TY - JOUR
T1 - Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease
AU - Ferenci, Peter
AU - Stremmel, Wolfgang
AU - Członkowska, Anna
AU - Szalay, Ferenc
AU - Viveiros, Andre
AU - Stättermayer, Albert Friedrich
AU - Bruha, Radan
AU - Houwen, Roderick
AU - Pop, Tudor
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
N1 - Funding Information:
We thank Michael Schilsky for his helpful comments, Drs. Datz Ch, Hofer H, Maieron A, Stadelbauer-Köllner V, Vogel W (Austria), Sokal E, Fevery J (Belgium), Moradpour D, Mühlhaupt B (CH), Engelmann G, Pfeil J, Caca K, Merle U, Schmidt H (Germany), Follhofer I, Nemeth D, (Hungary), Kupcova V (Slovakia), Gromadzka G, Kaszewska I, Tanaka B (Poland), Demir K (Turkey), and Sternlieb I (United States,†) for referring their patients, and Claudia Willheim for performing the genetic analysis.
Publisher Copyright:
© 2018 by the American Association for the Study of Liver Diseases.
PY - 2019/4
Y1 - 2019/4
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061442490&partnerID=8YFLogxK
U2 - 10.1002/hep.30280
DO - 10.1002/hep.30280
M3 - Article
C2 - 30232804
SN - 0270-9139
VL - 69
SP - 1464
EP - 1476
JO - Hepatology
JF - Hepatology
IS - 4
ER -