Wilson病合并妊娠

正Wilson病(WD)是一种以铜代谢障碍为特征的常染色体隐性遗传病,系人ATP7B基因突变所致,主要影响肝脏,但也能影响大脑、眼睛和肾脏。ATP7B基因位于常染色体13q14,编码细胞内铜转运P型ATP酶(Wilson ATP酶)。Wilson ATP酶在膳食铜与铜蓝蛋白的结合和胆汁酸排泄铜过程中发挥重要作用。ATP7B基因突变导致铜蓝蛋白的合成受损,影     

Wilson’s病诊疗现状与展望

<正>Wilson’s病(WD)是由ATP7B基因缺陷所致铜代谢障碍引起的以肝脏与神经等系统功能障碍为临床特征的常染色体隐性遗传疾病。1912年,Wilson医生首先介绍了一组12例以"肝豆状核变性"为特征的临床病例;1993年,ATP7B基因缺陷被认定为WD的致病基因。至今临床医师对于该病的发病机     

罕见基因型的肝豆状核变性姐妹及其家系报告

<正>肝豆状核变性（hepatolenticular degeneration, HLD）又称Wilson病，是一种由染色体13q14.3上ATP7B基因突变引起铜代谢障碍的常染色体隐性遗传疾病。目前已报道的ATP7B基因致病变异多达900余种，HLD的临床表现多种多样，最常见的包括肝脏和神经系统相关症状。本病在世界范围的患病率为1/2600～1/30 000,携带者频率约为1/90^[1-3]。虽然该病的发病率低，     

肝豆状核变性家系全基因组分析1例报告

<正>肝豆状核变性又称Wilson病,是由于铜转运蛋白相关基因ATP7B的突变或缺失而导致铜在体内蓄积而引起的疾病,遗传模式为常染色体隐性遗传^[1]。临床表现为肝脏损害、神经系统表现、肾脏损伤、出现角膜K-F环等,涉及机体多个系统和器官,以肝脏或神经系统的损伤为主要表现形式。ATP7B基因定位于人类染色体13p14.3上,具有21个外显子区域^[2]。目前已发现的有害基因突变有800余种（人类基因突变数据库www.hgmd.org）。研究表明,不同的基因突变位点与不同的临床表现相关。     

以中枢性尿崩症为首发表现的肝豆状核变性1例报告

正肝豆状核变性(hepatolenticular degeneration,HLD),又称Wilson病,是一种常染色体隐性遗传的铜代谢障碍性疾病~([1]),该病在世界范围内的发病率为1/3万～1/10万~([2]),是至今少数早期诊断及正确治疗可以得到较好疗效的遗传代谢性疾病之一。其主要发病机制为13号染色体上ATP7B基因纯合或复合杂合突变,导致其编码产物ATP7B的功能缺陷,引起血清铜蓝     

肝豆状核变性误诊1例临床特点分析

肝豆状核变性,又称为Wilson病,其主要病理特征是肝硬化和大脑基底节区的豆状核变性.本病已明确为常染色体隐性遗传的铜代谢障碍病,因位于13q14.3基因的ATP7B的基因发生突变.ATP7B编码铜转运P型三磷酸腺苷酶[1],当该酶功能缺乏或活性减弱时,肝脏排铜障碍,铜在肝脏内聚集,并进入血液而沉积于其他组织或器官,进而引起相应的临床症状如震颤、扭转痉挛、精神障碍、肝脾肿大、腹水等.因该病发病率相对较低,为1/30 000～100 000[2],临床上表现出多种多样的临床表现,故临床医师易误诊或漏诊.为了提高临床医师对肝豆状核变性的临床表现及发生过程的认识,现将2010年11月我院收治的1例曾被误诊为血吸虫性肝硬化后确诊为肝豆状核变性患者的临床特点分析如下.     

肝豆状核变性分子生物学研究进展

肝豆状核变性(Wilsondisease,WD)由Wilson于1912年首次描述,表现为铜代谢障碍所致的以基底神经节为主的中枢神经系统病变及肝脏损害,同时有肾脏受损及角膜病变。不同地区及人群的患病率不一,估计世界人群患病率为0.3/10万至3/10万[1,2],好发于青少年。我国目前尚无确切的流行病学资料。随着研究的不断深入,WD致病基因已被克隆并定位于13q14.3,基因全长约80kb,含21个外显子和20个内含子,编码一种P型铜转运ATP酶(ATP7B),参与铜跨膜转运的代谢过程,故WD基因又称ATP7B基因[3]。WD基因突变呈现遗传异质性,至今已发现了200多种突变形式,…     

Detection and analysis of the hot spots of ATP7B gene mutation in the members of a family with an adult Wilson's disease

目的 通过检测中国人Wilson病(WD)P型铜转运三磷酸腺苷酶(ATP7B)基因突变热区,对成人WD一家系成员进行早期基因诊断和突变特征分析.方法 提取该家系成员外周血基因组DNA,采用聚合酶链反应扩增ATP7B基因第8、12、13号外显子,并对扩增产物进行直接双向测序,然后应用在线BLAST软件分析.结果 Ⅰ1、Ⅰ2(先证者)、Ⅱ1和Ⅱ2第8号外显子存在Arg778Leu(2333G＞ T)错义杂合突变,且均伴有Leu770Leu( 2310C＞G)同义杂合突变;Ⅰ1、Ⅰ 2、Ⅰ3和Ⅱ1第12号外显子存在Lys952Arg(2855A＞G)错义杂合突变;所有受检者第13号外显子均未存在突变.结论 对有先证者的Wilson病家系成员应进行ATP7B基因第8、12、13号外显子检测,有助于早期发现症状前患者和携带者.     

以肝病为首发表现的Wilson病患者病理及突变位点分析

目的对以肝病为首发表现的Wilson病(Wilson’s disease,WD)患者ATP7B基因外显子进行PCR扩增并测序,研究WD患者基因突变的特点。方法研究对象包括20名无亲缘关系的正常对照者和45例WD患者,提取基因组DNA,扩增外显子的部分片段,并对扩增产物进行测序分析。结果健康对照者未见异常,WD组检测到21种突变,包括4种新发突变,其中12号外显子Lys952Arg和16号外显子Val1140Ala突变频率均为30.2%,为突变热点。肝脏病理主要表现为不同程度的肝脏损伤,48.9%有脂肪变性,所有患者均有不同程度的肝纤维化,86.7%铜染色阳性。结论我国以肝病为首发表现的WD患者ATP7B基因突变是以少数几个热点突变为主和其他广泛存在的少见突变为辅为特征。     

ATP7B基因突变致肝豆状核变性的分子机制研究进展

肝豆状核变性,即Wilson病,是一种由铜离子转运ATP酶β肽(ATPase Cu2+transporting beta polypeptide,ATP7B)基因突变导致的常染色体隐性遗传的铜代谢障碍性疾病。现归纳总结不同突变的致病机制,包括诱导突变蛋白错误定位、改变蛋白间或结构域间相互作用、调控ATP7B蛋白催化活性、改变ATP7B基因剪接方式等多个方面。临床上,系统总结了常见突变与临床表型间的关联,如p.R778L,被认为与更加严重的临床症状相关;同时,环境、饮食、生活习惯等因素的差异亦可能对患者是否发病或发病时间产生较大影响。在分子层面上对ATP7B基因突变致病机制及所致临床表征的研究进行综述,将有助于加深对肝豆状核变性发病机制的认识,并提示可针对不同的机制采用个性化的诊疗手段,以指导临床实践。     

Pathogenesis and management of Wilson disease

Hepatolenticular degeneration, commonly known as Wilson disease, is an autosomal recessive inherited disease of abnormal copper metabolism, characterized by the accumulation of copper in the body due to decreased biliary excretion of copper from hepatocytes. Wilson disease protein, ATP7B, functions in copper excretion into bile and in copper secretion to the bloodstream coupled with ceruloplasmin synthesis. Various kinds of mutations of ATP7B cause Wilson disease. Wilson disease is a rare genetic disease that can be treated pharmacologically. Recognition and prompt diagnosis are very important, because Wilson disease is fatal if left untreated. In this review, I summarize the pathogenesis and management of Wilson disease.     

Genetics of Wilson’s disease: a clinical perspective

Hepatic Wilson??s disease is often a difficult diagnosis to confirm. This review examines the current role of genetic tests for Wilson??s disease and is aimed at clinicians caring for patients with this disease. We discuss how genetic testing is carried out for Wilson??s disease, indications for these tests, and genetic counseling for the family. In contrast to the advances in diagnosis of Wilson??s disease by testing for ATP7B mutations, genotype-phenotype correlations are not yet sufficiently established. The non-Wilsonian copper overload syndromes causing cirrhosis in children are another important area for study. The review also identifies further areas for research into the genetics of Wilson??s disease in India.     

Clinical features of Wilson disease: Analysis of 10 cases

Aim: The diagnosis of Wilson disease is based on the results of several clinical and biochemical tests. This study aimed to clarify the clinical features and spectrum of Wilson disease, including severe Wilson disease. Methods: Between 1985 and 2009, 10 patients with clinical, biochemical or histological evidence of Wilson disease were either diagnosed or had a previously established diagnosis confirmed at Fukuoka University Hospital. Severe Wilson disease was defined by a serum prothrombin time ratio of more than 1.5 or serum prothrombin activity of less than 50%. The 10 Wilson disease patients were divided into two groups, one containing three non‐severe patients and the other containing seven severe patients, and the biochemical features of the patients in these two groups were compared. Results: The mean age at diagnosis was 21.5 ± 11.7 years (range, 7–39). Decreased serum ceruloplasmin, enhanced 24‐h urinary copper excretion, presence of Kayser–Fleischer rings and histological signs of chronic liver damage were confirmed in 100%, 100%, 66.7% and 100% of patients, respectively. Severe Wilson disease patients had higher levels of serum ceruloplasmin and serum copper (P < 0.05, P < 0.05, respectively) than non‐severe patients. Conclusion: In severe Wilson disease patients, the serum ceruloplasmin and serum copper levels were higher than those in non‐severe Wilson disease patients.     

Hämochromatose und Morbus Wilson

Hereditary hemochromatosis and Wilson disease are both autosomal recessively inherited metabolic diseases that can lead to liver cirrhosis. Hereditary hemochromatosis is characterized by iron overload due to elevated duodenal iron absorption, while copper overload in Wilson disease results from an impaired copper excretion into bile. Especially in hemochromatosis but also in Wilson disease, the last decade has seen extraordinary growth in our understanding of the pathophysiology of both diseases. In hemochromatosis, hepatic and extrahepatic symptoms can occur. Extrahepatic symptoms include cardiomyopathy, diabetes mellitus, arthritis, and endocrine dysfunction. In Wilson disease, hepatic and/or neuropsychiatric symptoms are typical. While genetic testing for a homozygote HFE C282Y mutation (or a compound heterozygote C282Y/H63D mutation) is very helpful in hemochromatosis, genetic analysis of the Wilson gene, ATP7B, is limited by the existence of a plethora of individual mutations. Hemochromatosis is treated effectively with phlebotomies, whereas Wilson disease is treated medically with chelators (D-penicillamine and triethylenetetramine) or zinc salts. Liver transplantation is a therapeutic option for both diseases and shows excellent long-term results in Wilson disease, but less favorable results in hemochromatosis. The prognosis of sufficiently treated disease is very good for both diseases, especially when the diagnosis is established early in the disease course.     

Pathophysiology and Clinical Features of Wilson Disease

Wilson disease is an autosomal recessive inherited disorder of copper metabolism resulting in pathological accumulation of copper in many organs and tissues. ATP7B is the gene product of the Wilson disease gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. Mutations of the gene result in impaired trafficking of copper in and through the hepatocytes. More than 200 mutations of Wilson disease gene were found, the most common ones being H1069Q (in Europe) and R778L (in Asia). Wilson disease may present under a variety of clinical conditions, commonly as liver and/or neuropsychiatric disease. The pathogenesis of hepatic and neurologic Wilson disease is a direct consequence of copper accumulation. Presence of copper causes oxidative stress resulting in cell destruction. The diagnosis of Wilson disease requires a combination of a variety of clinical symptoms, biochemical tests, and detection of gene mutations, which are the basis of a score proposed by a group of international experts. Initial treatment for symptomatic patients should include a chelating agent (penicillamine or trientine). Treatment of presymptomatic patients or maintenance therapy can also be accomplished with zinc.     

Pathology of the liver in copper overload

Copper accumulation in the liver is associated with cellular and apoptotic injury. Wilson disease is the most well-characterized disorder of disordered copper metabolism. Other less-common disorders include Indian childhood cirrhosis, endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. The histopathologic spectrum of the liver in Wilson disease is extremely variable and overlaps among the different entities, though this review will focus on the pathology of Wilson disease. The findings lack specificity, although characteristic findings are observed. Unlike other disorders of copper overload, the pathologic changes are typically sequential, ranging from little or no significant findings to cirrhosis with or without widespread hepatocellular damage. Steatosis and glycogenated nuclei are frequent. Staining of copper is an unreliable method of diagnosis of Wilson disease, whether there are minimal histologic abnormalities or chronic liver disease. Copper and copper-associated protein accumulation may also be seen in chronic biliary obstructive processes.     

血浆铜蓝蛋白在乙型肝炎不同肝功能状态的水平及意义

目的探讨肝豆状核变性、乙型肝炎不同肝功能状态时血浆铜蓝蛋白水平的差异及其临床意义。方法用终末期肝病模型(model for end-stage liver disease,MELD)评分衡量肝功能损害的严重性,采用散射比浊法检测并比较分析肝豆状核变性、慢加急性肝衰竭极期以及恢复期、慢性乙型肝炎患者的血浆铜蓝蛋白水平。结果肝豆状核变性(n=50)、慢加急性肝衰竭极期和恢复期(n=30)、慢性乙型病毒性肝炎患者(n=50)的MELD评分分别为11.1±6.5、20.4±4.2、10.9±4.9、9.6±9.8,血浆铜蓝蛋白分别为(0.065±0.036)g/L、(0.176±0.037)g/L、(0.210±0.056)g/L、(0.197±0.038)g/L;血浆铜蓝蛋白水平4组之间的两两比较存在差异(F=111.4,P<0.001),肝豆状核变性患者低于其他3组(P<0.001)。结论肝豆状核变性血浆铜蓝蛋白水平显著降低。相对于肝豆状核变性,没有肝衰竭的慢性乙型肝炎血浆铜蓝蛋白水平几乎正常。慢加急性肝衰竭极期血浆铜蓝蛋白水平仅轻度下降,随着肝功能衰竭的恢复,血浆铜蓝蛋白恢复正常。     

Copper toxicosis gene MURRl is not changed in Wilson disease patients with normal blood ceruloplasmin levels

AIM: To analyze our Wilson disease patient cohort (n = 106) for alterations in the gene coding for MURR1. METHODS: Patients with an established diagnosis of Wilson disease but normal ceruloplasmin blood levels were chosen for our study (n = 14). Patients with two known disease-causing mutations in the ATP7B gene were not included. The three exons of the human MURR1 gene were sequenced after amplification of the genomic DNA by polymerase chain reaction. RESULTS: Our study did not reveal any mutations leading to an amino acid change in the MURR1 sequence of Wilson disease patients. A polymorphism at 472 bp of the coding sequence could be confirmed. CONCLUSION: The MURR1 gene plays no role in the pathogenesis of Wilson disease patients with normal serum ceruloplasmin levels.     

Copper toxicosis gene MURR1 is not changed in Wilson disease patients with normal blood ceruloplasmin levels

AIM: To analyze our Wilson disease patient cohort (n=106) for alterations in the gene coding for MURR1. METHODS: Patients with an established diagnosis of Wilson disease but normal ceruloplasmin blood levels were chosen for our study (n = 14). Patients with two known disease-causing mutations in the ATP7B gene were not included. The three exons of the human MURR1 gene were sequenced after amplification of the genomic DNA by polymerase chain reaction. RESULTS: Our study did not reveal any mutations leading to an amino acid change in the MURR1 sequence of Wilson disease patients. A polymorphism at 472 bp of the coding sequence could be confirmed. CONCLUSION: The MURR1 gene plays no role in the pathogenesis of Wilson disease patients with normal serum ceruloplasmin levels.     

Diagnosis and phenotypic classification of Wilson disease1

Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non‐neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) ( 1 , 2 ). The Wilson disease gene ATP7B encodes a P‐type ATPase. More than 200 disease causing mutations of this gene have been described so far ( 3 ). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian ( 4 - 6 ) or R778L in Japanese ( 7 ), Chinese and Korean patients). Studies of phenotype‐genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16–18, 2001) ² 2This meeting was organized under the auspices of the European Association for the Study of the Liver (EASL) and was financially supported by the European Commission (High‐level Scientific Conference No. HPCF‐CT‐2000‐00327) and the Austrian Society of Gastroenterology and Hepatology (O¨GGH). . After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.