Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5% of children/adolescents (≤18 years) and 58% of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.

• MeSH
• ATPasy transportující měď genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• hepatolentikulární degenerace genetika   patologie   MeSH
• játra patologie   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutační analýza DNA MeSH
• registrace * MeSH
• sexuální faktory MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ATP7B protein, human MeSH Prohlížeč
• ATPasy transportující měď MeSH

Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B, which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B. Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD.

• MeSH
• chelátory terapeutické užití   MeSH
• hepatolentikulární degenerace diagnóza   genetika   patofyziologie   MeSH
• kvalita života psychologie   MeSH
• lidé MeSH
• měď škodlivé účinky   metabolismus   MeSH
• molybden terapeutické užití   MeSH
• potravní doplňky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• chelátory MeSH
• měď MeSH
• molybden MeSH
• tetrathiomolybdate MeSH Prohlížeč

Wilson disease is an autosomal-recessive disorder originating from a genetic defect in the copper-transporting ATPase ATP7B that is required for biliary copper secretion and loading of ceruloplasmin with copper. Impaired ATP7B function in Wilson disease results in excessive accumulation of copper in liver, brain, and other tissues. Toxic copper deposits may induce oxidative stress, modify expression of genes, directly inhibit proteins, and impair mitochondrial function, leading to hepatic, neuropsychiatric, renal, musculoskeletal, and other symptoms. Hepatocyte dysfunction initially manifests as steatosis and later may progress to other hepatic phenotypes such as acute liver failure, hepatitis, and fibrosis. In the brain, copper accumulates in astrocytes, leading to impairment of the blood-brain barrier and consequent damage to neurons and oligodendrocytes. Basal ganglia and brainstem are the brain regions with highest susceptibility to copper toxicity and their lesions lead to various combinations of movement and psychiatric disorders. This chapter will give an overview of the essential requirement of copper for biologic processes and the molecular mechanisms employed by cells to maintain their copper levels in a proper range. We will specify the physiologic functions of ATP7B and the consequences of its dysfunction and summarize the current knowledge on the pathogenesis of liver and neuropsychiatric disease. Finally, we will describe the consequences of copper overload in Wilson disease in other tissues.

• Klíčová slova
• ATP7B, Wilson disease, copper, liver fibrosis, neurodegeneration,
• MeSH
• ATPasy transportující měď genetika   fyziologie   MeSH
• duševní poruchy etiologie   MeSH
• hematoencefalická bariéra MeSH
• hepatolentikulární degenerace etiologie   genetika   metabolismus   MeSH
• lidé MeSH
• měď metabolismus   MeSH
• mozek metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ATP7B protein, human MeSH Prohlížeč
• ATPasy transportující měď MeSH
• měď MeSH

Wilsons disease is an autosomal recessive genetic disorder in which copper accumulates in tissues, especially in the liver and the brain. The genetic defect affects the P type ATPase gene (ATP7B). More than 500 mutations causing Wilsons disease have been described. The most common mutation in Central Europe concerns H1069Q. The symptoms of Wilsons disease include hepatic or neurological conditions. The hepatic condition is manifested as steatosis, acute or chronic hepatitis or cirrhosis. The neurological conditions are most often manifested after the age of 20 as motor disorders (tremor, speech and writing disorders), which may result in severe extrapyramidal syndrome with rigidity, dysarthria and muscle contractions. The dia-gnosis is based on clinical and laboratory assessments (neurological signs, liver lesions, low ceruloplasmin, increased free serum copper, high Cu volumes in urine, KayserFleischer ring). The dia-gnosis is confirmed by a high Cu level in liver tissue or genetic proof. Untreated Wilsons disease causes death of the patient. If treated properly the survival rate approximates to the survival rate of the common population. The treatment concerns either removal of copper from the body using chelating agents excreted into the urine (Penicillamine, Trientine) or limitation of copper absorption from the intestine and reducing the toxicity of copper (zinc, ammonium tetrathiomolybdate). In the Czech Republic, Penicillamine or zinc is used. A liver transplant is indicated in patients with fulminant hepatic failure or decompensated liver cirrhosis. In the family all siblings of the affected individual need to be screened in order to treat any asymptomatic subjects.

• MeSH
• adenosintrifosfatasy genetika   MeSH
• ATPasy transportující měď MeSH
• chelátory terapeutické užití   MeSH
• dospělí MeSH
• hepatolentikulární degenerace diagnóza   genetika   terapie   MeSH
• jaterní cirhóza chirurgie   MeSH
• lidé MeSH
• měď metabolismus   MeSH
• molybden terapeutické užití   MeSH
• mutace MeSH
• penicilamin terapeutické užití   MeSH
• proteiny přenášející kationty genetika   MeSH
• transplantace jater * MeSH
• trientin terapeutické užití   MeSH
• zinek terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• ATP7B protein, human MeSH Prohlížeč
• ATPasy transportující měď MeSH
• chelátory MeSH
• měď MeSH
• molybden MeSH
• penicilamin MeSH
• proteiny přenášející kationty MeSH
• tetrathiomolybdate MeSH Prohlížeč
• trientin MeSH
• zinek MeSH

BACKGROUND AND AIMS: Wilson disease (WD) is an inherited disorder of copper metabolism. When treated, the outcome can be excellent, although the long-term survival has yet to be well documented. The aim of this study was to describe the long-term outcome of a cohort of patients with WD and to assess those factors affecting the phenotypic manifestation of WD. METHODS: The presence of mutations to the ATP7B gene, the clinical manifestations, treatments and the long-term outcomes were analysed retrospectively in 117 patients with WD (59 men and 58 women, aged at evaluation 38.5 ± 11, range 16-63 years). RESULTS: Fifty-five patients with a neurological presentation, 51 patients with a hepatic presentation and 11 asymptomatic patients were followed up for an average of 15.1 ± 10 years (median 12 years, range 1-41 years). The H1069Q ATP7B gene mutation was the most frequent genetic variant (54.3%); the frequency of this mutation did not differ between patients with either the hepatic or the neurological presentation (P = 0.099). d-penicillamine or zinc salts (81 and 17% respectively) were used for treatment, and three patients underwent liver transplantation. The majority of symptomatic patients became asymptomatic, or improved, during the follow-up (82% patients with hepatic presentation, 69% with neurological presentation). The long-term survival of patients with WD did not differ from that of the general Czech population (P = 0.95). CONCLUSIONS: Long-term follow-up shows a satisfactory response in the great majority of adequately treated patients with WD and survival coincides with that of the general population.

• MeSH
• adenosintrifosfatasy genetika   metabolismus   MeSH
• asymptomatické nemoci MeSH
• ATPasy transportující měď MeSH
• časové faktory MeSH
• chelátory metabolismus   MeSH
• dospělí MeSH
• fenotyp MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• hepatolentikulární degenerace enzymologie   genetika   mortalita   terapie   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• měď metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• octan zinečnatý terapeutické užití   MeSH
• penicilamin terapeutické užití   MeSH
• progrese nemoci MeSH
• proteiny přenášející kationty genetika   metabolismus   MeSH
• retrospektivní studie MeSH
• rozdělení chí kvadrát MeSH
• síran zinečnatý terapeutické užití   MeSH
• transplantace jater MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• ATP7B protein, human MeSH Prohlížeč
• ATPasy transportující měď MeSH
• chelátory MeSH
• měď MeSH
• octan zinečnatý MeSH
• penicilamin MeSH
• proteiny přenášející kationty MeSH
• síran zinečnatý MeSH

BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The objective of this study is to present diagnostic pitfalls and long time follow-up data in Wilson disease. PATIENTS/METHODS: We studied 21 WD patients and 14 heterozygote carriers aged 2-43 years, retrospectively. 18 WD patients presented liver disease, three had mixed neurological and hepatic involvement and 9 patients underwent orthotopic liver transplantation (OLT). RESULTS: The median age at diagnosis of WD children without OLT was 10.16+/-3.8 (range, 5-16). All of females and younger age categories of patients prevailed in acute liver failure group. Serum ceruloplasmine levels were below 0.2 g/l in about (1/3) of WD carriers (X =0.27+/-0.09 g/l) and nearly (2/3) of children with WD (X = 0.21+/-0.13 g/l). A statistically significant difference (p<0.05) in the 24-h excretion of copper in urine was noticed between healthy controls, children with WD and WD heterozygote carriers. As diagnostic important proved the copper content of more than 250 microg/g hepatic dry weight. The Kayser-Fleischer?s ring was not observed in children. Ceruloplasmine, haemoglobin, ALT, ALP and plasma albumin were significantly different between fulminant and non-fulminant WD and could be used as indirect markers in evaluation of urgent OLT. CONCLUSION: Detection of WD in children remains very difficult. The most important investigation is liver biopsy with the assessment of liver copper. Genetic analysis may help in doubtful cases.

• MeSH
• adenosintrifosfatasy genetika   MeSH
• alely MeSH
• ATPasy transportující měď MeSH
• ceruloplasmin nedostatek   MeSH
• detekce genetických nosičů MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• dospělí MeSH
• hepatolentikulární degenerace diagnóza   genetika   MeSH
• jaterní testy MeSH
• lidé MeSH
• měď moč   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• následné studie MeSH
• neurologické vyšetření MeSH
• předškolní dítě MeSH
• proteiny přenášející kationty genetika   MeSH
• retrospektivní studie MeSH
• transplantace jater MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• ATPasy transportující měď MeSH
• ceruloplasmin MeSH
• měď MeSH
• proteiny přenášející kationty MeSH

Wilson's disease is an inherited disorder leading to accumulation of copper in tissues, mainly in the liver and brain. Genetic defect is in the gene coding ATPase type P (ATP7B). The inheritance is autosomal recessive. Up to now, more then 500 mutations causing Wilson's disease were described. The most frequent mutation in Central Europe is mutation H1069Q. The manifestation of Wilson's disease is usually hepatic or neurologic. Hepatic form is manifested by acute or chronic hepatitis, steatosis or cirrhosis. Neurologic involvement is manifested usually after 20 year of age by motor disturbances (tremor, disturbed speech, problems with writing), which could progress into severe extrapyramidal syndrome with tremor, rigidity, dysartria, dysfagia and muscle contracture. Diagnosis is based on clinical and laboratory examinations (neurologic symptoms, liver disease, low serum ceruloplasmin levels, elevated free copper concentration in serum, high urine copper excretion, and presence of Kayser-Fleischer rings). Confirmation of diagnosis is done by hepatic copper concentration in liver biopsy or by genetic examination. Untreated disease leads to the death of a patient. Treatment is based on chelating agents decreasing the copper content by excretion into urine (D-penicillamine, trientine) or on agents preventing absorption of copper from food (zinc, ammonium-tetrahiomolybdene). Patients with asymptomatic Wilson's disease have to be treated as well. In Czech Republic either penicillamine or zinc are used. Liver transplantation is indicated in patients with fulminant liver failure or decompensated cirrhosis. Screening in families of affected patients (all siblings) is obvious.

• MeSH
• hepatolentikulární degenerace * diagnóza   farmakoterapie   genetika   MeSH
• lidé MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Wilson disease (WD) is a serious autosomal recessive disorder caused by mutations in ATP7B-gene which encodes a copper-specific ATPase. WD patients suffer from impaired biliary excretion of copper from organism and its' accumulation in body organs. Molecular diagnostics of WD is an important part of correct diagnosis statement. The aim of the study was to design and validate a genotyping DNA microarray which enables to analyze 87 mutations and 17 polymorphisms in ATP7B gene, simultaneously. METHODS AND RESULTS: 97 WD patients with known genotypes and 46 samples prepared by mutagenesis were tested in the first phase of chip validation. All analyzed sequence variants were detected with 100% accuracy. Samples from WD suspected patients were tested in the second phase of validation. We have analyzed 58 unrelated patients, yet. The diagnosis of WD was confirmed in 10 patients, 13 patients were heterozygous for some mutation and 35 had no mutation in ATP7B gene. Samples with one or no mutation found by microarray analysis were sequenced directly and no further causal mutation was revealed. CONCLUSIONS: Wilson chip seems to be a fast and reliable method for screening of mutations in ATP7B gene.

• MeSH
• hepatolentikulární degenerace diagnóza   genetika   MeSH
• lidé MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

Cystic fibrosis-related liver disease affects approximately one third of all patients with cystic fibrosis. Initial signs of other liver diseases including the genetically determined disorders of the liver co-inherited with cystic fibrosis may be obscured by or ascribed to cystic fibrosis-related liver disease. We report a patient shown to suffer simultaneously from cystic fibrosis and hepatic Wilson disease. Our case documents that in patients with cystic fibrosis presenting with liver disease, when unusual clinical and/or laboratory abnormalities appear and fail to respond to standard therapy, a second disease, including rare inherited metabolic disorders such as the hepatic form of Wilson disease or alpha(1)-antitrypsin deficiency, should be suspected.

• MeSH
• chelátory terapeutické užití   MeSH
• cystická fibróza komplikace   diagnóza   MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• genetické testování MeSH
• genotyp MeSH
• Gilbertova nemoc diagnóza   genetika   MeSH
• hepatolentikulární degenerace diagnóza   farmakoterapie   genetika   MeSH
• jaterní testy MeSH
• játra patologie   MeSH
• lidé MeSH
• mutace MeSH
• novorozenec nedonošený MeSH
• novorozenec MeSH
• penicilamin terapeutické užití   MeSH
• předškolní dítě MeSH
• pyridoxin terapeutické užití   MeSH
• vitamin B komplex terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• penicilamin MeSH
• pyridoxin MeSH
• vitamin B komplex MeSH

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism that is caused by mutations in the ATP7B gene. To date, more than 300 mutations have been described in this gene. Molecular diagnostics of WD utilizes restriction enzyme digestion, multiplex ligation-dependent probe amplification or a direct sequencing of the whole gene. To simplify and speed up the screening of ATP7B mutations, we have developed a genotyping microarray for the simultaneous detection of 87 mutations and 17 polymorphisms in the ATP7B gene based on the arrayed primer extension reaction. The patient's DNA is amplified in four multiplex polymerase chain reactions, fragmented products are annealed to arrayed primers spotted on a chip, which enables DNA polymerase extension reactions with fluorescently labeled dideoxynucleotides. The Wilson microarray was validated by screening 97 previously genetically confirmed WD patients. In total, we detected 43 mutations and 15 polymorphisms that represent a majority of the common mutations occurring in the Czech and Slovak populations. All screened sequence variants were detected with 100% accuracy. The Wilson chip appears to be a rapid, sensitive and cost-effective tool, representing the prototype of a disease chip that facilitates and speeds up the screening of potential WD patients.

• MeSH
• adenosintrifosfatasy genetika   MeSH
• ATPasy transportující měď MeSH
• bodová mutace * MeSH
• detekce genetických nosičů metody   MeSH
• genotyp MeSH
• hepatolentikulární degenerace diagnóza   genetika   MeSH
• heterozygot MeSH
• lidé MeSH
• mikročipová analýza přístrojové vybavení   metody   MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• proteiny přenášející kationty genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• ATP7A protein, human MeSH Prohlížeč
• ATPasy transportující měď MeSH
• proteiny přenášející kationty MeSH