Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease

Peter Ferenci, Wolfgang Stremmel, Anna Członkowska, F. Szalay, André Viveiros, Albert Friedrich Stättermayer, Radan Bruha, Roderick Houwen, Tudor Lucian Pop, Rudolf Stauber, Michael Gschwantler, Jan Pfeiffenberger, Cihan Yurdaydin, Elmar Aigner, Petra Steindl-Munda, Hans Peter Dienes, Heinz Zoller, Karl Heinz Weiss

Research output: Article

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Abstract

Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5% of children/adolescents (≤18 years) and 58% of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.

Original languageEnglish
JournalHepatology
DOIs
Publication statusPublished - jan. 1 2019

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Hepatolenticular Degeneration
Genotype
Phenotype
Liver
Mutation
Fibrosis
Neurologic Manifestations
Nervous System Diseases
Natural History
Gene Frequency
Nervous System
Liver Diseases
Siblings
Copper
Biopsy
DNA

ASJC Scopus subject areas

  • Hepatology

Cite this

Ferenci, P., Stremmel, W., Członkowska, A., Szalay, F., Viveiros, A., Stättermayer, A. F., ... Weiss, K. H. (2019). Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease. Hepatology. https://doi.org/10.1002/hep.30280

Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease. / Ferenci, Peter; Stremmel, Wolfgang; Członkowska, Anna; Szalay, F.; Viveiros, André; Stättermayer, Albert Friedrich; Bruha, Radan; Houwen, Roderick; Pop, Tudor Lucian; Stauber, Rudolf; Gschwantler, Michael; Pfeiffenberger, Jan; Yurdaydin, Cihan; Aigner, Elmar; Steindl-Munda, Petra; Dienes, Hans Peter; Zoller, Heinz; Weiss, Karl Heinz.

In: Hepatology, 01.01.2019.

Research output: Article

Ferenci, P, Stremmel, W, Członkowska, A, Szalay, F, Viveiros, A, Stättermayer, AF, Bruha, R, Houwen, R, Pop, TL, Stauber, R, Gschwantler, M, Pfeiffenberger, J, Yurdaydin, C, Aigner, E, Steindl-Munda, P, Dienes, HP, Zoller, H & Weiss, KH 2019, 'Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease', Hepatology. https://doi.org/10.1002/hep.30280
Ferenci, Peter ; Stremmel, Wolfgang ; Członkowska, Anna ; Szalay, F. ; Viveiros, André ; Stättermayer, Albert Friedrich ; Bruha, Radan ; Houwen, Roderick ; Pop, Tudor Lucian ; Stauber, Rudolf ; Gschwantler, Michael ; Pfeiffenberger, Jan ; Yurdaydin, Cihan ; Aigner, Elmar ; Steindl-Munda, Petra ; Dienes, Hans Peter ; Zoller, Heinz ; Weiss, Karl Heinz. / Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease. In: Hepatology. 2019.
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abstract = "Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7{\%}) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9{\%}), followed by P767P-fs (c.2304dupC; 2.85{\%}), P1134P-fs (c.3402delC; 2.8{\%}), and R969Q (c.2755C>T; 2.18{\%}). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5{\%} of children/adolescents (≤18 years) and 58{\%} of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.",
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AU - Ferenci, Peter

AU - Stremmel, Wolfgang

AU - Członkowska, Anna

AU - Szalay, F.

AU - Viveiros, André

AU - Stättermayer, Albert Friedrich

AU - Bruha, Radan

AU - Houwen, Roderick

AU - Pop, Tudor Lucian

AU - Stauber, Rudolf

AU - Gschwantler, Michael

AU - Pfeiffenberger, Jan

AU - Yurdaydin, Cihan

AU - Aigner, Elmar

AU - Steindl-Munda, Petra

AU - Dienes, Hans Peter

AU - Zoller, Heinz

AU - Weiss, Karl Heinz

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5% of children/adolescents (≤18 years) and 58% of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.

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