The understanding and management of Wilson disease (WD) have dramatically improved since the first description of the disease by K. Wilson more than a century ago. However, the persistent long delay between the first symptoms and diagnosis emphasizes challenges in diagnosing earlier this copper overload disorder. As a treatable disease, WD should be detected early in the course of the disease by any health professionals at any care level, but the rare prevalence of the disease explains the lack of awareness of referring physicians. The most important challenge is to train physicians to recognize atypical or rare symptoms of WD that will lead to discuss the diagnosis more systematically. Atypia can come from the age of onset, the liver [non-alcoholic steatohepatitis (NASH) presentation], the central or peripheral nervous system (neuropathy, epilepsy, sleep disorders…) or may be due to lesions of other organs (renal manifestations, osteo-articular disorders or endocrine disturbances). Isolated biological anomalies, rare radiological findings or inadequate interpretation of copper test may also lead to misdiagnosis. The second challenge is to confirm the diagnosis faster and more effectively so as not to delay the initiation of treatment, and expand family screening as the genetic prevalence is higher than previously expected. Generalization of the exchangeable copper assay and the next generation sequencing (NGS) are two promising ways to overcome this ultimate challenge. By drawing attention to the earliest and rare symptoms and to new biomarkers and diagnostic tools, we hope that this article will increase diagnostic awareness and reduce delays so that patients can start their treatment earlier in the course of the illness and thus have a better disease prognosis.

Objective To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation. Methods French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson9s Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed. Results Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved (p < 0.0001 and p = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved (p = 0.0007). Severe sepsis (p = 0.011) and intensive care unit admission (p = 0.001) before LT were significantly associated with death. Conclusions LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk. Classification of evidence This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.

Wilson’s disease (WD) is a rare autosomal recessive metabolic disease caused by ATP7B gene mutations tat cause excessively high copper levels, particularly in the liver and brain. The WD phenotype varies in terms of its clinical presentation and intensity. Diagnosing this metabolic disorder is important as a lifelong treatment, based on the use of copper chelating agents or zinc salts, is more effective if it’s started early. Worldwide prevalence of WD is variable, with an average of 1/30,000. In France, a recent study based on French health insurance data estimated the clinical prevalence of the disease to be around 3/200,000. To estimate the genetic prevalence of WD in France, we analysed the ATP7B gene by Next Generation Sequencing from a large French cohort of indiscriminate subjects. We observed a high heterozygous carrier frequency of ATP7B in France. Among the 697 subjects studied, 18 variants classified as pathogenic or probably pathogenic were found at heterozygous level in 22 subjects (22 alleles/1394 alleles), yielding a prevalence of 0.032 or 1/31 subjects. This considerable and unexplained discrepancy between the heterozygous carrier frequency and the clinical prevalence of WD may be explained by the clinical variability, the incomplete penetrance and the existence of modifiers genes. It suggests that the molecular analysis of ATP7B should be interpreted with caution, always alongside copper assays (ceruloplasmin, relative exchangeable copper, 24 h-urinary copper excretion) with particular respect to exome sequencing.