Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain.
Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain.
J Gastroenterol. 2021 Jan;56(1):78-89. doi: 10.1007/s00535-020-01745-0. Epub 2020 Nov 7.
Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening.
A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value.
Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 μg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear.
Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.
威尔逊病是一种常染色体隐性遗传的铜代谢紊乱疾病，由 ATP7B 基因突变引起。早期诊断对于预防疾病进展至关重要，因为早期实施治疗措施可完全预防其症状。由于人群遗传学数据预测该病的患病率高于最初预期，因此定义基本的诊断工具以进行人群筛查非常重要。
选择了一个高度遗传同质的 70 例患者队列，他们来自 50 个无关家庭，作为分析所有临床、生化和遗传特征的框架，以确定我们人群中的疾病，估计患病率为 1/12369，并确定最有用的达到诊断价值的特征。
血清铜蓝蛋白低于 11.5mg/dL 和铜低于 60μg/mL，是无症状个体疾病的最佳分析预测指标，而铜尿或肝铜测定的预测价值较低。在可进行完整检测的 65 例患者中，基因分析均得出明确诊断。其中 48 例为至少一个 p.Leu708Pro 突变等位基因的携带者，24 例为纯合子。9 例患者携带启动子缺失突变，表明需要对 ATP7B 基因编码区以外的区域进行扩展测序。所有突变均导致肝脏损伤，且随着诊断延迟，肝脏损伤的严重程度增加，同时出现神经症状。
血清铜蓝蛋白测定后进行基因筛查可降低成本，并有利于优先选择非侵入性程序以获得明确诊断，甚至对于无症状病例也是如此。
