• ATP7B gene
• Arab world
• Clinical spectrum
• Molecular spectrum
• Wilson disease

• Hepatolenticular Degeneration/genetics
• Humans
• Copper-Transporting ATPases/genetics
• Copper-Transporting ATPases/metabolism
• Arab World
• Mutation
• Copper/metabolism

• copper accumulation
• hepatosplenomegaly in infancy
• liver cirrhosis
• pediatrics
• wilson`s disease

• ATP7B
• Wilson disease
• meta-analysis
• missense
• mutation

• Functional connectivity
• Resting-state electroencephalography
• Wilson's disease

• Humans
• Hepatolenticular Degeneration/physiopathology
• Male
• Female
• Electroencephalography/methods
• Adult
• Young Adult
• Nerve Net/physiopathology
• Cerebral Cortex/physiopathology
• Rest/physiology
• Adolescent

• Humans
• Dysarthria/etiology
• Liver Cirrhosis/complications
• Muscle Weakness/etiology
• Male
• Middle Aged

• Biomarker
• Subcortical topographic organization
• Support vector machine
• Wilson’s disease
• fMRI

• Humans
• Hepatolenticular Degeneration/physiopathology
• Hepatolenticular Degeneration/diagnostic imaging
• Hepatolenticular Degeneration/drug therapy
• Male
• Female
• Magnetic Resonance Imaging/methods
• Adult
• Young Adult
• Brain/diagnostic imaging
• Brain/physiopathology
• Adolescent
• Treatment Outcome
• Support Vector Machine

• Movement disorders
• Neurodegenerative disorders
• Neuroimaging
• Neuroradiology
• Wilson’s disease

• Male
• Humans
• Female
• Hepatolenticular Degeneration/diagnostic imaging
• White Matter/diagnostic imaging
• White Matter/pathology
• Diffusion Tensor Imaging/methods
• Diffusion Magnetic Resonance Imaging
• Corpus Callosum/pathology
• Brain/pathology

• Wilson disease
• biomarker
• cholinesterase
• orthotopic liver transplantation
• recovery
• spectrum of symptoms

• ATP7B
• Ceruloplasmin
• Ceruloplasmina
• Cobre
• Copper
• Enfermedad de Wilson
• Enfermedad hepática
• Enfermedad neurológica
• Liver disease
• Neurological disease
• Wilson's disease

• Humans
• Ceruloplasmin/analysis
• Ceruloplasmin/metabolism
• Chelating Agents/therapeutic use
• Copper/metabolism
• Hepatolenticular Degeneration/diagnosis
• Hepatolenticular Degeneration/genetics
• Hepatolenticular Degeneration/metabolism
• Hepatolenticular Degeneration/therapy
• Penicillamine/therapeutic use

• ATP7B
• Wilson’s disease
• hepatic encephalopathy

• copper
• exposure assessment
• health‐based guidance value

• Wilson’s disease
• biomarker
• cholinesterase
• diagnosis of Wilson’s disease
• heterozygotic gene carriers

• Humans
• Biomarkers/blood
• Biomarkers/urine
• Butyrylcholinesterase/blood
• Butyrylcholinesterase/urine
• Ceruloplasmin/analysis
• Ceruloplasmin/urine
• Hepatolenticular Degeneration/diagnosis
• ROC Curve

Wilson’s disease (WD) is a hereditary disorder of copper metabolism, producing abnormally high levels of non-ceruloplasmin-bound copper, the determinant of the pathogenic process causing brain and hepatic damage and dysfunction. Although the disease is invariably fatal without medication, it is treatable and many of its adverse effects are reversible. Diagnosis is difficult due to the large range and severity of symptoms. A high index of suspicion is required as patients may have only a few of the many possible biomarkers. The genetic prevalence of ATP7B variants indicates higher rates in the population than are currently diagnosed. Treatments have evolved from chelators that reduce stored copper to zinc, which reduces the toxic levels of circulating non-ceruloplasmin-bound copper. Zinc induces intestinal metallothionein, which blocks copper absorption and increases excretion in the stools, resulting in an improvement in symptoms. Two meta-analyses and several large retrospective studies indicate that zinc is equally effective as chelators for the treatment of WD, with the advantages of a very low level of toxicity and only the minor side effect of gastric disturbance. Zinc is recommended as a first-line treatment for neurological presentations and is gaining acceptance for hepatic presentations. It is universally recommended for lifelong maintenance therapy and for presymptomatic WD.

• Chelating Agents/therapeutic use
• Copper/metabolism
• Hepatolenticular Degeneration/metabolism
• Humans
• Retrospective Studies
• Zinc/therapeutic use

• Wilson's disease
• cognition
• magnetic resonance imaging

• ATP7B gene
• Hotspot regions
• Mutations
• Variants
• Wilson disease

• Copper
• Hepatolenticular Degeneration/diagnosis
• Hepatolenticular Degeneration/therapy
• Humans

• MC_EX_MR/N50192X/1 Medical Research Council
• 102176/B/13/Z Wellcome Trust

• MRI
• Wilson’s disease
• atrophy
• biomarker
• diffusion

• Adolescent
• Adult
• Aged
• Brain/diagnostic imaging
• Brain/pathology
• Brain Injuries/pathology
• Brain Mapping
• Cross-Sectional Studies
• Hepatolenticular Degeneration/diagnostic imaging
• Hepatolenticular Degeneration/pathology
• Humans
• Magnetic Resonance Imaging/methods
• Middle Aged
• Neuroimaging
• Young Adult

• MR/L023784/2 Medical Research Council
• MR/M008525/1 Medical Research Council
• Guarantors of Brain and Association of British Neurologists
• The Reta Lila Weston Institute and Wilson’s Disease Support Group UK
• Alzheimer’s Society
• UK Dementia Research Institute
• UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK
• UCL Leonard Wolfson Experimental Neurology Centre
• MRC Clinician Scientist
• NIHR Rare Diseases Translational Research Collaboration
• Bluefield Project and the Association for Frontotemporal Degeneration

Serum ceruloplasmin is one of the major diagnostic parameters for Wilson’s disease (WD). Age and gender difference of serum ceruloplasmin remain controversy. This study aims to assess diagnostic value of serum ceruloplasmin level for WD in children up to age of 15 years.

Serum ceruloplasmin levels were measured in 317 WD patients, 21 heterozygotes, 372 healthy control children and 154 non-WD patients with other liver diseases. Receiver operating characteristic (ROC) curve was used to determine the diagnostic accuracy of serum ceruloplasmin for WD in children.

Among healthy controls, serum ceruloplasmin level was slightly low in the infants younger than 6 months, and then maintained from 26 to 33 mg/dl after age of 6 months. A total of 8.1% of healthy children had levels of serum ceruloplasmin < 20 mg/dL. Serum ceruloplasmin level was 5.7 ± 4.7 mg/dl in WD patients, and 25.6 ± 5.9 mg/dl in heterozygous carriers. Only 1.9% of WD patients had serum ceruloplasmin levels > 20 mg/dL. Serum ceruloplasmin levels had gender difference, being higher in healthy boys than healthy girls, and higher in asymptomatic WD boys than asymptomatic WD girls (p < 0.01, p < 0.05). Serum ceruloplasmin levels also presented genotypic difference. WD patients with R778L homozygotes exhibited lower levels of serum ceruloplasmin than the patients without R778L (p < 0.05). The ROC curve revealed that serum ceruloplasmin level, at a cutoff value of 16.8 mg/dL, had the highest AUC value (0.990) with a sensitivity of 95.9% and a specificity of 93.6%.

Serum ceruloplasmin is one of sensitive diagnostic biomarkers for WD in children. Gender and genotypic difference of serum ceruloplasmin level should be considered. The cutoff value of serum ceruloplasmin level < 16.8 mg/dL may provide the highest accuracy for diagnosis of WD in children.

The online version contains supplementary material available at 10.1186/s12876-022-02186-0.

• Ceruloplasmin
• Children
• Diagnosis
• Wilson’s disease

• copper nanocomposite
• copper-dependent enzyme systems
• cytotoxicity
• hepatocyte
• poly-N-vinylimidazole

Wilson’s disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.

To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.

The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7B variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations.

We analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the ATP7B gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%).

It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.

• Wilson’s disease
• Children
• Acute liver failure
• Hemolytic anemia
• ATP7B variant
• Genotype-phenotype correlation

• Diagnostic yield
• Global developmental delay
• Inborn errors of metabolism
• Intellectual disability

Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson’s disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape.

• Parkinsonian disorders
• Parkinson’s disease
• adult-onset dystonia-parkinsonism
• autosomal recessive early-onset
• dopa-responsive dystonia
• genetic counseling
• secondary Parkinson’s disease

• Children
• Eye movement
• Movement disorders
• Neurometabolic diseases
• Nystagmus

The economic and health care use burdens of Wilson’s disease (WD) are unknown. In this study, we aimed to quantify this health care resource use and economic burden. We performed a retrospective case‐control analysis of individuals in the Truven Health MarketScan Commercial Claims database (2007‐2017). Using propensity scores, 424 WD cases were matched 1:1 to chronic liver disease (CLD) controls without WD. Total and service‐specific parameters, expressed in monthly averages, were quantified for the 6‐month pre‐WD diagnosis versus the 12‐month period after diagnosis. Wilcoxon signed‐rank tests and McNemar tests were used to examine incremental differences in burden between cases and controls. Adjusted multivariable generalized linear regression models were used to compare health care burdens. Relative to the 6‐month pre‐WD diagnosis, the 12 months after diagnosis had more claims per patient (2.87 vs. 3.35; P < 0.0001) and increased per patient health care costs (US $2,089 vs. US $3,887; P < 0.0001). WD cases incurred US $1,908 more in total unadjusted costs compared to controls in the 12‐month postindex date monthly averages. The increase in claims was primarily due to outpatient visits (1.62 vs. 1.82) and pharmaceutical claims (1.11 vs. 1.37). Cases also had higher health care costs for inpatient admissions (US $559 vs. US $1,264), outpatient visits (US $770 vs. US $1,037), and pharmaceutical claims (US $686 vs. US $1,489). Conclusion: WD is associated with significant health care cost and use burdens driven by increased inpatient admissions, outpatient visits, and pharmaceutical claims.

• ATP7B gene
• Leipzig scale
• Wilson-like
• Wilson’s disease
• biomarkers
• genetic modifiers

• PI18/00147 Instituto de Salud Carlos III
• PI19/01360 Instituto de Salud Carlos III
• PROMETEO/2018/135 Generalitat Valenciana
• FPAA-Wilson Fundació Per Amor a l'Art (FPAA)
• Unit CB06/04/0065 CIBERhed Instituto de Salud Carlos III

Wilson’s disease (WD) is a rare inherited impaired copper metabolism with diverse clinical pictures dominated by hepatic and neurologic manifestations. We report the case of a 14-year-old female patient who attended the Department of Neuropsychiatry at Ali Abad Teaching Hospital, Kabul, Afghanistan, with generalized tonic-clonic seizure and cerebellar dysfunction. The patient was initially diagnosed as encephalitis and epilepsy and finally diagnosed with WD based on the clinical and laboratory findings. After 6 months of follow-up, the patient showed substantial clinical recovery.

• KF rings
• Wilson’s disease
• cerebellar dysfunction
• copper accumulation
• seizure

• Wilson disease
• adherence
• cognition
• mental health
• neurodevelopment

• ATP7B
• Ceruloplasmin
• Chelator
• Copper
• Liver disease
• Wilson´s disease

• Biopsia hepática
• Elastografía hepática
• Enfermedad de Wilson
• Fibrosis hepática
• Liver biopsy
• Liver fibrosis
• Transient elastography
• Wilsońs Disease

• UL1 TR001863 NCATS NIH HHS

• Copper toxicity
• HIF-1 signaling
• Steatosis
• Wilson's disease
• Zebrafish

• Animals
• CRISPR-Cas Systems
• Copper/metabolism
• Copper/toxicity
• Copper-Transporting ATPases/genetics
• Disease Models, Animal
• Fatty Liver/genetics
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Female
• Gene Knockout Techniques
• Hep G2 Cells
• Hepatocytes/metabolism
• Hepatolenticular Degeneration/genetics
• Hepatolenticular Degeneration/metabolism
• Humans
• Hypoxia-Inducible Factor 1/metabolism
• Liver/metabolism
• Liver/pathology
• Male
• Mutation
• Signal Transduction/physiology
• Zebrafish
• Zebrafish Proteins/genetics

Acute liver failure as the initial presentation of Wilson’s disease is usually associated with onset in childhood, adolescence or early adulthood. Outcomes after transplantation for late-onset presentations, at or after 40 years, are seldom reported in the literature.

We report a case, review the literature and provide unpublished data from the UK Transplant Registry on late-onset acute liver failure in Wilson's disease.

We describe the case of a 62-year-old man presenting with acute liver failure who was successfully treated with urgent liver transplantation. We identified 7 cases presenting at age 40 years or over in the literature, for which individual outcomes were reported; 3 were treated with transplantation and 2 survived. We identified a further 8 cases listed for transplantation in the UK between 1995 and 2014; 7 were treated with transplantation and 6 survived. One patient was de-listed for unknown reasons.

Wilson's disease should be considered in older adults presenting with acute liver failure. We suggest that urgent liver transplantation has good outcomes for late-onset presentations and recommend that urgent transplantation should always be considered in Wilson's disease presenting as acute liver failure.

Wilson's disease is a rare inherited disease that causes copper accumulation in the liver and brain and usually manifests during childhood, adolescence or early adulthood. We report the case of a 62-year-old who developed acute liver failure and was successfully treated with urgent liver transplantation. We discuss the outcomes of other late-onset cases of acute liver failure due to Wilson's disease in the literature and provide additional data from the UK Transplant Registry.

•

We describe the case of a 62-year-old transplanted for acute liver failure in Wilson's disease.

• ACLF, acute-on-chronic liver failure
• ALF, acute liver failure
• INR, international normalised ratio
• KF, Kayser-Fleischer
• NHSBT, NHS blood and transplant
• OPTN, Organ Procurement and Transplant Network
• WD, Wilson's disease
• Wilson's disease
• hepatolenticular degeneration
• liver failure
• liver transplantation

• Wilson's disease
• copper
• late-onset
• liver metastatic-like changes
• older age