scholarly journals ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease

2018 ◽  
Author(s):  
Daniel F. Wallace ◽  
James S. Dooley
Keyword(s):  
Wilson Disease ◽  
Genomic Sequence ◽  
Genetic Disorder ◽  
Copper Metabolism ◽  
Genetic Studies ◽  
Population Prevalence ◽  
Atpase Gene ◽  
Prevalence Estimates ◽  
The Uk ◽  
P Type

AbstractWilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency of ATP7B variants in a genomic sequence database. A catalogue of WD-associated ATP7B variants was constructed and then frequency information for these was extracted from the gnomAD dataset. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associated ATP7B variants were identified in the gnomAD dataset, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated ATP7B variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD. They also highlight the challenge in defining penetrance when assigning causality to some ATP7B variants.

scholarly journals Immunoglobulin A Nephropathy as the First Clinical Presentation of Wilson Disease: A Case Report and Literature Review

2021 ◽  
Author(s):  
Yong-Zhe Zhang ◽  
Geng Jian ◽  
Ping He ◽  
Rui Yu ◽  
Mi Tian ◽  
...  
Keyword(s):  
Renal Function ◽  
Iga Nephropathy ◽  
Wilson Disease ◽  
Genetic Disorder ◽  
Immunoglobulin A ◽  
Elevated Serum ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Copper Metabolism ◽  
Normal Liver

Abstract Background: Wilson disease (WD) is a rare genetic disorder of copper metabolism. The difference in copper tissue accumulation lead to various clinical manifestations, including some atypical presentations. The complex clinical picture makes it easy to miss and misdiagnose, even delay the best chance for treatment. Case presentation: A 26-year-old male patient who had nephritis-range proteinuria and elevated serum creatinine. The renal pathology indicated Immunoglobulin A (IgA) nephropathy and tubular injury which was inconsistent with glomerular lesions. Cirrhosis was also detected by imaging examination. Considering both kidney injury and liver damage, WD was suspected. According to further detected results of abnormal copper metabolism, corneal Kayser-Fleischer rings(K-F rings), and genetic disorder of ATP7B gene, he was finally diagnosed as a case of WD.The patient was given oral penicillamine and zinc sulfate daily and he was also prescribed losartan to control proteinuria on the premise of monitoring renal function and blood pressure. During the 2 years follow-up, the patient’s 24h uric cooper dropped to normal. The sign of tremor hands disappeared. The Urine protein and renal function keep stable. The patient had normal liver function and maintained good quality of daily life. Conclusions: In some cases, IgA nephropathy patients with suspicious and unexplained neurological and liver symptoms cannot be ignored. They may eventually be diagnosed with WD.

scholarly journals Immunoglobulin a nephropathy as the first clinical presentation of Wilson disease: a case report and literature review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yong-Zhe Zhang ◽  
Geng Jian ◽  
Ping He ◽  
Rui Yu ◽  
Mi Tian ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Wilson Disease ◽  
Genetic Disorders ◽  
Genetic Disorder ◽  
Immunoglobulin A ◽  
Elevated Serum ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Copper Metabolism ◽  
Atypical Presentations

Abstract Background Wilson disease (WD) is a rare genetic disorder of copper metabolism. Differences in copper tissue accumulation lead to various clinical manifestations, including some atypical presentations. The complex clinical features of WD make diagnosis challenging, delaying the best chance for treatment. Case presentation We report a case of a 26-year-old man with nephritis-range proteinuria and elevated serum creatinine. The renal pathology indicated immunoglobulin A (IgA) nephropathy and tubular injury, which was inconsistent with glomerular lesions. Cirrhosis was also detected by imaging examination. Considering both kidney injury and liver damage, WD was suspected. Based on results showing abnormal copper metabolism, corneal Kayser–Fleischer rings, and genetic disorders in the ATP7B gene, the patient was finally diagnosed with WD. After treatment with oral penicillamine, zinc sulfate and losartan, the patient showed alleviation of both WD and nephropathy after 3 years of follow-up. He maintained a good quality of daily life. Conclusion This case highlights that unexplained neurological and liver symptoms in patients with IgA nephropathy can be clues for WD.

scholarly journals Two forms of Wilson disease protein produced by alternative splicing are localized in distinct cellular compartments

1997 ◽  
Vol 326 (3) ◽  
pp. 897-902 ◽  
Author(s):  
Xiao-Li YANG ◽  
Naoyuki MIURA ◽  
Yoshihiko KAWARADA ◽  
Kunihiko TERADA ◽  
Konstantin PETRUKHIN ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Wilson Disease ◽  
Intracellular Transport ◽  
Copper Metabolism ◽  
Copper Transporter ◽  
Wilson Disease Protein ◽  
Disease Protein ◽  
Human Disorders ◽  
P Type ◽  
Cellular Compartments

Copper is an essential trace element in prokaryotes and eukaryotes and is strictly regulated by biological mechanisms. Menkes and Wilson diseases are human disorders that arise from disruption of the normal process of copper export from the cytosol to the extracellular environment. Recently a gene for Wilson disease (WD) (also named the ATP7B gene) was cloned. This gene encodes a copper transporter of the P-type ATPase. We prepared monoclonal and polyclonal anti-(WD protein) antibodies and characterized the full-length WD protein as well as a shorter form that is produced by alternative splicing in the human brain. We found that the WD protein is localized mainly in the Golgi apparatus, whereas the shorter form is present in the cytosol. These results suggest that the alternative WD proteins act as key regulators of copper metabolism, perhaps by performing distinct roles in the intracellular transport and export of copper.

scholarly journals Wilson disease and psychiatric symptoms: A brief case report

2019 ◽  
Vol 32 (3) ◽  
pp. e100066
Author(s):  
Margarita Guerrero-Jiménez ◽  
Carmen Maura Carrillo de Albornoz Calahorro ◽  
Luis Gutierrez Rojas
Keyword(s):  
Wilson Disease ◽  
Psychiatric Symptoms ◽  
Genetic Disorder ◽  
Neuropsychiatric Symptoms ◽  
Copper Metabolism ◽  
Short Review ◽  
Neurological Damage ◽  
Delay In Diagnosis ◽  
Causal Treatment ◽  
Delay Of Diagnosis

Wilson disease (WD) is an uncommon recessive genetic disorder affecting copper metabolism. Cardiac, neurological, hepatic and renal manifestations are well defined, nevertheless approximately 30% of patients debut with neuropsychiatric symptoms. These psychiatric alterations resulting from the accumulation of this heavy metal in the basal ganglia are some how less specific. We present a short review of psychiatric symptoms of WD and describe a case of a 37-year-old woman diagnosed with WD who presented neuropsychiatric symptoms and had a consequent delay in diagnosis and causal treatment. Patients who develop WD starting with a predominance of neuropsychiatric symptoms tend to manifest hepatic symptoms later, therefore have a longer delay of diagnosis and a poorer outcome than patients with hepatic symptoms. An early diagnosis of WD can avoid irreversible neurological damage.

scholarly journals Neurological Manifestation of Wilson Disease at an Early Age: A Case Report

2010 ◽  
Vol 23 (1) ◽  
pp. 87-90
Author(s):  
MI Bari ◽  
LS Sharmin ◽  
T Alam
Keyword(s):  
Case Report ◽  
Liver Disease ◽  
Wilson Disease ◽  
Inborn Error ◽  
Autosomal Recessive ◽  
Copper Metabolism ◽  
Autosomal Recessive Disorder ◽  
Neurological Manifestation ◽  
Early Age ◽  
P Type

Wilson’s disease (hepatolenticuler degeneration), an inborn error of copper metabolism, is an autosomal recessive disorder characterized by degenerative changes in brain, liver disease and Kayser Fleisher (KF) rings in the cornea. It is due to a defect of p-type ATPase which is probably required for normal excretion of copper through bile. Hepatic manifestation of the disease is common at early age and neurological manifestation is common at an older age. We are reporting Wilson disease with neurological manifestation in a 10 year old boy. TAJ 2010; 23(1): 87-90

scholarly journals Histopathology of Wilson Disease

2020 ◽  
Author(s):  
Nese Karadag Soylu
Keyword(s):  
Wilson Disease ◽  
Psychiatric Symptoms ◽  
Copper Metabolism ◽  
Copper Accumulation ◽  
Serum Ceruloplasmin ◽  
Liver Histopathology ◽  
Urinary Copper ◽  
Clinical Presentations ◽  
P Type ◽  
Age Range

Wilson Disease (WD) is a genetic metabolic disease of copper metabolism. The implicated gene is ATP7B, encodes a P-type ATPase which transports copper. The resultant defective metabolism of copper results in copper accumulation in multiple tissues especially liver, eye and central nervous system. WD occurs worldwide, usually between 5 and 35 years; a wider age range is also reported. Clinical presentations are diverse and include combinations of hepatic, neurological, ophthalmic and psychiatric manifestations. Other organs or tissues may also be affected. Biochemical abnormalities such as serum ceruloplasmin and 24-h urinary copper excretion are important for the diagnosis but are not always abnormal in WD. The liver histopathology has several different patterns from mild nonspecific changes to acute fulminant hepatitis and cirrhosis. Copper histochemistry is helpful in diagnosis. Genetic testing is another diagnostic tool. It is important to diagnose WD because it is fatal when overlooked, curable when diagnosed. The diagnosis should be keep in mind at all ages in patients with hepatic disease, neurological disease, or psychiatric symptoms.

Copper-Induced Epigenetic Changes Shape the Clinical Phenotype in Wilson Disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Daniela Fanni ◽  
Clara Gerosa ◽  
Valeria Marina Nurchi ◽  
Rosita Cappai ◽  
Marta Mureddu ◽  
...  
Keyword(s):  
Wilson Disease ◽  
Clinical Presentation ◽  
Clinical Phenotype ◽  
Methylation Status ◽  
Copper Metabolism ◽  
Epigenetic Factors ◽  
Genetic Changes ◽  
Illness Onset ◽  
Phenotypic Manifestation ◽  
Copper Overload

: Wilson disease is a congenital disorder of copper metabolism whose pathogenesis remains, al least in part, unknown. Subjects carrying the same genotype may show completely different phenotypes, differing for the age at illness onset or for the hepatic, neurologic or psychiatric clinical presentation. The inhability to find a unequivocal correlation between the type of mutation in the ATPase copper transporting beta (ATP7B) gene and the phenotypic manifestation, induced many authors to look for epigenetic factors interacting with the genetic changes. Here the evidences regarding the ability of copper overload to change the global DNA methylation status are discussed.

scholarly journals A Bayesian approach to estimating the population prevalence of mood and anxiety disorders using multiple measures

2021 ◽  
Vol 30 ◽  
Author(s):  
Jordan Edwards ◽  
A. Demetri Pananos ◽  
Amardeep Thind ◽  
Saverio Stranges ◽  
Maria Chiu ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Anxiety Disorders ◽  
Administrative Data ◽  
Population Based ◽  
Accurate Estimate ◽  
Service Planning ◽  
Prevalence Estimate ◽  
Population Prevalence ◽  
Mood And Anxiety Disorders ◽  
Prevalence Estimates

Abstract Aims There is currently no universally accepted measure for population-based surveillance of mood and anxiety disorders. As such, the use of multiple linked measures could provide a more accurate estimate of population prevalence. Our primary objective was to apply Bayesian methods to two commonly employed population measures of mood and anxiety disorders to make inferences regarding the population prevalence and measurement properties of a combined measure. Methods We used data from the 2012 Canadian Community Health Survey – Mental Health linked to health administrative databases in Ontario, Canada. Structured interview diagnoses were obtained from the survey, and health administrative diagnoses were identified using a standardised algorithm. These two prevalence estimates, in addition to data on the concordance between these measures and prior estimates of their psychometric properties, were used to inform our combined estimate. The marginal posterior densities of all parameters were estimated using Hamiltonian Monte Carlo (HMC), a Markov Chain Monte Carlo technique. Summaries of posterior distributions, including the means and 95% equally tailed posterior credible intervals, were used for interpretation of the results. Results The combined prevalence mean was 8.6%, with a credible interval of 6.8–10.6%. This combined estimate sits between Bayesian-derived prevalence estimates from administrative data-derived diagnoses (mean = 7.4%) and the survey-derived diagnoses (mean = 13.9%). The results of our sensitivity analysis suggest that varying the specificity of the survey-derived measure has an appreciable impact on the combined posterior prevalence estimate. Our combined posterior prevalence estimate remained stable when varying other prior information. We detected no problematic HMC behaviour, and our posterior predictive checks suggest that our model can reliably recreate our data. Conclusions Accurate population-based estimates of disease are the cornerstone of health service planning and resource allocation. As a greater number of linked population data sources become available, so too does the opportunity for researchers to fully capitalise on the data. The true population prevalence of mood and anxiety disorders may reside between estimates obtained from survey data and health administrative data. We have demonstrated how the use of Bayesian approaches may provide a more informed and accurate estimate of mood and anxiety disorders in the population. This work provides a blueprint for future population-based estimates of disease using linked health data.

scholarly journals Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Clemens Höflich ◽  
Angela Brieger ◽  
Stefan Zeuzem ◽  
Guido Plotz
Keyword(s):  
Wilson Disease ◽  
Transcription Initiation ◽  
Transcriptional Activity ◽  
Core Promoter ◽  
Transcriptional Start Site ◽  
Copper Metabolism ◽  
Biologically Relevant ◽  
The Core ◽  
Translational Start

AbstractPathogenic genetic variants in the ATP7B gene cause Wilson disease, a recessive disorder of copper metabolism showing a significant variability in clinical phenotype. Promoter mutations have been rarely reported, and controversial data exist on the site of transcription initiation (the core promoter). We quantitatively investigated transcription initiation and found it to be located in immediate proximity of the translational start. The effects human single-nucleotide alterations of conserved bases in the core promoter on transcriptional activity were moderate, explaining why clearly pathogenic mutations within the core promoter have not been reported. Furthermore, the core promoter contains two frequent polymorphisms (rs148013251 and rs2277448) that could contribute to phenotypical variability in Wilson disease patients with incompletely inactivating mutations. However, neither polymorphism significantly modulated ATP7B expression in vitro, nor were copper household parameters in healthy probands affected. In summary, the investigations allowed to determine the biologically relevant site of ATP7B transcription initiation and demonstrated that genetic variations in this site, although being the focus of transcriptional activity, do not contribute significantly to Wilson disease pathogenesis.

scholarly journals Wilson Disease-Induced Acute Liver Failure (NWI = 13) Salvaged without Liver Transplant by Plasmapheresis

2021 ◽  
Vol 11 (01) ◽  
pp. e145-e147
Author(s):  
Nida Mirza ◽  
Ravi Bharadwaj ◽  
Smita Malhotra ◽  
Anupam Sibal
Keyword(s):  
Liver Transplantation ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Wilson Disease ◽  
Prognostic Score ◽  
Prognostic Index ◽  
Kidney Injury ◽  
Copper Metabolism ◽  
Life Saving ◽  
The Brain

AbstractWilson disease (WD) is a disorder of copper metabolism resulting in accumulation of copper in vital organs of the human body, predominantly in the liver and the brain. Acute liver failure in WD has a bad prognosis, especially with a score ≥11 in the revised WD prognostic index; emergency liver transplantation is considered the only life-saving option in this scenario. Here, we reported a girl patient with WD-induced liver failure and poor prognostic score who was rescued by plasmapheresis. She also manifested severe Coombs negative hemolytic anemia and acute kidney injury. This case report highlights the utility of an adjunctive modality besides liver transplantation for the management of fulminant liver failure caused by WD.

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