신경학적 윌슨병의 생화학 및 유전학적 특징

Abstract

Background: Wilson disease (WD) is a disorder of copper metabolism caused by the ATPase copper transporting beta (ATP7B) deficiency. The clinical courses of patients with neurological manifestations (nWD) were suggested as surreptitiously progressive and less favorable. The aim of this study was to identify biochemical and genetic features that characterize nWD as a distinct disease subgroup. Methods: Detailed biochemical profiles and genotypic characteristics of 86 nWD and 233 hepatic (hWD) patients from 368 unrelated Korean families were analyzed. In addition, in order to establish pathogenesis of nWD, we analyzed biochemical findings and behavioral characteristics by using Atp7b-/- knock out mouse model. Results: The age at presentation and diagnosis was older in nWD than in hWD patients. At diagnosis, nWD patients also showed lower serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase, and total bilirubin levels, and prothrombin time than hWD. Kayser-Fleischer ring, liver cirrhosis, unfavorable outcome (62% vs 80%, P < 0.016), and higher serum creatinine level were more common in nWD patients. Regarding copper (Cu) metabolism, nWD patients showed lower serum ceruloplasmin (3.1 ± 2.1 vs. 4.2 ± 3.2 mg/dL, P < 0.001), Cu (26.4 ± 13.8 vs. 35.8 ± 42.4 μg/dL, P = 0.005), free Cu (17.2 ± 12.5 vs. 23.5 ± 38.2 μg/dL, P = 0.038), and 24-h urinary Cu (280.9 ± 162.9 vs. 611.1 ± 1124.2 μg/day, P < 0.001) levels. Frameshift, nonsense, or splice-site mutations in at least one allele of ATP7B were less frequent in nWD patients. Additionally, both mutations in the transduction and/or ATP hinge domain (2.4% vs. 23.1%, P = 0.006) were identified less frequently in nWD patients. There was no significant difference in locomotor performance and metabolic profiles including iron and methionine in Atp7b-/- knock out mouse model. On the other hand, copper accumulation in brain and liver was much more identified in Atp7b-/- knockout mice than in wild type mice Conclusion: The nWD patients had distinct clinical, biochemical, and genetic profiles, while there was no significant difference in locomotor performance and metabolic profiles including iron and methionine in between WT and MT mice. Further studies are required to identify the factors, with or without association with copper metabolism, underlying the neurological presentation for which treatment needs to be targeted to improve the clinical outcome of this subgroup.