250 09 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 09 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 09 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 09 s pos_8 2013 01 DE-16-250 10 p (DE-627)1493265547 Posset, Roland 2013 01 DE-16-250 10 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 10 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 10 s pos_9 |
| allfields_unstemmed |
10.1002/humu.23983 doi (DE-627)1766610641 (DE-599)KXP1766610641 (OCoLC)1295680684 DE-627 ger DE-627 rda eng Zielonka, Matthias 1983- verfasserin (DE-588)1056891297 (DE-627)79418670X (DE-576)412871637 aut From genotype to phenotype early prediction of disease severity in argininosuccinic aciduria Matthias Zielonka, Sven F. Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. Hoffmann, Stefan Kölker, Roland Posset for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group 15 January 2020 15 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 12.08.2021 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. argininosuccinic aciduria clinical outcome disease course enzymatic ASL activity predictive biomarker Garbade, Sven 1971- verfasserin (DE-588)129234362 (DE-627)707186889 (DE-576)297554263 aut Gleich, Florian verfasserin (DE-588)1114740195 (DE-627)86900445X (DE-576)47746100X aut Okun, Jürgen G. 1968- verfasserin (DE-588)121578232 (DE-627)705551415 (DE-576)292781296 aut Nagamani, Sandesh C. S. verfasserin aut Gropman, Andrea L. verfasserin aut Hoffmann, Georg F. 1957- verfasserin (DE-588)115652868 (DE-627)077386116 (DE-576)261230042 aut Kölker, Stefan verfasserin (DE-588)1022937758 (DE-627)717335771 (DE-576)366197568 aut Posset, Roland 1986- verfasserin (DE-588)1058087347 (DE-627)796372160 (DE-576)414059034 aut Enthalten in Human mutation London : Hindawi Limited, 1992 41(2020), 5, Seite 946-960 Online-Ressource (DE-627)306586193 (DE-600)1498165-8 (DE-576)250043572 1098-1004 nnns volume:41 year:2020 number:5 pages:946-960 extent:15 https://doi.org/10.1002/humu.23983 Verlag Resolving-System lizenzpflichtig Volltext https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23983 Verlag lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2011 ISIL_DE-16 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2013 GBV_ILN_2013 ISIL_DE-16-250 AR 41 2020 5 946-960 15 2011 01 DE-16 3969545226 00 --%%-- --%%-- --%%-- --%%-- l01 17-08-21 2013 01 DE-16-250 3966410281 00 --%%-- --%%-- --%%-- --%%-- l01 12-08-21 2013 01 DE-16-250 00 s hd2020 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_9 2013 01 DE-16-250 03 s s_15 2013 01 DE-16-250 04 p (DE-627)1493468650 Zielonka, Matthias 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1529261783 Garbade, Sven 2013 01 DE-16-250 05 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2 2013 01 DE-16-250 06 p (DE-627)1547461748 Gleich, Florian 2013 01 DE-16-250 06 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_3 2013 01 DE-16-250 07 p (DE-627)148007991X Okun, Jürgen G. 2013 01 DE-16-250 07 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 07 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 07 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 07 s pos_4 2013 01 DE-16-250 08 p (DE-627)1436198674 Hoffmann, Georg F. 2013 01 DE-16-250 08 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 08 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 08 s pos_7 2013 01 DE-16-250 09 p (DE-627)1436198933 Kölker, Stefan 2013 01 DE-16-250 09 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 09 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 09 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 09 s pos_8 2013 01 DE-16-250 10 p (DE-627)1493265547 Posset, Roland 2013 01 DE-16-250 10 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 10 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 10 s pos_9 |
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10.1002/humu.23983 doi (DE-627)1766610641 (DE-599)KXP1766610641 (OCoLC)1295680684 DE-627 ger DE-627 rda eng Zielonka, Matthias 1983- verfasserin (DE-588)1056891297 (DE-627)79418670X (DE-576)412871637 aut From genotype to phenotype early prediction of disease severity in argininosuccinic aciduria Matthias Zielonka, Sven F. Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. Hoffmann, Stefan Kölker, Roland Posset for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group 15 January 2020 15 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 12.08.2021 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. argininosuccinic aciduria clinical outcome disease course enzymatic ASL activity predictive biomarker Garbade, Sven 1971- verfasserin (DE-588)129234362 (DE-627)707186889 (DE-576)297554263 aut Gleich, Florian verfasserin (DE-588)1114740195 (DE-627)86900445X (DE-576)47746100X aut Okun, Jürgen G. 1968- verfasserin (DE-588)121578232 (DE-627)705551415 (DE-576)292781296 aut Nagamani, Sandesh C. 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10.1002/humu.23983 doi (DE-627)1766610641 (DE-599)KXP1766610641 (OCoLC)1295680684 DE-627 ger DE-627 rda eng Zielonka, Matthias 1983- verfasserin (DE-588)1056891297 (DE-627)79418670X (DE-576)412871637 aut From genotype to phenotype early prediction of disease severity in argininosuccinic aciduria Matthias Zielonka, Sven F. Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. Hoffmann, Stefan Kölker, Roland Posset for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group 15 January 2020 15 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 12.08.2021 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. argininosuccinic aciduria clinical outcome disease course enzymatic ASL activity predictive biomarker Garbade, Sven 1971- verfasserin (DE-588)129234362 (DE-627)707186889 (DE-576)297554263 aut Gleich, Florian verfasserin (DE-588)1114740195 (DE-627)86900445X (DE-576)47746100X aut Okun, Jürgen G. 1968- verfasserin (DE-588)121578232 (DE-627)705551415 (DE-576)292781296 aut Nagamani, Sandesh C. S. verfasserin aut Gropman, Andrea L. verfasserin aut Hoffmann, Georg F. 1957- verfasserin (DE-588)115652868 (DE-627)077386116 (DE-576)261230042 aut Kölker, Stefan verfasserin (DE-588)1022937758 (DE-627)717335771 (DE-576)366197568 aut Posset, Roland 1986- verfasserin (DE-588)1058087347 (DE-627)796372160 (DE-576)414059034 aut Enthalten in Human mutation London : Hindawi Limited, 1992 41(2020), 5, Seite 946-960 Online-Ressource (DE-627)306586193 (DE-600)1498165-8 (DE-576)250043572 1098-1004 nnns volume:41 year:2020 number:5 pages:946-960 extent:15 https://doi.org/10.1002/humu.23983 Verlag Resolving-System lizenzpflichtig Volltext https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23983 Verlag lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2011 ISIL_DE-16 SYSFLAG_1 GBV_KXP SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2013 GBV_ILN_2013 ISIL_DE-16-250 AR 41 2020 5 946-960 15 2011 01 DE-16 3969545226 00 --%%-- --%%-- --%%-- --%%-- l01 17-08-21 2013 01 DE-16-250 3966410281 00 --%%-- --%%-- --%%-- --%%-- l01 12-08-21 2013 01 DE-16-250 00 s hd2020 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_9 2013 01 DE-16-250 03 s s_15 2013 01 DE-16-250 04 p (DE-627)1493468650 Zielonka, Matthias 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_1 2013 01 DE-16-250 05 p (DE-627)1529261783 Garbade, Sven 2013 01 DE-16-250 05 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_2 2013 01 DE-16-250 06 p (DE-627)1547461748 Gleich, Florian 2013 01 DE-16-250 06 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 06 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 06 s pos_3 2013 01 DE-16-250 07 p (DE-627)148007991X Okun, Jürgen G. 2013 01 DE-16-250 07 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 07 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 07 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 07 s pos_4 2013 01 DE-16-250 08 p (DE-627)1436198674 Hoffmann, Georg F. 2013 01 DE-16-250 08 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 08 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 08 s pos_7 2013 01 DE-16-250 09 p (DE-627)1436198933 Kölker, Stefan 2013 01 DE-16-250 09 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 09 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 09 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 09 s pos_8 2013 01 DE-16-250 10 p (DE-627)1493265547 Posset, Roland 2013 01 DE-16-250 10 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 10 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 10 s pos_9 |
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Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. 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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. 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From genotype to phenotype early prediction of disease severity in argininosuccinic aciduria Matthias Zielonka, Sven F. Garbade, Florian Gleich, Jürgen G. Okun, Sandesh C. S. Nagamani, Andrea L. Gropman, Georg F. Hoffmann, Stefan Kölker, Roland Posset for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group |
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early prediction of disease severity in argininosuccinic aciduria |
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from genotype to phenotypeearly prediction of disease severity in argininosuccinic aciduria |
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From genotype to phenotype early prediction of disease severity in argininosuccinic aciduria |
| 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. Gesehen am 12.08.2021 |
| abstractGer |
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. Gesehen am 12.08.2021 |
| abstract_unstemmed |
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. Gesehen am 12.08.2021 |
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From genotype to phenotype |
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https://doi.org/10.1002/humu.23983 https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23983 |
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Garbade, Sven 1971- Gleich, Florian Okun, Jürgen G. 1968- Nagamani, Sandesh C. S. Gropman, Andrea L. Hoffmann, Georg F. 1957- Kölker, Stefan Posset, Roland 1986- |
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Garbade, Sven 1971- Gleich, Florian Okun, Jürgen G. 1968- Nagamani, Sandesh C. S. Gropman, Andrea L. Hoffmann, Georg F. 1957- Kölker, Stefan Posset, Roland 1986- |
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Zielonka, Matthias Garbade, S. F. Garbade, Sven Friedrich Garbade, Sven F. Garbade, Sven Gleich, Florian Okun, Jürgen Okun, Jürgen Günther Okun, J. G. Okun, Jürgen G. Hoffmann, G. F. Hoffmann, Georg-Friedrich Hoffmann, Georg Hoffmann, Georg Friedrich Hoffmann, Georg F. Koelker, Stefan Kölker, S. Kölker, Stefan Posset, Roland Robert Posset, Roland |
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Zielonka, Matthias Garbade, S. F. Garbade, Sven Friedrich Garbade, Sven F. Garbade, Sven Gleich, Florian Okun, Jürgen Okun, Jürgen Günther Okun, J. G. Okun, Jürgen G. Hoffmann, G. F. Hoffmann, Georg-Friedrich Hoffmann, Georg Hoffmann, Georg Friedrich Hoffmann, Georg F. Koelker, Stefan Kölker, S. Kölker, Stefan Posset, Roland Robert Posset, Roland |
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Zielonka, Matthias Garbade, S. F. Garbade, Sven Friedrich Garbade, Sven F. Garbade, Sven Gleich, Florian Okun, Jürgen Okun, Jürgen Günther Okun, J. G. Okun, Jürgen G. Hoffmann, G. F. Hoffmann, Georg-Friedrich Hoffmann, Georg Hoffmann, Georg Friedrich Hoffmann, Georg F. Koelker, Stefan Kölker, S. Kölker, Stefan Posset, Roland Robert Posset, Roland |
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2024-07-04T21:10:12.118Z |
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