Biochemical and molecular characterisation of neurological Wilson disease

2018 ◽  
Vol 55 (9) ◽  
pp. 587-593 ◽  
Author(s):  
Go Hun Seo ◽  
Yoon-Myung Kim ◽  
Seak Hee Oh ◽  
Sun Ju Chung ◽  
In Hee Choi ◽  
...  
Keyword(s):  
Wilson Disease ◽  
Age At Onset ◽  
Copper Metabolism ◽  
Favourable Outcome ◽  
Treatment Needs ◽  
Serum Ceruloplasmin ◽  
Urinary Copper ◽  
Genetic Features ◽  
Distinct Disease ◽  
Serum Aspartate Aminotransferase

BackgroundTo identify biochemical and genetic features that characterise neurological Wilson disease as a distinct disease subgroup.MethodsDetailed biochemical profiles and genotypic characteristics of neurological (86 patients) and hepatic subgroups (233 patients) from 368 unrelated Korean families were analysed.ResultsCompared with patients in the hepatic subgroup, patients in the neurological subgroup had a later age at onset, a higher proportion with Kayser-Fleischer rings and higher serum creatinine levels, and a lower proportion with favourable outcome (62% vs 80%, P<0.016). At diagnosis, the neurological subgroup had lower serum ceruloplasmin (3.1±2.1 mg/dL vs 4.2±3.2 mg/dL, P<0.001), total copper (26.4±13.8 µg/dL vs 35.8±42.4 µg/dL, P=0.005), free copper (17.2±12.5 µg/dL vs 23.5±38.2 µg/dL, P=0.038) and urinary copper (280.9±162.9 µg/day vs 611.1±1124.2 µg/day, P<0.001) levels. Serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase and total bilirubin levels, as well as prothrombin time, were also lower in the neurological subgroup. Liver cirrhosis was more common but mostly compensated in the neurological subgroup. Frameshift, nonsense or splice-site ATP7B mutations and mutations in transduction or ATP hinge domains (2.4% vs 23.1%, P=0.006) were less common in the neurological subgroup.ConclusionThe neurological subgroup had distinct clinical, biochemical and genetic profiles. Further studies are required to identify the factors, with or without association with copper metabolism, underlying the neurological presentation for which treatment needs to be targeted to improve the clinical outcome of this subgroup.

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.

Evaluation and grading of Kayser–Fleischer ring in Wilson disease by Scheimpflug camera

2020 ◽  
pp. 112067212093102
Author(s):  
Cumali Degirmenci ◽  
Melis Palamar
Keyword(s):  
Wilson Disease ◽  
Corneal Thickness ◽  
Anterior Segment ◽  
Serum Ceruloplasmin ◽  
Endothelial Surface ◽  
Ceruloplasmin Level ◽  
Urinary Copper ◽  
Scheimpflug Imaging ◽  
Anterior Segment Parameters ◽  
Grade 3

Purpose: Evaluation the anterior segment parameters of Wilson disease patients with Kayser–Fleischer ring, the diagnostic power of Scheimpflug imaging for Kayser–Fleischer ring and suggest a scoring system. Materials and Methods: A total of 44 eyes of 22 Wilson disease patients with Kayser–Fleischer ring and 40 right eyes of 40 healthy age matched subjects were enrolled to the study. Serum ceruloplasmin and urine copper/24 hours levels were recorded. Anterior segment parameters including steep and flat keratometry, corneal thickness at central, 2, 4, 6, 8 and 10 mm, anterior chamber angle width, volume and depth, corneal volume, pupillary diameter were evaluated by Scheimpflug imaging. Images of cornea were scored according to Kayser–Fleischer ring size. Results: Serum ceruloplasmin level was below 10 mg/dL in 17 patients and was 12, 18.5, 20, 22, 37 mg/dl in the remaining five patients. Urinary copper/24 hours was 249.55 ± 304.14 (23–1050) µg/day. Central corneal thickness and corneal thickness at 2 mm were statistically different ( p values 0.02, 0.04, respectively). Scheimpflug images apparently showed Kayser–Fleischer ring as a hyper-reflective band at the corneal endothelial surface. Kayser–Fleischer ring in 24 eyes was grade 1, 16 eyes were grade 2 and 4 eyes were grade 3. Conclusion: Scheimpflug imaging seems to be a helpful diagnostic tool for detecting and grading the Kayser–Fleischer ring. Corneal thickness in Wilson disease patients with Kayser–Fleischer ring tends to be higher, so that the possible affection in corneal thickness should be kept in mind for clinical evaluation of these patients.

scholarly journals Zinc Monotherapy as an Alternative Treatment Option for Decompensated Liver Disease due to Wilson Disease?

2020 ◽  
Vol 2020 ◽  
pp. 1-5 ◽  
Author(s):  
Hansa Haftu ◽  
Mohammed Mustefa ◽  
Teklu Gebrehiwot
Keyword(s):  
Liver Disease ◽  
Treatment Option ◽  
Alternative Treatment ◽  
Wilson Disease ◽  
Copper Metabolism ◽  
Variable Degree ◽  
Decompensated Liver Disease ◽  
Serum Ceruloplasmin ◽  
Asymptomatic Patients ◽  
Alternative Treatment Option

Background. Wilson disease is a rare metabolic disorder involving copper metabolism, and patients may present with a variable degree of hepatic, neurologic, and psychiatric manifestations. In the case of hepatic presentation, treatment is usually initiated with potentially toxic copper chelators (D-penicillamine or Trenton). Although zinc is of low toxicity and low cost for treatment of Wilson disease, it has been limited to the adjunctive as a single maintenance drug or for asymptomatic patients. The use of zinc monotherapy in patients suffering from a severe liver disease was not well studied. In our case report, we describe a pediatric patient who presented with liver failure and the use of zinc monotherapy in patients with severe hepatic manifestations. Case presentation. A 15-year-old male patient from Ethiopia presented with generalized body swelling (edema and ascites) with yellowish discoloration of his eyes and easy fatigability. He had hyperbilirubinemia, coagulopathy, hypoalbuminemia, and deranged liver enzymes. He had a Keyser–Fleischer ring visible with the naked eye, which was confirmed by slit-lamp examination. He had very low serum ceruloplasmin (<8 mg/L) and high 24-hour urine copper (150 mcg/dl). In accordance with the scoring system proposed by the 8th International Meeting on Wilson Disease and Menkes Disease, a diagnosis of Wilson disease was made. Zinc monotherapy with low copper diet was initiated for decompensated liver disease due to Wilson disease because of the inaccessibility of chelators (D-penicillamine or Trientine). After months of treatment with zinc, the patient experienced normalization of hepatic synthetic function and resolution of hypoalbuminemia and coagulopathy. The patient had also clinically stabilized (ascites, lower extremity swelling, edema, and jaundice were improved. Currently, the patient is on follow-up almost for the last four years in the gastrointestinal clinic. Conclusion. Our case shows that zinc has the potential for treatment in improving liver function. Though zinc has its own side effects, it is important and maybe an alternative treatment option in those with limited resources (not able to access chelators). This example hopefully will encourage future investigations and researches on zinc monotherapy for treating symptomatic decompensated hepatic Wilson disease.

scholarly journals Wilson Disease: Canadian Perspectives on Presentation And Outcomes from an Adult Ambulatory Setting

2012 ◽  
Vol 26 (6) ◽  
pp. 333-339 ◽  
Author(s):  
A Moores ◽  
SH Fox ◽  
AE Lang ◽  
GM Hirschfield
Keyword(s):  
Basal Ganglia ◽  
Wilson Disease ◽  
Copper Metabolism ◽  
Retrospective Chart Review ◽  
Complete Recovery ◽  
Initial Therapy ◽  
Ambulatory Setting ◽  
Venous Flow ◽  
Variceal Bleed ◽  
Urinary Copper

BACKGROUND: Wilson disease (WD) is a rare disorder of copper metabolism.OBJECTIVE: To describe the authors’ clinical experience with a cohort of 48 adult patients followed in an ambulatory setting.METHODS: A retrospective chart review of patients with a diagnosis of WD was performed.RESULTS: Fifty-nine charts were identified and 11 were excluded on further review. At diagnosis, 14 patients were asymptomatic, with 13 hepatic, 15 neurological and six mixed hepatic/neurological presentations. Ceruloplasmin levels were low (<0.20 g/L) in 94%, and 24 h urinary copper levels high (>0.60 μmol/L) in 95% of cases. D-penicillamine was the most common initial therapy (48%), with zinc the most common at review (65%). Overall, biopsy and ultrasound reports documented cirrhosis in 53%. Portal hypertension, defined as splenomegaly (>12.0 cm), reversed portal venous flow on ultrasound or varices/gastropathy on endoscopy was seen in 63%. At last review, 39% had elevated aspartate aminotransferase (>34 U/L) and/or alanine aminotransferase levels (>40 U/L). One death and one transplant occurred, while three patients had encephalopathy, two became jaundiced, two developed ascites and one experienced variceal bleed. Of 21 neurological presenting patients, 14 improved compared with baseline, with four making almost complete recovery. Eleven patients experienced documented episodes of neurological decline, including four with non-neurological presentation. Diagnostic magnetic resonance imaging showed basal ganglia (64%), brainstem (64%) abnormalities and atrophy (36%); follow-up showed basal ganglia lesions (50%) and atrophy (55%).CONCLUSION: WD is a diverse chronic disease with generally favourable outcomes for patients who respond to initial therapy, which can be managed predominantly in an ambulatory setting.

scholarly journals Zinc Monotherapy for Young Patients with Presymptomatic Wilson Disease: A Single Center, Retrospective Study

2020 ◽  
Author(s):  
Haiman Hou ◽  
Dingbang Chen ◽  
Junxiu Liu ◽  
Li Feng ◽  
Jiwei Zhang ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Wilson Disease ◽  
Age At Onset ◽  
Young Patients ◽  
Abdominal Ultrasonography ◽  
Serum Aminotransferase ◽  
Urinary Copper ◽  
Group 2 ◽  
Experienced Treatment ◽  
Group 1

Abstract Background Few studies have focused on the treatment failure of zinc monotherapy for presymptomatic Wilson disease (WD) patients. Therefore, we aimed to evaluate the long-term efficacy of zinc monotherapy in presymptomatic patients and to analyze the possible factors that may influence the outcome of this treatment. Methods We retrospectively reviewed the medical records of presymptomatic WD patients who received zinc monotherapy from the time of diagnosis. Then, the characteristics of patients who were treated with zinc monotherapy successfully and those who experienced treatment failure were investigated. Results Forty presymptomatic WD patients were identified that have received zinc monotherapy as initial treatment, with a median age of 3.83 years at the time of diagnosis. 36 (90%) patients had abnormal alanine transaminase/aspartate transaminase levels at baseline. None of the patients became symptomatic during zinc monotherapy. 28 (70%, Group 1) patients were treated with zinc monotherapy successfully for a median period of 2.8 years. In Group 1, serum aminotransferase levels significantly decreased 6 and 12 months after zinc therapy compared to the baseline levels (P < 0.05). 12 (30%, Group 2) patients experienced treatment failure with zinc monotherapy due to uncontrolled serum liver enzyme levels, and D-penicillamine was combined. The baseline 24-hour urine copper levels before treatment were significantly higher in Group 2 compared to that in Group 1 (P = 0.018). Comparing the age at onset; ceruloplasmin, serum copper, ALT, and AST levels; and proportions of abdominal ultrasonography abnormality at baseline between Groups 1 and 2 revealed no statistically significant differences. Conclusions We found that high initial 24-hour urinary copper levels may lead to treatment failure of zinc monotherapy in presymptomatic WD patients. It might be reasonable to follow up liver function tests more closely during zinc monotherapy and to begin combination treatment with chelators early in patients with high level of 24-hour urinary copper.

Serum ceruloplasmin oxidase activity is a specific and non-invasive marker for Wilson disease

2008 ◽  
Vol 46 (01) ◽  
Author(s):  
U Merle ◽  
C Eisenbach ◽  
KH Weiss ◽  
S Tuma ◽  
W Stremmel
Keyword(s):  
Wilson Disease ◽  
Oxidase Activity ◽  
Serum Ceruloplasmin ◽  
Non Invasive

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 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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