biomedicines Review Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease Ana Sánchez-Monteagudo 1,2, Edna Ripollés 1,2, Marina Berenguer 2,3,4,5,† and Carmen Espinós 1,2,*,† 1 Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; [email protected] (A.S.-M.); [email protected] (E.R.) 2 Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain; [email protected] 3 Hepatology-Liver Transplantation Unit, Digestive Medicine Service, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain 4 Department of Medicine, Universitat de València, 46010 Valencia, Spain 5 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-963289680 † These authors have contributed equally. Abstract: Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychi- atric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD’s phenotype (Wilson-like). Many patients are diagnosed using current Citation: Sánchez-Monteagudo, A.; available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, Ripollés, E.; Berenguer, M.; Espinós, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD C. Wilson’s Disease: Facing the are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, Challenge of Diagnosing a Rare the characterization of biomarkers that allow us to anticipate the evolution of the disease and the Disease. Biomedicines 2021, 9, 1100. monitoring of new drugs is essential to improve its diagnosis and prognosis. https://doi.org/10.3390/ biomedicines9091100 Keywords: Wilson’s disease; Leipzig scale; ATP7B gene; Wilson-like; genetic modifiers; biomarkers Academic Editor: Marica Meroni Received: 6 July 2021 1. Introduction Accepted: 25 August 2021 Published: 28 August 2021 Wilson’s disease (WD; MIM 277900) is an autosomal recessive disorder related to the metabolism of copper, a metal that accumulates in tissues, mainly in the liver and brain. ATP7B Publisher’s Note: MDPI stays neutral WD is caused by mutations in the gene, which encodes for a copper transporter that with regard to jurisdictional claims in is responsible for biliary excretion of copper and its incorporation into ceruloplasmin. WD published maps and institutional affil- was first described by the British neurologist Samuel Alexander Kinnier Wilson as a “pro- iations. gressive lenticular degeneration accompanied by cirrhosis in the liver” [1]. The manuscript included six cases that presented with involuntary movements, spasticity, dysarthria, psy- chiatric disturbances, and advanced cirrhosis. In the first half of the 20th century, several researchers made important contributions to the knowledge of the pathophysiological mechanisms of the disease. Rumpel reported excess copper in the liver of a patient with WD Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. for the first time, and Cumings corroborated it and established that copper accumulation This article is an open access article in the liver and in the basal ganglia were the etiological basis of the disease [2,3]. Less than distributed under the terms and 50 years after its discovery, WD became the first chronic hereditary liver disease that had a conditions of the Creative Commons specific treatment, which made it possible to stop the devastating progression of the disease Attribution (CC BY) license (https:// and prevent the eventual death. Despite these initial advances, its diagnosis remains a creativecommons.org/licenses/by/ challenge and WD is currently an underdiagnosed disorder. Epidemiologic estimates have 4.0/). indeed established notable differences between clinical and genetic prevalence, which Biomedicines 2021, 9, 1100. https://doi.org/10.3390/biomedicines9091100 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 1100 2 of 24 may be due to multiple factors including genetic modifiers, epigenetics, and habits. The main underlying problem lies in suboptimal diagnostic tests and elusive biomarkers to Biomedicines 2021, 9, x FOR PEER REVIEWdiagnose a rare genetic disease characterized by incomplete penetrance and highly variable3 of 26 expression. In this review, we discuss the difficulties in achieving a definitive diagnosis and the need for biomarkers to improve the diagnosis of WD. 2. ClinicalWilson’s Picture disease of Wilson’s(WD) is a Disease multisystemic disorder with variable symptoms charac- terized by abnormal deposits of copper. Clinical signs depend on the organs where copper Wilson’s disease (WD) is a multisystemic disorder with variable symptoms char- is accumulated over the course of the pathological process (Figure 1; reviewed in [4–6]). acterized by abnormal deposits of copper. Clinical signs depend on the organs where Accordingly, liver and neurological involvement predominates, and WD can present as a copper is accumulated over the course of the pathological process (Figure1; reviewed liver, neurological or mixed disease. Most pediatric patients usually exhibit a liver presen- in [4–6]). Accordingly, liver and neurological involvement predominates, and WD can tation, whereas patients diagnosed in adulthood predominantly manifest with a mixed present as a liver, neurological or mixed disease. Most pediatric patients usually exhibit presentation. While diagnosis is typically made in childhood, adolescence, or early adult- a liver presentation, whereas patients diagnosed in adulthood predominantly manifest hood, between 5 and 35 years old, late presentations have been described. with a mixed presentation. While diagnosis is typically made in childhood, adolescence, or Zhourui Shang early adulthood, between 5 and 35 years old, late presentations have been described. Figure 1. Copper toxicity in the pathogenesis of Wilson’s disease. Main signs and symptoms observed in patients are Figure 1. Copper toxicity in the pathogenesis of Wilson’s disease. Main signs and symptoms observed in patients are included in green boxes and circles, while secondary findings are contained in blue circles. included in green boxes and circles, while secondary findings are contained in blue circles. Reasons that explain different phenotypes despite similar mutations are unclear. In- Reasons that explain different phenotypes despite similar mutations are unclear. Inter- terestingly, gender differences have been described in WD. In a large series with 627 pa- estingly, gender differences have been described in WD. In a large series with 627 patients (337tients men (337 versus men 290versus women), 290 neuropsychiatricwomen), neurop disturbancessychiatric disturbances (mainly rigidity-tremor, (mainly rigidity- rigid- tremor,ity and psychiatricrigidity and symptoms) psychiatric predominated symptoms) predominated and occurred inand men, occurred while hepaticin men, presen- while hepatic presentation was more common in women [7]. Gender differences have been ob- served even on brain magnetic resonance imaging (MRI). With neurological presentation, men suffer from cerebellar atrophy and cortical brain atrophy more often than women, whereas women suffer from globus pallidus lesions more frequently than men; with re- spect to the hepatic presentation, no variability is appreciated between sexes [8]. As with many disorders, differences seem to be attributed to a protective action of estrogens that Biomedicines 2021, 9, 1100 3 of 24 tation was more common in women [7]. Gender differences have been observed even on brain magnetic resonance imaging (MRI). With neurological presentation, men suffer from cerebellar atrophy and cortical brain atrophy more often than women, whereas women suffer from globus pallidus lesions more frequently than men; with respect to the hepatic presentation, no variability is appreciated between sexes [8]. As with many disorders, dif- ferences seem to be attributed to a protective action of estrogens that may exert antioxidant, neurotrophic, and anti-inflammatory effects, but also partly to a distinct iron metabolism between men and women [9]. 2.1. Clinical Signs 2.1.1. Liver Disease Liver damage ranges from steatosis to chronic hepatitis, fibrosis, and cirrhosis. Clini- cally, it may present as asymptomatic hypertransaminasemia, with any of the manifesta- tions of liver cirrhosis, or as severe acute liver failure (ALF). Diagnosis should be suspected when faced with patients, particularly children, adolescents, or young adults with any manifestations of liver disease without known etiological factor and/or when signs of neurological disease are also present. Of note, only 3.5% of patients with WD are diag- nosed after 45 years of age, while more than half of the cases show some symptom or biochemical alteration during childhood (after 3–4 years)