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119例肝豆状核变性临床特征及致病基因ATP7B变异谱分析
Clinical characteristics and mutation spectrum of the pathogenic gene ATP7B in Chinese patients with Wilson's disease: analysis of 119 cases
- 第三军医大学学报 2018年40卷第18期 页码：1674-1681
- 作者机构：
1.400038 重庆, 陆军军医大学(第三军医大学)第一附属医院：感染科
2.400038 重庆, 陆军军医大学(第三军医大学)第一附属医院：神经内科
- 作者简介：
[ 邓国宏，E-mail:gh_deng@hotmail.com DENG Guohong, E-mail: gh_deng@hotmail.com
- 基金信息：西南医院重大技术创新计划重大项目(SWH2016ZDCX1007);；西南医院军事医学科技创新计划(SWH2017YBXM-05)
DOI：10.16016/j.1000-5404.201806104
中图分类号： R3921-33;R394.3;R596.1收稿：2018-06-15，
修回：2018-08-13，
纸质出版：2018-09-30
- 稿件说明：
移动端阅览
谭文婷, 向密, 但芸婕, 等. 119例肝豆状核变性临床特征及致病基因ATP7B变异谱分析[J]. 第三军医大学学报, 2018,40(18):1674-1681.
Wenting TAN, Mi XIANG, Yunjie DAN, et al. Clinical characteristics and mutation spectrum of the pathogenic gene ATP7B in Chinese patients with Wilson's disease: analysis of 119 cases[J]. Journal of Third Military Medical University, 2018, 40(18): 1674-1681.
谭文婷, 向密, 但芸婕, 等. 119例肝豆状核变性临床特征及致病基因ATP7B变异谱分析[J]. 第三军医大学学报, 2018,40(18):1674-1681. DOI： 10.16016/j.1000-5404.201806104.
Wenting TAN, Mi XIANG, Yunjie DAN, et al. Clinical characteristics and mutation spectrum of the pathogenic gene ATP7B in Chinese patients with Wilson's disease: analysis of 119 cases[J]. Journal of Third Military Medical University, 2018, 40(18): 1674-1681. DOI： 10.16016/j.1000-5404.201806104.
摘要
目的
2
探讨肝豆状核变性的临床特征及其致病基因ATP7B的中国人群变异谱。
方法
2
收集2011年1月-2017年10月我院肝豆状核变性119例，随访至2018年4月，分析发病年龄、临床特征、生化指标、ATP7B基因变异谱及转归，比较肝型和脑型患者的差异。
结果
2
119例患者中肝型占57.1%，脑型占27.7%，混合型占15.1%。肝型与脑型患者发病年龄差异有统计学意义(
P
=0.0036)，脑型患者全部集中在儿童青少年期起病，肝型患者各年龄段均有发病。本组患者肝损害主要表现为肝功能异常(53.8%)、肝硬化(50.4%)、肝脾肿大(47.9%)和皮肤巩膜黄染(40.3%)；神经系统损伤主要表现为口下颌肌张力障碍(31.9%)、精神症状(24.4%)和不自主运动(23.5%)；成年患者的肝硬化、腹水、不自主运动等症状显著多于未成年患者(分别为：
P
=0.005、0.008、0.026)。对诊断时效进行分析，从首次发病至明确诊断中位病程为5个月，最长82个月，52.1%的患者在起病5个月之后才得以明确诊断，肝型患者确诊所用时间显著少于脑型和混合型患者(分别为：
Z
=-2.233，
P
=0.026；
Z
=-2.424，
P
=0.015)。31例患者进行ATP7B基因检测，阳性率83.9%，最常见致病变异位点是Arg778Leu，等位频率17.4%，其次是Pro992Leu、Met769HisfsX26、Ala874Val和Ile1148Thr。生存分析结果显示，有肝硬化的肝豆状核变性患者的生存率显著低于非肝硬化患者(χ
2
=4.202，
P
=0.04)。
结论
2
婴幼儿及中老年人发病并不少见，应重视年幼和年老患者的诊治；进展为肝硬化的患者因铜沉积久、肝损伤重，其生存率显著低于非肝硬化患者，而基因检测有助于提高早期诊断率。
Abstract
Objective
2
To investigate the clinical and molecular characteristics of Wilson's disease (WD) in Chinese patients.
Methods
2
The clinical data were retrospectively collected from 119 Chinese patients with WD admitted in our hospital between January
2011 and October
2017. All the patients were followed up to April
2018
and the age of disease onset
clinical characteristics
biochemical profiles
mutation spectrum of the pathogenic gene ATP7B
and outcomes were analyzed comparatively between the patients with neurological and hepatic subtypes.
Results
2
Among the 119 patients
diagnoses of hepatic subtype of WD were established in 68 (57.1%) patients
neurological subtype in 33 (27.7%) patients and mix subtype in 18 (15.1%) patients. The age of disease onset was significantly different between the neurological and hepatic subtypes (
P
=0.003 6); the neurological subtype occurred mostly in children and adolescents (from 8 to 40 years old) while the hepatic subtype could occur in all age ranges (1 to 58 years old). The common hepatic manifestations of AD included abnormal liver functions (53.8%)
cirrhosis (50.4%)
hepatosplenomegaly (47.9%) and jaundice (75.9%)
while the neurological manifestations included oromandibular dystonia (31.9%)
psychiatric symptoms (24.4%) and involuntary movements (23.5%). Compared with the juvenile patients
the adult patients had significantly higher incidences of liver cirrhosis (
P
=0.005)
ascites (
P
=0.008) and involuntary movements (
P
=0.026). In the overall patients
the median interval between disease onset and a confirmed diagnosis was 5 months
and the longest interval could reach 6.8 years; the interval between disease onset and diagnosis was significantly shorter in patients with the hepatic subtype than in those with the neurological subtype (
Z
=-2.233
P
=0.026) and the mixed subtype (
Z
=-2.424
P
=0.015). ATP7B gene sequencing was carried out in 31 cases
and 83.9% of them were found positive for gene mutations. The common mutation sites included p.Arg778Leu (17.4%)
p.Pro992Leu (6.8%)
Met769HisfsX26 (4.8%)
p.Ala874Val (4.8%) and p.Ile1148Thr (4.8%). Survival analysis showed that WD patients with cirrhosis had a significantly lower survival rate than the non-cirrhotic patients (Chisquare=4.202
P
=0.04).
Conclusion
2
WD is not uncommon in children and middle-aged individuals
which urges an increased awareness of WD in these populations. This disease is particularly severe in cirrhotic patients
who often have a lowered survival rate compared to the non-cirrhotic patients. For a highly suspected case
ATP7B gene detection can be helpful to obtain an early diagnosis.
关键词
Keywords
references
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