Low penetrance of frequent ATP7B mutations explains the low prevalence of Wilson disease. Lessons from real-life registries.

IF 4 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Digestive and Liver Disease Pub Date : 2024-09-24 DOI:10.1016/j.dld.2024.09.002
Pablo Alonso-Castellano, Antonio Tugores, Zoe Mariño, Antonio Olveira, Marina Berenguer, M Pilar Huarte, Jose R Fernández-Ramos, María Lázaro-Ríos, María L González-Diéguez, José M Moreno-Planas, Manuel Hernández-Guerra, Paula Fernández-Álvarez, Manuel Delgado-Blanco, José M Pinazo-Bandera, Marta Romero, Javier Ampuero, Helena Masnou-Ridaura, Alba Cachero, Víctor Vargas, Judith Gómez-Camarero, María J Morillas-Ariño, Esther Molina-Pérez, Anna Miralpeix, Luis García-Villarreal
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Abstract

Background & aims: Wilson disease (WD) is a copper metabolism disorder caused by mutations in ATP7B gene, with significant clinical variability. Several studies have analyzed the prevalence and penetrance of mutations. We evaluated both characteristics for our more frequent mutations.

Methods: Evaluation of 260 patients from the National Registry: clinical, analytical and genetic data. Estimation of homozygotes and total cases according to Hardy-Weinberg equilibrium and comparison with Registry records.

Results: The estimated number of homozygotes were higher than registered: p.Met645Arg (1949/6), p.His1069Gln (20/8), p.Leu708Pro (63/24) and p.Gly869Arg (147/0). p.Met645Arg homozygotes presented less cirrhosis at diagnosis, extrahepatic disease and Kayser-Fleischer ring (KFR) and more presymptomatic cases and diagnosis after 40 years of age than p.Leu708Pro and p.His1069Gln homozygotes. p.Met645Arg homozygotes presented more late diagnosis than p.Met645Arg compound heterozygotes. Compound heterozygotes carrying p.Met645Arg or p.Gly869Arg showed less cirrhosis at diagnosis, KFR and neurological symptoms and more hepatic and presymptomatic cases, despite clearly low ceruloplasmin levels. The estimated prevalence was 1:3.785, predicting more than 10.500 patients.

Conclusions: The widespread mutations p.Met645Arg and p.Gly869Arg show low penetrance. WD might be underdiagnosed in Spain due to less severe phenotype of the most frequent mutations, a crucial fact to avoid misdiagnosis and to offer early therapy.

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ATP7B频繁突变的低穿透性解释了威尔逊病发病率低的原因。从实际登记中汲取的教训。
背景与目的:威尔逊病(WD)是一种由 ATP7B 基因突变引起的铜代谢紊乱疾病,具有显著的临床变异性。一些研究分析了突变的发生率和渗透率。我们对较常见突变的这两个特征进行了评估:方法:评估国家登记处的 260 名患者:临床、分析和遗传数据。根据哈代-温伯格平衡法估算同卵双生者和病例总数,并与登记处的记录进行比较:结果:估计的同卵双生子数量高于登记的数量:p.Met645Arg(1949/6)、p.His1069Gln(20/8)、p.Leu708Pro(63/24)和 p.Gly869Arg(147/0)。与p.Leu708Pro和p.His1069Gln同卵杂合子相比,p.Met645Arg同卵杂合子在确诊时出现肝硬化、肝外疾病和Kayser-Fleischer环(KFR)的情况较少,而无症状病例和40岁以后确诊的病例较多。携带p.Met645Arg或p.Gly869Arg的复合杂合子在诊断时肝硬化、KFR和神经系统症状较少,而肝病和无症状病例较多,尽管ceruloplasmin水平明显较低。估计发病率为1:3.785,预测患者超过10500人:p.Met645Arg和p.Gly869Arg的广泛突变显示出低渗透性。在西班牙,由于最常见突变的表型不太严重,WD 可能诊断不足,这是避免误诊和提供早期治疗的关键所在。
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来源期刊
Digestive and Liver Disease
Digestive and Liver Disease 医学-胃肠肝病学
CiteScore
6.10
自引率
2.20%
发文量
632
审稿时长
19 days
期刊介绍: Digestive and Liver Disease is an international journal of Gastroenterology and Hepatology. It is the official journal of Italian Association for the Study of the Liver (AISF); Italian Association for the Study of the Pancreas (AISP); Italian Association for Digestive Endoscopy (SIED); Italian Association for Hospital Gastroenterologists and Digestive Endoscopists (AIGO); Italian Society of Gastroenterology (SIGE); Italian Society of Pediatric Gastroenterology and Hepatology (SIGENP) and Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD). Digestive and Liver Disease publishes papers on basic and clinical research in the field of gastroenterology and hepatology. Contributions consist of: Original Papers Correspondence to the Editor Editorials, Reviews and Special Articles Progress Reports Image of the Month Congress Proceedings Symposia and Mini-symposia.
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