DNA多态性在肝豆状核变性症状前诊断中的应用

为探寻肝豆状核变性早期确诊的方法，应用ＤＮＡ多态性对中国北方２０个ＷＤ家系中２０名表型正常的先证者同胞进行了症状前诊断。结果：１人被确诊为症状前患者，８人为正常个体，７人为杂合子，４人可能是正常个体，也可能是杂合子，２人可能是症状前患者，也可能是杂合子，只有１人无法分析，临床诊断率为８６．９％，为肝豆状核变性先证者同胞提供了可靠的症状前诊断方法。     

Hypercalciuria and nephrolithiasis as a presenting sign in Wilson disease

A 9-year-old boy presented with recurrent episodes of renal colic. One year later Wilson disease was diagnosed. Evaluation of liver function and assessment of serum copper, caeruloplasmin concentration and urinary copper excretion in any child presenting with nephrolithiasis is suggested.     

Direct diagnosis of Wilson disease by molecular genetics

In 3 children with chronic liver disease, although multiple studies of copper metabolism were normal, which made the diagnosis of Wilson disease unlikely, analysis of ATP7B gene showed disease causing mutations in all. Molecular diagnosis should be considered in children with enigmatic liver disease, especially those with features of nonalcoholic fatty liver disease.     

暴发性肝衰竭型肝豆状核变性2 例报告并文献复习

目的探讨儿童暴发性肝衰竭型肝豆状核变性的临床特点,早期诊断及治疗。方法回顾2例暴发性肝衰竭型肝豆状核变性患儿的临床资料,并复习相关文献。结果 2例患儿均为女性,分别为5岁和8岁,临床表现为急性黄疸、血红蛋白尿、肝衰竭、肝性脑病、肾衰竭、心肌损伤、脏器出血,肝大,裂隙灯下K-F环阳性,符合肝豆状核变性诊断。应用DNA序列分析检测ATP7B基因外显子区域,2例患儿分别为p.P992L和p.A1063V复合杂合突变、2764del9缺失突变。结论儿童急性肝损伤应警惕暴发性肝衰竭型肝豆状核变性。     

肝豆状核变性的产前诊断:附3例家系报告

目的 筛查和确定肝豆状核变性（Wilson disease,WD）家系成员中的致病基因携带者与正常者, 为进一步行产前诊断或产前遗传学诊断提供信息。方法 采用外周血及羊水细胞基因组DNA抽提、PCR-RFLP、测序、微卫星等方法对WD患者进行ATP7B基因最常见突变点检测和3例产前诊断。结果 22个多子女WD家系,共生育子女47名,其中有28例患者,9例因患或高度疑似WD已故,10例表型正常。3个家系产前诊断2例杂合型,1例正常（另外1例孕5月待产）。结论 对有先证者的肝豆状核变性的家系进行普查有助于降低发病率。产前诊断有助于WD患者以及携带者的优生优育。     

P型ATP酶阻滞剂和激动剂对肝豆状核变性成纤维细胞胞浆铜的影响

探讨P型ATP酶阻滞剂、激动剂对肝豆状核变性患儿离体培养皮肤成纤维细胞胞浆铜含量的影响。方法采用高浓度铜及P型AFP酶阻滞剂（矾酸钠）、激动剂（长春新碱）孵育细胞，分析孵育6、12、24小时后，肝豆状核变性患儿、杂合子及正常儿童成纤维细胞胞浆中铜含量的变化。结果铜及长春新碱孵育后，患儿成纤维细胞胞浆钢水平在各时点均高于杂合子及正常儿童。铜及矾酸钠孵育后，患儿、杂合子及正常儿童胞浆铜含量在各时点均明显少于其他条件孵育后。结论患儿钢转运P型ATP酶对P型ATP酶阻滞剂的敏感性与杂合子及正常儿童相同，对激动剂的敏感性异常。P型ATP酶能减少患儿成纤维细胞对铜的摄取，在肝豆状核变性的治疗方面有一定的提示意义。     

Early and severe neurological features in a Wilson disease patient compound heterozygous for two frameshift mutations

We describe a patient with Wilson disease who presented at 11 years of age with neurological symptoms and subsequent rapid progression of neurological impairment but absent hepatic manifestations. Molecular analysis showed compound heterozygosity for two frameshift mutations, 2299insC and 214delAT, which most likely result in an absent or inactive protein product. Mutation-phenotypic analysis indicates that this genotype does not explain the severe phenotype, suggesting the presence of modifying factors. Conclusion Wilson disease may present even in childhood or adolescence with neurological abnormalities in the absence of hepatic manifestations. Received: 22 October 1996 / Accepted in revised form: 31 July 1997     

Severely decompensated abdominal Wilson disease treated with peritoneal dialysis: A case report

A 12-year-old girl with severely decompensated abdominal Wilson disease was treated with abdominal dialysis in order to accelerate the excretion of chelated copper. Dialysate without human serum albumin or D-penicillamine was used and was able to accelerate the excretion of chelated copper, with an increment of 5.5–19.7% compared with urinary excretion only.     

Oral zinc sulphate as primary therapeutic intervention in a child with Wilson disease

An 8-year-old boy with an hepatic form of Wilson disease was treated with oral zinc sulphate as the primary and sole therapy. After 4 months, liver function had dramatically improved, and the parameters characterizing copper metabolism had also normalized.Abbreviations d-pen d-penicillamine - IU international units - SCp serum ceruloplasmin - SD standard deviation - SGGT serum gamma-glutamyltransferase - SGOT serum glutamic-oxalic transaminase - SGPT serum glutamic-pyruvic transaminase     

Wilson病ATP7B基因Arg778Leu突变与临床表型之相关性探讨

目的了解Ｗｉｌｓｏｎ病ＡＴＰ７Ｂ基因的突变与临床表现型的相关性。方法采用ＰＣＲ、ＭｓｐＩ酶消化和ＤＮＡ测序等技术对来自５１个家庭的５４例Ｗｉｌｓｏｎ病患者进行ＡＴＰ７Ｂ基因外显子８Ａｒｇ７７８Ｌｅｕ的检测。结果５４例Ｗｉｌｓｏｎ病患者中３６例存在Ａｒｇ７７８Ｌｅｕ（ＣＧＧ→ＣＴＧ）基因突变,１５例为纯合型,２１例为杂合型,Ａｒｇ７７８Ｌｅｕ等位基因突变频率为４７２％;４６例伴肝损害的患者中３３例存在ＡＴＰ７Ｂ基因外显子８的Ａｒｇ７７８Ｌｅｕ突变;３６例Ａｒｇ７７８Ｌｅｕ突变者中３４例同时伴有Ｌｅｕ７７０Ｌｅｕ多态性。结论Ａｒｇ７７８Ｌｅｕ突变类型是中国人Ｗｉｌｓｏｎ病的高频率突变点（４７２％）;Ａｒｇ７７８Ｌｅｕ突变基因型多数与肝损害临床型相关。     

小儿肝豆状核变性误诊病例分析及治疗观察

目的分析小儿肝豆状核变性临床误诊的原因以及因误诊而对治疗效果的影响. 方法回顾分析初次住院的患儿,分为临床误诊、诊断不明和近期确诊三组,并对各组误诊误治有关资料进行统计学分析. 结果 363例中217例入院前被长期误诊(59.8%),52例长期诊断不明(14.3%),仅94例 (25.9%)能在首发症状出现3个月内获得正确诊断.被长期误诊的217例中误诊病名多达50 余种,最常见的依次为各种类型肝炎、肝硬化和(或)腹水、脾肿大、脾功能亢进、关节炎、肾炎及脑炎(或脑病)等, 共347例次.治疗前后三组间的严重程度及治疗效果对比有显著差异(P<0.01). 结论本病易被长期误诊或诊断不明,早期治疗对预后至关重要.建议对具有上述易被误诊疾病症状的患儿常规行角膜K-F环及铜代谢检查,以免误诊误治.     

青霉胺与锌盐联合治疗肝豆状核变性的随访研究

目的：探讨青霉胺与锌盐联合治疗肝豆状核变性的疗效。方法：采用联合治疗方案,青霉胺每日用量10-30mg/kg,锌盐按元素锌每次22.5mg,每日3次服用。患儿随访以来院和（或）通信及电话随诊的方式进行。结果：本组21例治疗前均有慢性肝病,13例（62％）治疗有效,5例（24％）死亡,3例（14％）失访。5例死亡者中,3例于治疗开始的40d内死亡,1例自行停药后死亡,1例青霉胺剂量不足。治疗前12例有神经症状,治疗后神经症状全部消失或仅好转者11例,失访1例。以肾小管酸中毒并发佝偻病骨骼改变为主要表现者1例,治疗后好转。治疗前7例有血尿者中,6例随访尿常规,1例正常,1例好转,4例无变化。本组除1例出现青霉胺过敏反应,3例外周血白细胞和血小板下降,未见其他毒副作用。结论：青霉胺与锌盐联合治疗肝豆状核变性是有效的安全的。     

Analysis of seven pedigrees of childhood Wilson's disease characterized by abdominal symptoms

In a survey of childhood Wilson's disease (WD) characterized by abdominal symptoms, three patients with high levels of immunologically detectable ceruloplasmin (CP) in serum were found. These three cases were compared with typical cases of WD in which serum CP level was low. In order to clarify the cause of WD, serum CP levels were quantified by two methods, an immunological protein assay and an oxidase activity assay. Using the results of these two assays, WD cases were classified into three groups on the basis of CP content; the first group consisted of patients with low enzyme activity and low CP protein content, the second group consisted of patients with low enzyme activity and normal CP protein content, and the third group, those patients with normal enzyme activity and normal CP protein content. No significant difference in symptoms was observed between these three groups. Since relatively high levels of CP were detected in some WD patients, genetic variation in CP in WD patients was examined by restriction enzyme fragment length polymorphism analysis using CP cDNA. However, no large deletion in the CP gene was detected. Using four types of gene probes for chromosome 13 known to be related to WD, the DNA of WD patients was examined in a similar fashion, but no significant difference was observed between the groups.     

与ATP7B基因紧密连锁的微卫星DNA单体型在汉族Wilson病的多态性分析

目的：了解与ATP7B基因紧密连锁的微卫星DNA(D13S314,D13S301和D13S316)单体型在正常人、Wilson病(WD)患者及其杂合子的分布特点及意义。方法：采用荧光标记3个短串联重复标记(D13S314,D13S301和D13S316),测序定位和Genotype TM 软件技术分析71例WD患者和123位父母的单体型。结果：在D13S314,D13S301和D13S316位点分析中得到71例WD患者和123位携带者及54例正常个体等位基因片段;片段大小分别为134～157 bp,128～156 bp 和136～154 bp;获得等位基因数分别为19,20和15个;3个位点的杂合率分别是 0.79,0.82 和 0.23。D13S314,D13S301和D13S316位点的等位基因分布在WD患者和正常人群之间明显不同,其中D13S314和D13S301位点显示各有9个等位基因片段存在明显差异(P<0.05),D13S316位点显示有4个等位基因片段存在明显差异(P<0.01);显示的81种单体型中以 12-6-5,15-10-5,6-10-5和6-14-5最多见,分别占 5.2%,4.5%,4.5% 和 3.7%,其次为12-8-5,12-9-5和6-16-5,各占 3.0%,13-10-8,6-13-5,6-14-13和6-9-5各占 2.2%。结论：单体型的类型较多可能和基因突变的类型多样化相关,D13S314-D13S301-D13S316的单体型分析对WD的诊断,尤其是症状前或产前诊断都有重要的意义,是有效及可行的方法之一。     

D13S301标记在Wilson病诊断的应用

肝豆状核变性病（Wilson disease,WD)是由于P型ATP7B酶缺陷引起的常染色体隐性遗传性疾病。分子生物学方法有助于鉴别WD患者家系中症状前患者和杂合子。此研究对62例WD患者及家属进行了微卫星D13S301位点分析和血清铜氧化酶活性测定。结果显示：62例患者中，10例（16%）和患者父母（92名）中41例（45%）的血清铜氧化酶活性在（0.1-0.3)OD之间，经D13S301位点分析，在有同胞的17个WD家系中，3例同胞为WD患者（带型与先症者相同），6例为杂合子（带型来自父母一方）。7例为正常人，1例未检测，提示对WD病患者家属进行微卫星D13S301位点分析有助于患者家庭成员的鉴别诊断。     

两种剂量青霉胺治疗肝豆状核变性的临床观察

目的     

磁共振成像在儿童肝豆状核变性临床各期中的变化

目的了解儿童肝豆状核变性(hepatolenticulardegeneration,HLD)临床各期中的磁共振成像(MRI)表现,以评价MRI在肝豆状核变性疗效及预后判断中的意义.方法对临床确诊为HLD的30例未治和初治患者及27例随访患者应用荷兰Philips0.5T超导MRI系统进行脑及肝常规序列扫描,并结合临床资料综合分析.结果57例患者中37例(64.9%)MBI显示脑和(或)肝异常信号,18例(31.6%)脑和肝同时受累.脑部异常者,基底节是最常见的受累部位,其次是丘脑,多表现为双侧对称性T2W高信号或(和)T1W低信号.肝脏异常者,表现为多发性弥漫性圆型T1W高信号,T2W低信号.未治及初治患者首次MRI异常率(脑、肝)明显高于随访患者(x2=12.5,P＜0.01),疗程与MRI异常率成反比.28例正规治疗患者(19例的随访患者及9例初治患者)的随访MRI异常率与治疗前病程(均在5年以内)无关,(x2=2.44,P＞0.05).未治、短程或不规则治疗与MRI异常明显相关.多数病灶经合理治疗后可随临床好转而逐渐消失或减少.治疗不当且总病程超过10年者,MRI呈脑软化、肝内巨大结节等严重异常信号,并伴有明显的临床症状和体征,复治后临床及MRI改善缓慢.结论肝豆状核变性经合理治疗,肝及脑部MRI异常信号可随临床症状改善而逐渐减少或消失.MRI有助于肝豆状核变性疗效及预后的判断.     

Fabry disease and the heart: an overview of the natural history and the effect of enzyme replacement therapy

Fabry disease is a genetic disorder caused by the deficiency of α-galactosidase A, resulting in the lysosomal accumulation of glycosphingolipids. Fabry disease may result in cardiac, cerebral and renal complications. Cardiac abnormalities in patients with Fabry disease were first described in the 1960s. In the 1990s a form of Fabry disease confined to the heart was reported; however, this variant is extremely rare and a more appropriate concept is of cardiac predominance of the disease in some patients. Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular hypertrophy, valvular dysfunction and conduction abnormalities. Recent data suggest that left ventricular mass and systolic function in patients with Fabry disease improve after 12 months of enzyme replacement therapy (ERT); however, many of the patients studied are relatively young and have mild cardiac abnormalities, suggesting that more research into the efficacy of ERT in older patients is necessary.
Conclusion: Cardiac manifestations are common in patients with Fabry disease and are not confined to a 'cardiac variant' of the disease.