Background and Aims In 1984, Scheinberg and Sternlieb estimated the prevalence of Wilson’s disease to be 1:30,000 based on the limited available data. This suggested a large number of overlooked cases with potentially fatal consequences. The “Scheinberg‐Sternlieb Estimate” is still widely used, although more recent clinical and genetic studies of higher quality are now available. In the present study, we included these data to update the prevalence estimate. Approach and Results A MEDLINE Ovid, Science Citation Index Expanded, and PubMed systematic search for all relevant studies on the prevalence of Wilson’s disease was conducted. In total, 59 studies (50 clinical and 9 population‐based genetic) were included in the final analysis. We identified 4 recent clinical studies based on nationwide databases of high quality, providing prevalence estimates from 1:29,000 to 1:40,000. Higher frequency populations do exist because of frequent first‐cousin marriages and/or a higher mutation frequency. When calculating prevalence from the incidence related to number of births, estimates were 1:40,000‐1:50,000. Clinical screening studies, including examination for Kayser‐Fleischer rings or ceruloplasmin, did not improve these estimates because of insufficient sample size or selection biases. Population‐based genetic studies in US and UK populations were not in disagreement with the clinically based estimates. At the same time, studies from France and Sardinia suggested that the genetic prevalence may be 3‐4 times higher than the clinical disease prevalence. This raises the question whether the penetrance is indeed 100% as generally assumed. Conclusions The original prevalence estimate from 1984 of 1:30,000‐1:50,000 still appears valid, at least for the United States, Europe, and Asia. In some population‐based studies, the genetic prevalence was 3‐4 times higher than clinically based estimates. The question of penetrance needs further evaluation.

Background and Aims Wilson’s disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using PET with copper‐64 (64Cu) as a tracer. Furthermore, we assessed the diagnostic potential of the method. Approach and Results Nine patients with WD, 5 healthy heterozygote subjects, and 8 healthy controls were injected with an i.v. bolus of 64Cu followed by a 90‐min dynamic PET scan of the liver and static whole‐body PET/CT scans after 1.5, 6, and 20 h. Blood 64Cu concentrations were measured in parallel. Hepatic copper retention and redistribution were evaluated by standardized uptake values (SUVs). At 90 min, hepatic SUVs were similar in the three groups. In contrast, at 20 h postinjection, the SUV in WD patients (mean ± SEM, 31 ± 4) was higher than in heterozygotes (24 ± 3) and controls (21 ± 4; p < 0.001). An SUV‐ratio of hepatic 64Cu concentration at 20 and 1.5 h completely discriminated between WD patients and control groups (p < 0.0001; ANOVA). By Patlak analysis of the initial 90 min of the PET scan, the steady‐state hepatic clearance of 64Cu was estimated to be slightly lower in patients with WD than in controls (p = 0.04). Conclusions 64Cu PET imaging enables visualization and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, and may assist the development of therapies, and accurate diagnosis.

Zinc inhibits intestinal copper uptake, an effect utilized for treating Wilson’s disease (WD). We used copper-64 (64Cu) PET/CT to examine how much four weeks of treatment with different zinc regimens reduced the hepatic 64Cu content after oral 64Cu administration and test if alternative regimens were noninferior to the standard regimen of zinc acetate 50 mg × 3 daily. Forty healthy persons were randomized to four different zinc protocols. The WD standard treatment zinc acetate 50 mg × 3 reduced the hepatic 64Cu content from 26.9 ± 7.5% to 13.3 ± 5.6% of the administered 64Cu. Zinc gluconate 50 mg × 3 was noninferior (P = 0.02) (35.8 ± 9.0% to 17.4 ± 7.5%). Zinc acetate 150 mg × 1 (33.1 ± 9.9% to 17.4 ± 7.5%) and zinc gluconate 150 mg × 1 (28.1 ± 6.7% to 22.0 ± 6.7%) were less effective. These effects were intra- and inter-individually highly variable, and 14% had no effect of any zinc regimen, which may explain disparities in zinc treatment efficacy in WD patients.

Background: In Wilson disease (WD), mutations in the gene encoding the ATP7B copper transport protein causes accumulation of copper especially in liver and brain. WD typically presents with hepatic and/or neuropsychiatric symptoms. Impaired cognition is a well-described feature in patients neurological WD, while the reports on cognition in hepatic WD patients are fewer and less conclusive. We examined cognition in a cohort of WD patients with both phenotypes. Methods: In this cross-sectional pilot study, we investigated cognition in 28 stable Danish WD patients by portosystemic encephalopathy (PSE) and continuous reaction time (CRT) tests. Half of the patients were female and median age was 35.5 years (IQR 24.5). The phenotype was hepatic in 14 (50%), neurologic in 10 (36%) and mixed in 4 4 (14%). The duration of treatment was >2 year in all patients, and the condition stable as judged by urinary copper excretion, liver enzymes, and clinical assessment.Results: In total, 16 (57%) patients performed worse than normal in the PSE and/or CRT tests. The two tests correlated (rho=0.60, p=0.0007) with each other, but neither correlated with phenotype, MELD-, Child-Pugh score, 24h-U-Cu, or treatment type.Conclusion: Measurable cognitive impairment was present in more than half of the stable WD patients independent of phenotype. Thus, our data questions the existence of a purely hepatic phenotype.

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Background: In Wilson disease (WD), mutations in the gene encoding the ATP7B copper transport protein causes accumulation of copper especially in liver and brain. WD typically presents with hepatic and/or neuropsychiatric symptoms. Impaired cognition is a well-described feature in patients neurological WD, while the reports on cognition in hepatic WD patients are fewer and less conclusive. We examined cognition in a cohort of WD patients with both phenotypes.Methods: In this cross-sectional pilot study, we investigated cognition in 28 stable Danish WD patients by portosystemic encephalopathy (PSE) and continuous reaction time (CRT) tests. Half of the patients were female and median age was 35.5 years (IQR 24.5). The phenotype was hepatic in 14 (50%), neurologic in 10 (36%) and mixed in 4 4 (14%). The duration of treatment was >2 year in all patients, and the condition stable as judged by urinary copper excretion, liver enzymes, and clinical assessment.Results: In total, 16 (57%) patients performed worse than normal in the PSE and/or CRT tests. The two tests correlated (rho=0.60, p=0.0007) with each other, but neither correlated with phenotype, MELD-, Child-Pugh score, 24h-U-Cu, or treatment type. Conclusion:Measurable cognitive impairment was present in more than half of the stable WD patients independent of phenotype. Thus, our data questions the existence of a purely hepatic phenotype.

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BackgroundHuppke–Brendel (HB) syndrome is an autosomal recessive disease caused by variants in the SLC33A1 gene. Since 2012, less than ten patients have been reported, none survived year six. With neurologic involvement and ceruloplasmin deficiency, it may mimic Wilson disease (WD).Objectives and methodsWe report the first adult patient with HB.ResultsThe patient suffered from moderate intellectual disability, partial hearing loss, spastic ataxia, hypotonia, and unilateral tremor of parkinsonian type. At age 29, she was diagnosed with WD based on neurology, elevated 24H urinary copper, low ceruloplasmin, and pathological 65Cu test. Approximately 25 years later, genetic testing did not support WD or aceruloplasminemia. Full genome sequencing revealed two likely pathogenic variants in SLC33A1 which combined with re-evaluation of neurologic symptoms and MRI suggested the diagnosis of HB.ConclusionAdult patients with HB exist and may be confused with WD. Low ceruloplasmin and the absence of ATP7B variants should raise suspicion.