Copper incorporation into ceruloplasmin is regulated by Niemann–Pick C1 protein

Aim: Wilson disease is a genetic disorder of copper metabolism characterized by impaired biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. Our previous study showed the late endosome localization of ATP7B and described the copper transport pathway from the late endosome to trans‐Golgi network (TGN). However, the cellular localization of ATP7B and copper metabolism in hepatocytes remains controversial. The present study was performed to evaluate the role of Niemann–Pick type C (NPC) gene product NPC1 on intracellular copper transport in hepatocytes. Methods: We induced the NPC phenotype using U18666A to modulate the vesicle traffic from the late endosome to TGN. Then, we examined the effect of NPC1 overexpression on the localization of ATP7B and secretion of holo‐Cp, a copper‐binding mature form of Cp. Results: Overexpression of NPC1 increased holo‐Cp secretion to culture medium of U18666A‐treated cells, but did not affect the secretion of albumin. Manipulation of NPC1 function affected the localization of ATP7B and late endosome markers, but did not change the localization of a TGN marker. ATP7B co‐localized with the late endosome markers, but not with the TGN marker. Conclusion: These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via an NPC1‐dependent pathway and incorporated into Cp.     

Potential of the international scoring system for the diagnosis of Wilson disease to differentiate Japanese patients who need anti‐copper treatment

Aim: Patients with Wilson disease show complex clinical features. Accurate diagnosis at the initial clinical manifestation is important for patients to receive effective treatment with anti‐copper agents. In this study, we assessed whether the international scoring system for the diagnosis of Wilson disease is a reliable tool for screening Japanese patients with primary copper toxicosis requiring anti‐copper treatment. Methods: Twenty‐three Japanese patients suspected of Wilson disease were enrolled in this study. We performed long‐range polymerase chain reaction to detect ATP7B mutations in this series. Finally, we retrospectively assessed the reliability of using a diagnostic score of 4 or more points as the cut‐off for this scoring system. Results: Ten patients were homozygous or compound heterozygous for ATP7B mutations including a novel mutation of 3837 bp deletion including 3 exons. The mutation would have been missed by the traditional analysis. Six patients were heterozygous for ATP7B mutations. Three of these six patients had additional diagnostic points. The other three patients were diagnosed as carriers of a mutant gene based on their low scores. One of the seven patients free from ATP7B mutation was affected by copper toxicosis. Though the score was 3 points based on increased urinary copper and copper‐positive cirrhosis, anti‐copper treatment promptly improved liver failure, which was likely due to idiopathic copper toxicosis. Conclusion: The international scoring system for diagnosis of Wilson disease is a fairly reliable tool for screening Japanese patients who need anti‐copper treatment. Caution is needed for patients with possible idiopathic copper toxicosis because the maximal score is 4 points.     

A mutation of the Wilson disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates

BACKGROUND & AIMS: Wilson disease is a genetic disorder characterized by the accumulation of copper in the body as a result of a defect of copper excretion from hepatocytes. The intracellular localization of the Wilson disease gene product, ATP7B, was recently identified as the late endosomes. Various mutations have been documented in patients with Wilson disease. The clinical manifestations vary greatly among the patients; however, there is little information on the genotype-phenotype correlation. METHODS: We investigated the distribution of a common ATP7B mutant His1069Gln and a mutant Asp1270Ser by expressing the mutants tagged with green fluorescent protein in Huh7 and HEK293 cells. Intracellular organelles were visualized by fluorescence microscopy. RESULTS: Although the wild-type ATP7B and Asp1270Ser mutant localized in the late endosomes, His1069Gln mutant did not locate in the late endosomes and was degraded by the proteasomes in the cytoplasm. Furthermore, His1069Gln formed aggresomes composed of the degradates and intermediate filaments at the microtubule-organizing center. These aggresomes were similar to Mallory bodies on electron microscopy. CONCLUSIONS: The different protein properties of ATP7B mutants may explain the variety of clinical spectrums in patients with Wilson disease.     

The interactions between iron and copper in genetic iron overload syndromes and primary copper toxicoses in Japan

Iron and copper are trace elements essential for health, and iron metabolism is tightly regulated by cuproproteins. Clarification of the interactions between iron and copper may provide a better understanding of the pathophysiology and treatment strategy for hemochromatosis, Wilson disease, and related disorders. The hepcidin/ferroportin system was used to classify genetic iron overload syndromes in Japan, and ceruloplasmin and ATP7B were introduced for subtyping Wilson disease into the severe hepatic and classical forms. Interactions between iron and copper were reviewed in these genetic diseases. Iron overload syndromes were classified into pre‐hepatic iron loading anemia and aceruloplasminemia, hepatic hemochromatosis, and post‐hepatic ferroportin disease. The ATP7B‐classical form with hypoceruloplasminemia has primary hepatopathy and late extra‐hepatic complications, while the severe hepatic form is free from ATP7B mutation and hypoceruloplasminemia, and silently progresses to liver failure. A large amount of iron and trace copper co‐exist in hepatocellular dense bodies of all iron overload syndromes. Cuproprotein induction to stabilize excess iron should be differentiated from copper retention in Wilson disease. The classical form of Wilson disease associated with suppressed hepacidin25 secretion may be double‐loaded with copper and iron, and transformed to an iron disease after long‐term copper chelation. Iron disease may not be complicated with the severe hepatic form with normal ferroxidase activity. Hepatocellular dense bodies of iron overload syndromes may be loaded with a large amount of iron and trace copper, while the classical Wilson disease may be double‐loaded with copper and iron.     

Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease

Background

Wilson disease (WD) is an autosomal recessive disorder. The WD gene, ATP7B, encodes a copper-transporting ATPase involved in the transport of copper into the plasma protein ceruloplasmin and in excretion of copper from the liver. ATP7B mutations cause copper to accumulate in the liver and brain.

Objectives

We examined the ATP7B mutation spectrum in Wilson disease patients in Iran.

Patients and Methods

Genomic DNA was extracted from patients with Wilson disease. The entire coding region of the ATP7B gene was amplified using PCR and analyzed using direct sequencing.

Results

We identified five novel mutations in 5 Iranian patients with Wilson disease. The first was a transversion, c.2363C > T, which led to an amino acid change from threonine to isoleucine. The second mutation was a deletion, c.2532delA (Val845Ser), which occurred in exon 10. The third mutation was a transition mutation, c.2311C > G (Leu770Leu), which occurred in the TM4 domain of the ATP7B protein. The fourth mutation was a transversion, (c.3061G > A) (Lys1020Lys), in exon 14. Lastly, we identified a transversion, c.3206C > A (His1069Asn) in exon 14 which led to a change in function of the ATP loop domain of the ATP7B protein. The H1069Q mutation was identified as the most common mutation in our study population.

Conclusions

Based on our findings, the H1069Q may be a biomarker that can be used in a rapid detection assay for diagnosing WD patients     

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.     

Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats: An animal model for Wilson disease

Objective. Wilson disease is a copper storage disorder caused by mutations in the ATP7B gene leading to liver cirrhosis. It has previously been shown that lentiviral vectors can govern an efficient delivery and stable expression of a transgene. The aim of this pilot study was to prove the principle of a lentiviral gene transfer in the Long-Evans cinnamon (LEC) rat, an animal model of Wilson disease. Material and methods. LEC rats were treated either by systemic application of lentiviral vectors or by intrasplenic transplantation of LEC-rat hepatocytes lentivirally transduced with ATP7B. The ATP7B gene expression was analyzed by RT-PCR and immunofluorescence analysis. The therapeutic effect was assessed by analysis of liver histology, serum ceruloplasmin oxidase activity, and liver copper content. Results, Hepatic expression of the transgene was detected at different time-points post-treatment and lasted for up to 24 weeks (end of experiment). Liver copper levels were lowered in all treatment groups compared to untreated LEC rats. Twenty-four weeks after treatment, the area of the examined liver-tissue sections occupied by fibrosis was 48.3–57.9% in untreated LEC rats and 10.7–19.8% in rats treated with cell therapy. In systemically treated rats, only small fibrous septa could be observed. Conclusions. These data prove for the first time that lentiviral ATP7B gene transfer is feasible in Wilson disease. In our pilot study the systemic approach was more promising in ameliorating disease progression than the transplantation of lentivirally transduced hepatocytes.     

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.     

Clinical molecular diagnosis of Wilson disease

Wilson disease is an autosomal recessive disorder of copper transport characterized by toxic accumulation of copper in the liver, brain, and other organs. It is lethal if untreated, but effective treatment is available. The broad spectrum of clinical manifestations, including hepatic and neuropsychiatric symptoms, can present over a large age range, contributing to difficulty in recognition of this disease. The diagnosis has traditionally rested on measurements of ceruloplasmin and copper in urine and liver, but it remains a challenge due to ambiguous biochemical results that can overlap with healthy carriers. Although hepatic copper concentration has been the gold standard for diagnosis, direct sequencing of the ATP7B gene is sensitive, specific, and can obviate the need for invasive liver biopsy. In this article, the authors review the sensitivity, limitations, and pitfalls of ATP7B sequencing in the diagnosis of Wilson disease. ATP7B sequencing should be standard practice in the diagnosis of Wilson disease.     

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.     

Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism

Summary Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient’s fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI–III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.     

Advances in the molecular diagnosis of Wilson's disease

Wilson?s disease is an autosomal recessive disorder characterized by toxic copper accumulation in the liver and subsequently in the brain and other organs. Clinical diagnosis is based on the detection of low serum ceruloplasmin concentrations, increased urinary copper excretion, Kayser-Fleisher rings in the cornea, and/or high copper levels in hepatic tissue. Diagnosis can be difficult when the typical symptoms of the disease are absent, a situation that can lead to a lack of prophylactic therapy in these patients. Molecular study has improved the diagnosis of this disease, even in doubtful cases. The present article outlines the various techniques applied in the molecular diagnosis of Wilson's disease and the most commonly described mutations. Currently, direct sequencing of the ATP7B gene is the most widely used method to detect mutations. Molecular study and identification of ATP7B gene mutations allow diagnosis of individuals with Wilson's disease and their relatives, as well as the possibility of genetic counselling and prenatal and preimplantation genetic diagnosis.     

Wilson Disease

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism, resulting in pathological accumulation of copper in many organs and tissues. The hallmarks of the disease are the presence of liver disease, neurologic symptoms, and Kayser–Fleischer corneal rings. The leading neurologic symptoms in WD are dysathria, dyspraxia, ataxia, and Parkinsonian-like extrapyramidal signs. Changes in the basal ganglia in brain magnetic resonance imaging (MRI) are characteristic features of the disease. In presence of liver cirrhosis, some features may resemble hepatic encephalopathy. Symptoms and MRI abnormalities may be fully reversible on treatment with zinc or copper chelators. Improvement can be monitored by serial recording of brain-stem-evoked responses. The basic defect is an impaired traficking of copper in hepatocytes. ATP7B is the gene product of the WD 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. While about 40% of patients preset with neurologic symptoms, little is known about the role of copper and ATP7B in the central nervous system. In some brain areas, like in the pineal gland, ATP7B is expressed and functionally active. Increasing evidence supports an important role for metals in neurobiology. Two proteins related to neurodegeneration are copper-binding proteins (1) the amyloid precursor protein (APP), a protein related to Alzheimer's disease, and (2) the Prion protein, related to Creutzfeldt–Jakob disease. A major source of free-radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. APP is a major regulator of neuronal copper homeostasis and has a copper-binding domain (CuBD). The surface location of this site, structural homology of CuBD to copper chaperones, and the role of APP in neuronal copper homeostasis are consistent with the CuBD acting as a neuronal metallotransporter. There are several copper-containing enzymes in the brain, like dopamine beta hydroxylase or Cu/Zn superoxide dismutase (SOD1). Their function may be altered because of copper overload. WD appears to be associated with a dopaminergic deficit. Mutations in the SOD1gene cause familial amyotrophic lateral sclerosis. Survival of transgenic mice with a mutant SOD1 which fails to incorporate Cu(²⁺) in its active site was improved by copper depletion. Wilson disease (WD) is an autosomal recessive inherited disorder in which copper pathologically accumulates primarily within the liver and subsequently in the neurologic system and many other organs and tissues. Presence of liver disease, neurologic symptoms, and Kayser–Fleischer corneal rings are the hallmarks of the disease.     

Whom and how to screen for Wilson disease

Wilson disease is a genetic disorder of hepatic copper excretion leading to copper accumulation in various tissues. The disease expression is highly variable, ranging from totally asymptomatic subjects to patients with severe liver disease or movement disorders. Thus, it is difficult to define in which patient Wilson disease has to be considered as diagnosis. The suspicion should be high in patients presenting with extrapyramidal disorders or with liver diseases or of unknown origin. For diagnosis, in many patients a combination of tests reflecting disturbed copper metabolism may be needed. Not a single test is per se specific and, thus, a range of tests has to be applied (presence or absence of Kayser–Fleischer rings or neurologic symptoms, serum ceruloplasmin, liver copper content, urinary copper excretion, mutation analysis; rated –1 to 4 depending on the test) and clinical symptoms. A diagnostic sum score of ≥4 confirms the diagnosis.     

ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion

BACKGROUND & AIMS: The Wilson protein (ATP7B) regulates levels of systemic copper by excreting excess copper into bile. It is not clear whether ATP7B translocates excess intrahepatic copper directly across the canalicular membrane or sequesters this copper into exocytic vesicles, which subsequently fuse with canalicular membrane to expel their contents into bile. The aim of this study was to clarify the mechanism underlying ATP7B-mediated copper detoxification by investigating endogenous ATP7B localization in the HepG2 hepatoma cell line and its ability to mediate vesicular sequestration of excess intracellular copper. METHODS: Immunofluorescence microscopy was used to investigate the effect of copper concentration on the localization of endogenous ATP7B in HepG2 cells. Copper accumulation studies to determine whether ATP7B can mediate vesicular sequestration of excess intracellular copper were performed using Chinese hamster ovary cells that exogenously expressed wild-type and mutant ATP7B proteins. RESULTS: In HepG2 cells, elevated copper levels stimulated trafficking of ATP7B to pericanalicular vesicles and not to the canalicular membrane as previously reported. Mutation of an endocytic retrieval signal in ATP7B caused the protein to constitutively localize to vesicles and not to the plasma membrane, suggesting that a vesicular compartment(s) is the final trafficking destination for ATP7B. Expression of wild-type and mutant ATP7B caused Chinese hamster ovary cells to accumulate copper in vesicles, which subsequently undergo exocytosis, releasing copper across the plasma membrane. CONCLUSIONS: This report provides compelling evidence that the primary mechanism of biliary copper excretion involves ATP7B-mediated vesicular sequestration of copper rather than direct copper translocation across the canalicular membrane.     

Chances and shortcomins of adenovirus-mediated ATP7B gene transfer in Wilson disease: proof of principle demonstrated in a pilot study with LEC rats

BACKGROUND & AIMS: Wilson disease (WD) is an autosomal recessively inherited copper storage disease due to mutations in the ATP7B gene. It results in impaired biliary copper excretion followed by liver injury leading to cirrhosis. In parallel, copper accumulates in other tissues e. g. basal ganglia of the brain inducing motoric disorders. Phenotypical cure of Wilson disease by liver transplantation raised the question whether gene therapy may represent a successful alternative treatment procedure. To examine the principle feasibility of this approach we investigated the effects of gene transfer using an adenoviral vector construct expressing the human ATP7B cDNA in an established rodent model for WD, the Long-Evans Cinnemon rat (LEC). METHODS: Transduction efficiency was assessed by RT-PCR, Western blot and immunofluorescence analysis. The therapeutic effect was estimated by analyzing holoceruloplasmin and its ferroxidase activity in serum, and the copper content of excrements. Changes in copper homeostasis were determined by positron emission tomography (PET). RESULTS: Successful, but temporary gene transfer was clearly detectable on RNA and protein levels. In parallel the temporary therapeutic effect was documented by restoration of serum holoceruloplasmin and of its ferroxidase activity. Additionally the Ad-ATP7B treated LEC rat revealed a higher (64)Cu content in stool. PET was able to visualize differences in (64)Cu distribution between wild type and LEC rats, indicating its principle usefulness as analytical tool. CONCLUSION: The data demonstrate proof of principle of successful gene therapy in an experimental model of WD. As a consequence of successful but only transient therapeutic effect of adenoviral gene transfer we can now focus more efficient and permanent gene transfer strategies.     

Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion

BACKGROUND & AIMS: Mutations in the ATP7B gene, encoding a copper-transporting P-type adenosine triphosphatase, lead to excessive hepatic copper accumulation because of impaired biliary copper excretion in Wilson's disease. In human liver, ATP7B is predominantly localized to the trans-Golgi network, which appears incompatible with a role of ATP7B in biliary copper excretion. The aim of this study was to elucidate this discrepancy. METHODS: Immunofluorescence and electron-microscopic methods were used to study the effects of excess copper on ATP7B localization in polarized HepG2 hepatoma cells. RESULTS: ATP7B is localized to the trans-Golgi network only when extracellular copper concentration is low (<1 micromol/L). At increased copper levels, ATP7B redistributes to vesicular structures and to apical vacuoles reminiscent of bile canaliculi. After copper depletion, ATP7B returns to the trans-Golgi network. Brefeldin A and nocodazole impair copper-induced apical trafficking of ATP7B and cause accumulation of apically retrieved transporters in a subapical compartment, suggesting continuous recycling of ATP7B between this vesicular compartment and the apical membrane when copper is increased. CONCLUSIONS: Copper induces trafficking of its own transporter from the trans-Golgi network to the apical membrane, where it may facilitate biliary copper excretion. This system of ligand-induced apical sorting provides a novel mechanism to control copper homeostasis in hepatic cells.     

肝豆状核变性与慢性乙型肝炎重度患者临床特征分析*

目的 观察肝豆状核变性（WD）伴黄疸患者的临床特征,探讨肝豆状核变性黄疸患者临床鉴别诊断的侧重点。方法 回顾性分析52例以“黄疸待查”初次入院的WD患者的临床资料,包括临床表现和常规实验室指标的变化。采用序列分析法检测全血基因组8、12、13、16外显子的突变情况。结果 本研究纳入WD患者24例和慢性乙型肝炎重度患者28例。WD患者发病中位年龄（33.2岁）显著低于乙型肝炎（41.8岁,P=0.049）,WD患者自起病至明确诊断的中位时间（8.2月）显著长于乙型肝炎（1月,P<0.001）;WD患者24 h尿铜水平（919.83±1017.15 μg）显著高于乙型肝炎（204.79±191.85 μg,P<0.001）;WD患者血清γ-谷氨酰转肽酶水平（175.74±245.99 U/L）显著高于乙型肝炎（133.44±115.95 U/L,P=0.004）,且与24 h尿铜水平呈正相关（r=0.552,P=0.012）;24例WD患者全部,而仅4例乙型肝炎患者可检出ATP7B突变。结论 肝豆状核变性伴黄疸患者除可利用血清铜、铜蓝蛋白检测进行筛选性诊断外,24 h尿铜检测为重要的鉴别诊断指标,而血清γ-谷氨酰转肽酶可能是该病潜在的诊断指标。     

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.     

Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment

Nearly a century after Dr. Samuel Alexander Kinnier Wilson composed his doctoral thesis on the pathologic findings of "lenticular degeneration" in the brain associated with cirrhosis of the liver we know that the underlying molecular basis for this autosomal recessive inherited disorder that now bears his name is mutation of a copper transporting ATPase, ATP7B, an intracellular copper transporter mainly expressed in hepatocytes. Loss of ATP7B function is the basis for reduced hepatic biliary copper excretion and reduced incorporation of copper into ceruloplasmin. During the intervening years, there was recognition of the clinical signs, histologic, biochemical features, and mutation analysis of ATP7B that characterize and enable diagnosis of this disorder. These include the presence of signs of liver or neurologic disease and detection of Kayser-Fleischer rings, low ceruloplasmin, elevated urine and hepatic copper, and associated histologic changes in the liver. Medical therapies and liver transplantation can effectively treat patients with this once uniformly fatal disorder. The earlier detection of the disease led to the initiation of treatment to prevent disease progression and reverse pathologic findings if present, and family screening to detect the disorder in first-degree relatives is warranted. Gene therapy and hepatocyte cell transplantation for Wilson disease has only been tested in animal models but represent future areas for study. Despite all the advances we still have to consider the diagnosis of Wilson disease to test patients for this disorder and properly establish the diagnosis before committing to life-long treatment.