Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
BMC Med Genet. 2020 Jun 12;21(1):128. doi: 10.1186/s12881-020-01062-6.
Wilson disease (WD) is an Autosomal-Recessive disorder due to mutations of ATP7B gene on chromosome 13q14.3. Inadequate protein function leads to low ceruloplasmin blood levels and copper accumulation in liver, basal ganglia and chornea. Main clinical manifestations are hypertransaminasemia, tremors, dysarthria, dystonia and psychiatric symptoms. The phenotypic variability in WD is considerable and its onset can be heterogeneous: the most common type in childhood is the hepatic involvement, followed by the neurological one or others. The presence of a genotype-phenotype correlation has not yet been fully demonstrated. The phenotypic variability may be explained by the intervention of other modifier genes regulating copper metabolism in the presence of mutations ATP7B.
A streaking phenotypic variability was observed in two Sicilian sisters carrying the same genotype for ATB7B gene [c.3207C > A / c.3904-2A > G]. Although both started to present signs at age 10 years, onset was characterized by neurological signs in the first (tremors, motor incoordination, language and cognitive impairment), while liver involvement has been the only sign in the other. They started the same chelation therapy. After a 20-year follow-up the former is severely affected (MRI evidence of basal ganglia copper deposits and hyperchogenic liver, thrombocytopenia), while the latter presents only a moderate liver enlargement. In literature, the splice mutation c.3904-2A > G is also reported in Egypt population, associated with acute liver failure or chronic hepatic disease, and it could be typical of Mediterranean area, not being reported in other geographical zones.
Based on our clinical experience in Eastern Sicily, there is a considerable phenotypic variability in WD, even in the presence of an identical genotype. The mutation c.3904-2A > G could be associated with this phenotypic variability in Mediterranean population, but further studies should be conducted. This condition could be explained by the intervention of modifier genes regulating copper metabolism in the presence of defective ATP7B protein function. Further investigations on their role by Next Generation Sequencing or Whole Exome Analysis might have a profound impact on patients' management and in particular on therapy.
威尔逊病（WD）是一种常染色体隐性遗传病，由 13q14.3 染色体上的 ATP7B 基因突变引起。由于蛋白功能不足，导致铜蓝蛋白血液水平降低，铜在肝脏、基底神经节和角膜中蓄积。主要临床表现为高转氨酸血症、震颤、构音障碍、肌张力障碍和精神症状。WD 的表型变异性相当大，其发病也具有异质性：儿童期最常见的类型为肝脏受累，其次是神经受累或其他类型。基因型-表型相关性尚未得到充分证实。表型变异性可能是由于存在 ATP7B 突变时，其他调节铜代谢的修饰基因的干预所致。
两位西西里岛姐妹携带相同的 ATP7B 基因突变 [c.3207C > A / c.3904-2A > G]，表现出条纹状表型变异性。尽管两人均在 10 岁时开始出现症状，但首发症状在前者为神经系统症状（震颤、运动不协调、语言和认知障碍），而后者仅为肝脏受累。她们开始接受相同的螯合疗法。经过 20 年的随访，前者病情严重（基底神经节铜沉积和肝脏高回声的 MRI 证据、血小板减少），而后者仅表现为中度肝肿大。文献中还报道了埃及人群中剪接突变 c.3904-2A > G，与急性肝衰竭或慢性肝病相关，可能是地中海地区的典型特征，在其他地理区域并未报道。
基于我们在西西里岛东部的临床经验，即使存在相同的基因型，WD 也存在相当大的表型变异性。突变 c.3904-2A > G 可能与地中海人群的这种表型变异性相关，但还需要进一步研究。这种情况可能是由于存在缺陷的 ATP7B 蛋白功能时，调节铜代谢的修饰基因的干预所致。通过下一代测序或全外显子分析进一步研究其作用可能对患者的管理，特别是治疗产生深远影响。
