肝豆状核变性的分子生物学研究进展

本文旨在对肝豆状核变性分子机制研究进展进行综述。肝豆状核变性是一种以多器官铜沉积为特征的常染色体隐性遗传疾病,未经及时治疗的患者可能出现严重的功能损害甚至死亡。目前对其致病基因表达产物ATP7B的亚细胞定位、空间结构及其各结构域的功能特点已有不少研究。研究者们探讨ATP7B各位点的突变,尤其是欧洲人群和亚洲人群各自的突变热点H1069Q和R778L,与某种特定疾病表型联系起来,但是仍未发现二者之间肯定的相关性。此外,近年来肝豆状核变性基因诊断日益普及,检测技术也不断进步,这些分子生物学水平的进展为未来肝豆状核变性的生理学研究、诊断及治疗提供了新的方向。     

Wilson disease

Wilson disease is an autosomal, recessive inherited disorder of copper metabolism, characterized by the accumulation of copper in the body due to defective biliary copper excretion of hepatocytes. Recently, novel components involved in copper metabolism, Wilson disease protein (ATP7B) and copper chaperones, have been identified. It has been demonstrated that ATP7B functions in copper secretion into the plasma, coupled with coeruloplasmin synthesis and biliary copper excretion. Genetic testing may help early diagnosis and with the beginning of therapy the development of symptoms can be prevented. Various mutations of ATP7B have been identified, the most common is in Hungary, the H1069Q mutation. Genetic screening should only be advised if there is a predominant mutation characteristic for the geographic area. The authors discuss the modern diagnostic and therapeutic possibilities of Wilson disease.     

An adolescent with hemolytic anemia and coagulation disorders as manifestation of Wilson's disease, treated with liver transplantation

A 16-year-old woman presented with anaemia, jaundice, vomiting and nosebleed. She had acute hepatic failure and haemolytic anaemia and developed acute respiratory distress syndrome (ARDS). Wilson's disease was diagnosed. After the ARDS resolved the patient underwent a successful orthotopic liver transplantation. Diagnostic combinations for Wilson's disease are ceruloplasmin < 0.2 g/l with Kayser-Fleischer rings, liver copper > 250 micrograms/g (dry weight) with Kayser-Fleischer rings, or homozygosity for a Wilson mutation on the 13th chromosome. In acute liver failure a copper excretion in 24 h-urine above 1 mg is diagnostic for Wilson's disease, while an elevated serum copper concentration makes this diagnosis very likely. Therapeutic options for Wilson's disease are chelation therapy and liver transplantation; in most cases of acute liver failure due to Wilson's disease orthotopic liver transplantation (preceded by albumin dialysis) is indicated. Nazer's index should be used in addition to the regular King's College criteria for liver transplantation indication.     

遗传性耳聋基因芯片检测的临床应用研究

目的 探讨遗传性耳聋基因芯片检测的临床意义,评价其在临床上快速检测常见遗传性耳聋基因的可行性.方法 研究对象为105例聋哑患儿,取外周血5ml,分离提取全血淋巴细胞基因组DNA,用遗传性耳聋基因芯片检测中国人中常见的4个耳聋相关基因上的9个热点突变,包括GJB2(35delG,176del16bp,235delC及299delAT),GJB3 (C538T),SLC26A4 (IVS7-2A＞G、2168A＞G)和线粒体DNA 12S rRNA (A1555G、C1494T).结果 在105例样本中,共检出17例携带致聋突变(16.19％).其中,线粒体DNA 12S rRNA 1555 A＞G异质突变1例(0.95％); GJB2基因突变7例(6.67％),包括235 del C纯合突变2例,235 del C/GJB2 299 del AT复合杂合突变2例,235 del C单杂合突变3例;SLC26A4基因突变9例(8.57％),包括IVS7-2 A＞G纯合突变1例,2168 A＞G纯合突变1例,IVS7-2 A＞G单杂合突变3例,2168 A＞G单杂合突变4例.未检出GJB3基因突变.结论 耳聋相关基因突变位点在我国也具有较高的阳性率,基因检查方法和以往传统的检测想法相比,具有准确性高、速度快、假阳性率低的优点,而且该检查方法操作简便,建议临床上进一步推广运用.     

基因芯片在耳聋基因检测中的应用

目的:通过采用基因芯片的方法在耳聋人群中进行突变基因检测,探讨该方法在耳聋预防和阻断中的应用价值。方法:采用基因芯片方法进行突变位点的检测。采集29例沈阳市聋哑人的外周血,提取基因组DNA进行PCR扩增、杂交、扫描检测,其可以同时检测4种常见的耳聋相关基因中的9个热点突变,包括GJB2(35delG,176del16,235delC及299delAT)、GJB3(538C>T)、SLC26A4(IVS7-2A>G、2168A>G)和线粒体DNA12SrRNA(1494C>T,1555A>G)。结果:在29例耳聋患者中,基因芯片方法共检测出13例携带致聋突变(44.83%)。其中,GJB2基因突变6例(20.69%),包括235delC位点杂合突变型3例,235delC位点纯合突变型1例,299del AT位点杂合突变型2例,235delC和176del 16位点复合杂合突变型1例;SLC26A4基因突变10例(34.48%),包括IVS7-2A>G位点杂合突变型7例,IVS7-2A>G位点纯合突变型2例,2168 A>G位点杂合突变型1例,其中1例为GJB2基因235delC位点,299del AT位点和SLC26A4基因2168 A>G位点复合杂合突变。结论:基因芯片作为一种基因检测的方法,在预防"聋-聋"垂直传递,降低聋儿的出生率方面起到重要的作用。     

cblC型甲基丙二酸血症合并同型半胱氨酸血症临床资料分析

目的 分析cblC型甲基丙二酸血症合并同型半胱氨酸血症(cblC病)患者的临床、生化特点及基因突变特点,以提高临床医生对该病近年来的临床特点的认识.方法 回顾性分析2014至2016年5例cblC病患者的临床资料,总结临床表现、辅助化验检查和基因突变的特点,并对其临床特征及转归情况进行总结.结果 临床特点:5例患儿起病在婴儿期,均存在有不同程度的喂养困难、精神智力运动发育落后、营养不良;血C3(丙酰肉碱)、C3/C2(丙酰肉碱与乙酰肉碱比值)、C3/C0(丙酰肉碱与游离肉碱比值)、尿甲基丙二酸、乳酸及血同型半胱氨酸均增高,C3/C2和C3/C0比C3增高更显著,3例患儿血氨轻度增高,4例头颅MRI异常.基因突变特点:共发现6个基因突变,c.104T>G(p.L35W) 、c.482G>A(p.R161Q)、c.567_568insT(p.I190fs)、656_658del(p.219_220del)及217C>T(p.R73X)各1例;c.440-441del(p.G147fs)2例;c.609G>A(p.W203X)3例,609G>A是本研究中突变最多的类型.临床转归:给予VitB12、叶酸、左旋肉碱、甜菜碱及VitB6等治疗后病情明显好转.结论 cblC病的主要临床特征包括有不同程度的喂养困难、精神智力运动发育落后、营养不良;C3/C0、C3/C2、尿甲基丙二酸和同型半胱氨酸明显增高,C3/C2和C3/C0比C3增高更显著;MMACHC基因的突变是cblC病的原因;了解cblC病在婴儿期的各种临床表现和新生儿血串联质谱检测的重要性,可使此类疾病得到及时的诊断和干预,减少此类病人的致残率.     

甲基丙二酸血症合并同型半胱氨酸血症患儿基因突变分析

目的：分析甲基丙二酸血症合并同型半胱氨酸血症患儿基因突变类型及突变频率，探讨基因型与表型之间的关系。方法：采用液相串联质谱-非衍生法对石家庄市2014年1月—2018年3月出生的113 810例新生儿进行酰基肉碱谱筛查，联合气相色谱-质谱及维生素B12负荷试验对可疑患儿进行确诊并分型，采用二代测序技术进行MMACHC、HCFC1基因突变分析，Sanger测序技术进行验证。结果：确诊的25例甲基丙二酸血症患儿中11例做了基因检测，3例为单纯型，8例为合并型。基因分析发现11种基因突变位点，已见报道8种，分别为C.666C＞A、C.482G＞A、C.656＿658delAGA、c.609G＞A、C.80A＞G、C.394C＞T、C.440＿441del和C.599G＞A；未见报道3种，分别为C.239A＞G、C.4535A＞T和C.4442C＞T。突变频率分析表明C.482G＞A较为常见，突变频率为0.25。随访发现8例合并型的患儿1例夭折，基因型为C.656＿658delAGA/C.440＿441del；3例发育迟缓，基因型分别为C.599G＞A/C.656＿658delAGA/C.4535A＞T、C.609G＞A/C.609G＞A和C.80A＞G/C.394C＞T；其余4例无异常表现。结论：8例合并型甲基丙二酸血症患儿基因突变分析发现，C.482G＞A为热点突变。基因型与临床症状及预后结合分析表明C.656＿658delAGA /C.440＿441del基因型致病性较强；基因型C.599G＞A/C.656＿658delAGA/C.4535A＞T和C.80A＞G/C.394C＞T预后较差；基因突变位点C.656＿658delAGA致病性较强，且预后差；基因突变位点C.482G＞A预后相对较好。通过新生儿串联质谱筛查可及早发现甲基丙二酸血症患儿，明确患儿基因突变情况，可为家庭再生育指导、产前诊断及预后提供依据。     

Use of zinc-copper metabolic interactions in the treatment of Wilson's disease

Zinc acetate is becoming a well-established therapy for the treatment of Wilson's disease. It is excellent for maintenance therapy and for the treatment of the presymptomatic patient. Current evidence suggests that it will also be excellent for the treatment of the pregnant patient. Zinc acts by inducing intestinal cell metallothionein, which binds copper with high affinity, blocking its absorption, and causing its excretion in the stool. We have shown that zinc, even in doses as low as 25 mg daily, negatively affects copper balance. Zinc in doses of 50 mg three times daily, with all doses separated from food, controls the abnormal positive copper balance, blocks uptake of orally administered 64Cu, controls urine and plasma copper, prevents the reaccumulation of hepatic copper, and prevents the development or progression of symptoms of copper toxicosis in Wilson's disease patients. Zinc acetate will probably be licensed in the near future for the treatment of Wilson's disease. We recommend that physicians use urine and plasma copper, and urine zinc, as primary monitoring tools. In contrast to the comfortable situation with maintenance therapy, the initial treatment of acutely ill Wilson's disease patients is not well worked out. Patients with neurological disease often get worse initially on penicillamine, and zinc acts more slowly than is ideal. We have initiated studies of tetrathiomolybdate for this purpose. Studies of biliary secretions of normal subjects suggest that they excrete regulatory (excess) copper packaged in a protease-resistant ceruloplasmin fragment. This fragment is missing in Wilson's disease bile. The gene for Wilson's disease is on chromosome 13, close to the retinoblastoma locus.(ABSTRACT TRUNCATED AT 250 WORDS)     

肝豆状核变性病患者尿中铜、锌、钙、镁火焰原子吸收光谱测定中3种前处理方法的研究

目的 研究肝豆状核变性病患者尿中铜、锌、钙、镁含量的测定方法.方法 通过对湿法消化、经硫酸酸化和直接进样法(包括钙和镁用氯化锶溶液稀释后进样)3种样品前处理方法的比较,选择合适的前处理方法,用火焰原子吸收法检测铜、锌、钙、镁含量.结果铜、锌、钙、镁直接进样与湿法消化测定的结果相关性好,测定结果之间差异均无统计学意义(P＞0.05);铜和锌直接进样与经硫酸酸化后进样测定的结果相关性好,测定结果之间差异均无统计学意义(P＞0.05);钙和镁直接进样与经硫酸酸化后进样测定的结果之间有相关性,但测定结果之间差异有统计学意义(P＜0.01).铜、锌、钙、镁直接进样法的线性范围分别为0～2.4、0～1.6、0～2.5、0～2.5 mg/L,检测限分别为0.0060、0.0027、0.0098、0.015 8mg/L,精密度测定相对标准偏差分别为0.59％～1.37％、0.39％ ～ 2.04％、0.87％ ～1.80％、1.17％ ～3.40％,加标回收率测定分别为93.0％ ～ 95.0％、90.0％～94.0％、96.0％～101.0％、96.0％ ～ 104.0％.结论直接进样法准确、灵敏、精确度高,而且简便、快速,可直接用于尿中元素含量的测定,结果满意可靠.     

A Case of Wilson's Disease in Patient with Mildly Elevated Liver Enzymes

Wilson's disease is an autosomal recessive disorder affecting copper transport; it results in the accumulation of copper in the liver, brain, and other organs. Wilson's disease is the most common inherited liver disease with more than 500 cases reported in Korea. An impairment in biliary excretion process leads to copper accumulation in the liver, which progressively damages the liver, leading to cirrhosis. Since effective treatment is available for this disease, early and correct diagnosis is very important. Here, we report a case of Wilson's disease with mildly elevated liver enzyme levels in a 29-year-old breast-feeding woman with weight loss.     

Role of copper transporters in copper homeostasis

Copper is a redox active metal that is essential for biological function. Copper is potentially toxic; thus, its homeostasis is carefully regulated through a system of protein transporters. Copper is taken up across the lumen surface of the small intestinal microvilli as cuprous ion by Ctr1. Cupric ion may also be taken up, but those processes are less well understood. Within the cell, intestinal as well as others, copper is escorted to specific compartments by metallochaperones. One, CCS, donates copper to superoxide dismutase. Another, COX17, delivers copper to additional chaperones within the mitochondria for synthesis of cytochrome c oxidase. A third chaperone, Atox1, delivers copper to the secretory pathway by docking with 2 P-type ATPases. One, ATP7A, is the protein nonfunctional in Menkes disease. This protein is required for cuproenzyme biosynthesis, and in the enterocyte it is required for copper efflux to portal blood. The second, ATP7B, predominantly expressed in liver, is required for copper metallation of ceruloplasmin and biliary copper excretion. Mutations in ATP7B lead to Wilson disease. Additional intracellular hepatic copper-binding proteins COMMD1 (copper metabolism MURR1 domain) and XIAP (X-linked inhibitor of apoptosis protein) may also be required for excretion. Other proteins involved in copper homeostasis may include metallothionein and amyloid precursor protein. Plasma protein transport of copper from the intestine to liver and in systemic circulation probably includes both albumin and alpha2-macroglobulin. Changes in the expression of copper "transporters" may be useful to monitor copper status of humans, provided a suitable cell type can be sampled.     

Interaction between airborne copper exposure and ATP7B polymorphisms on inattentiveness in scholar children

Recent research indicates that airborne copper exposure in scholar children negatively affects brain functioning. These effects are likely to be influenced by the efficiency of copper metabolism, which is partly regulated by the ATPase copper transporting beta (ATP7B) gene. We investigated whether indoor and outdoor airborne copper exposure is differentially associated with child inattentiveness depending on genetic variation within the ATP7B gene in 1645 scholar children from the BREATHE project. Outdoor (courtyard) and indoor (classroom) air pollution levels were measured during class hours in each school. Inattentiveness was assessed through a follow-up with four measurements via the Attentional Network Test (4475 observations). Linear mixed models considering repeated measures were conducted to assess genetic and exposure main and interaction effects. Two interactions were detected indicating that ATP7B-rs1061472 (P for interaction 0.016) and ATP7B-rs1801243 (P for interaction 0.003) polymorphisms modified the association between indoor copper exposure and inattentiveness. Stratified analysis by genotypes revealed that both outdoor and indoor copper exposure increased inattentiveness in rs1061472-CC and rs1801243-CC carriers. These findings suggest that the genetic background promotes the association between airborne copper exposure at school with inattentiveness in children.     

新生儿常见致聋基因突变位点的大样本筛查分析

目的 探讨新生儿常见聋病易感基因突变位点分布情况,为临床干预奠定基础.方法 采用实时荧光聚合酶链反应(PCR)技术对11121例新生儿进行常见聋病易感基因突变位点筛查,筛查位点为我国常见的3个致聋基因GJB2(c.235 del C、c.299-300 del AT)、线粒体DNA 12S rRNA(c.1494 C>T、c.1555 A>C)和SLC26A4(c.2168 A>G、c.IVS7-2 A>G)的6个突变位点;基因突变者进行测序验证及听力诊断.结果 11121例新生儿中发生耳聋基因突变者517例,其中纯合突变39例、杂合突变469例、单基因复合杂合突变2例,双基因复合杂合突变7例,阳性率4.65%.基因突变包括:GJB2突变286例(包括2例c.235 del C杂合突变复合c.299-300 del AT杂合突变);线粒体DNA 12S rRNA基因突变189例;SLC26A4基因突变35例;双基因复合杂合突变7例,男婴耳聋基因突变阳性率显著高于女婴(χ2=8.653,P<0.01).测序结果与PCR结果一致,517例基因突变新生儿中13例发生听力损伤,其中轻度6例,中度3例,极重度4例.结论 GJB2基因的c.235 del C位点突变率最高,其次为SLC26A4基因的c.IVS7-2A>G位点,线粒体DNA 12S rRNA基因的c.1494C>T位点突变极低,不属于本地区的致聋热点基因,且男女婴之间突变阳性率存在显著差异,为该地区耳聋基因筛查方向提供了重要依据.     

WD患者肝细胞中P型ATP7B酶和CP存在及相关性的研究

目的：探讨肝豆状核变性（Wilson’s disease，WD）患者肝细胞存在P型ATP7B酶（P-type ATPase7B）和铜蓝蛋白（Ceruloplasmin，CP）及两者间相关性。方法：采用细胞培养技术，体外培养9例WD患者和5例非WD脾破裂或胆囊疾病患者（对照组）的肝细胞。采用SDS-PAGE电泳及Western-blot蛋白印迹技术，测定两组细胞P型ATP7B酶含量；采用放射免疫技术，测定两组肝细胞CP含量并对照比较。结果：与对照者比较，9例WD患者均表现出不同程度P型ATP7B酶和CP含量减少，且各组肝细胞CP含量与P型ATP7B酶具有明显的相关性。结论：WD患者肝细胞内存在ATP7B基因各种形式的变异，引起程度不等的P型ATP7B酶合成减少，是导致CP合成障碍的原因。     

From gene to disease; Menkes disease: copper deficiency due to an ATP7A-gene defect

Menkes disease is an X-linked recessive disorder characterized by neurological deterioration, failure to thrive, peculiar hair and death in childhood, secondary to mutations in the ATP7A gene. The ATP7A gene encodes for a copper transporting P-type ATPase (ATP7A), which is ubiquitously expressed. A defect of the ATP7A protein leads to both a reduced transport of copper from the intestine into the circulation and into the central nervous system, as well as reduced transport of copper into the Golgi apparatus for incorporation into various copper-dependent enzymes. This results in a systemic copper deficiency as well as reduced activity of various copper-dependent enzymes. The reduced activity of these copper-dependent enzymes accounts for most of the characteristic features ofMenkes disease patients.     

Soy protein isolate enhances hepatic copper accumulation and cell damage in LEC rats

In a series of experiments, the effects of soy protein isolate (SPI), defatted soy (DFS) or SPI supplemented with L-methionine (SPIM) were examined in the Long-Evans rat with a cinnamon coat color (LEC rat), a model animal of Wilson's disease with a hereditary defect in the Atp7b gene resulting in defective copper metabolism and copper accumulation in hepatocytes. Milk casein in the control AIN-93G diet (20 g/100 g) was totally or 60% replaced by the soy products, SPI, DFS or SPIM (L-Met added to be equal to that in the control diet) beginning when rats were 6 wk old. Copper and iron concentrations in SPI and DFS were measured and the concentrations of these metals in the salt mix were adjusted so that test and the control diets had the same final concentrations. Food intake did not differ among groups. Rats were euthanized when they became moribund with jaundice. Survival time in the SPI diet group was shorter (14.0 +/- 0.8 wk) than in the control group (19.1 +/- 1.7 wk) (P < 0.001), and that in the DFS diet group was intermediate (16.0 +/- 1.7 wk). Survival time in the SPIM diet group did not differ from that of the SPI diet group. Copper concentrations in the livers of rats in the SPI and SPIM diet groups were approximately 80% higher than in rats fed the control diet. Liver iron concentrations did not differ among the groups. The results, including histological analyses, indicate that SPI enhances copper uptake into the liver cells and promotes liver cell damage in LEC rats. However, this did not occur in the livers of F344 rats with wild-type Atp7b. Recommendations to individuals suffering from Wilson's disease to avoid consuming soy protein may be warranted.     

Interactions of trace elements: clinical significance

We examined interaction of the trace element zinc with copper and lead. In sickle cell anemia, the usual situation is one of mild to moderate zinc deficiency owing to renal loss of zinc. Zinc deficiency seems to produce a mild overburden of copper and an increased ceruloplasmin level, probably by enhancing copper absorption. With zinc therapy, this process is reversed. Pharmacological doses of zinc, when administered in a way to ensure effectiveness (without food) will usually lead to copper deficiency. We have taken advantage of the copper-depleting effect of zinc to design a new therapy for Wilson's disease. Zinc, by inducing intestinal metallothionein, inhibits absorption of copper from food, and inhibits reabsorption of endogenously secreted copper, thereby producing a negative copper balance in Wilson's disease. Once we are certain that zinc blocks accumulation of copper in the liver of Wilson's disease patients, zinc therapy will be available as one approach for treating this fatal disease. The animal literature indicates that zinc protects against lead toxicity when both elements are given orally, no doubt through the intestinal metallothionein mechanism. In preliminary experiments in rats, we have not been able to show that toxicity from lead that arrives into the body through a nonoral route is affected by oral zinc supplements.     

Copper exposure induces trafficking of the menkes protein in intestinal epithelium of ATP7A transgenic mice

The final steps in the absorption and excretion of copper at the molecular level are accomplished by 2 closely related proteins that catalyze the ATP-dependent transport of copper across the plasma membrane. These proteins, ATP7A and ATP7B, are encoded by the genes affected in human genetic copper-transport disorders, namely, Menkes and Wilson diseases. We studied the effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections. Our results indicate that ATP7A is retained in the trans-Golgi network under copper-limiting conditions, but relocalized to a vesicular compartment adjacent to the basolateral membrane in intestines perfused with copper. The findings support the hypothesis that the basolateral transport of copper from the enterocyte into the portal blood may involve ATP7A pumping copper into a vesicular compartment followed by exocytosis to release the copper, rather than direct pumping of copper across the basolateral membrane.     

Dietary and genetic determinants of homocysteine levels among Mexican women of reproductive age

OBJECTIVE: To evaluate the independent and joint effects of dietary folate, vitamin B(12) consumption and methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677C>T and 1298A>C) on the circulating folate and homocysteine (Hcy) levels among Mexican women of reproductive age. DESIGN: A cross-sectional, population-based study. SUBJECTS: The first 130 healthy non-pregnant women (aged 16-34 years) who agreed to participate in a reproductive cohort in Morelos, Mexico. MAIN OUTCOME MEASUREMENTS: Dietary intakes of vitamin B(12) and folate were estimated using a semiquantitative food frequency questionnaire. MTHFR 677C>T and 1298A>C polymorphisms were ascertained using the PCR-based method. Serum levels of Hcy and folate were determined using high-performance liquid chromatography and radioimmunoassay, respectively. RESULTS: Genotype frequencies for the MTHFR 677C>T polymorphism were 21.5% (CC), 52.3% (CT) and 26.2% (TT) among Mexican women. Of the population, 22% had the MTHFR 1298AC genotype, while no individual carried the 1298CC genotype. We observed an increased level of Hcy among carriers of the 677TT genotype, compared to carriers of the 677CC genotype. The highest level of Hcy was observed among MTHFR 677TT carriers with low B(12) intake (<2.0 microg/day), which resulted with a significant interaction (P=0.01). CONCLUSION: Vitamin B(12) is an important determinant of Hcy levels in Mexico. Supplementation of folic acid with vitamin B(12) may be preferable when the MTHFR 677T variant allele is prevalent.     

Work ability assessment in a patient with Wilson's disease

Wilson's disease (WD) is a rare, progressive autosomal recessive disorder characterised by impaired transport and excessive accumulation of copper in the liver, brain, and other tissues. The disease is diagnosed based on clinical manifestations and screening tests results. Work ability assessment of patients with WD is based on the analysis of liver, kidney, neurological, and cognitive impairments, and takes into account patient's level of education.This article presents a case with a 48-year-old male patient, who was admitted for work ability assessment due to polymorphic symptoms. The patient had been working as a salesman for 28 years. A detailed interview and examination by occupational health and other medical specialists revealed that the patient had been suffering from Wilson's disease from the age of 13, and had now developed hepatic manifestations (compensated liver cirrhosis with portal hypertension), neurological manifestations (dystonia, dysarthria, muscle weakness, vertigo), and psychiatric manifestations (depression, insomnia, cognitive impairment) of the disease, including problems partially caused by long-lasting treatment with copper chelating agents (neurological and haematological manifestations). There were no ocular manifestations of Wilson's disease (Kayser-Fleischer rings or sunflower cataract).The patient was assessed as having drastically diminished general work ability, dominantly due to neurological and psychiatric impairments caused by Wilson's disease.