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Wilson disease

Abstract

Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B, which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B. Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD.

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Fig. 1: A timeline of key discoveries in WD.
Fig. 2: Copper homeostasis in hepatocytes.
Fig. 3: Copper toxicity in the pathogenesis of WD.
Fig. 4: Liver pathology in WD.
Fig. 5: Post-mortem MRI and histopathology in neurological WD.
Fig. 6: Dystonia, a characteristic symptom in WD.
Fig. 7: Brain MRI changes in WD.
Fig. 8: Kayser-Fleischer rings in WD.

References

  1. 1.

    Bandmann, O., Weiss, K. H. & Kaler, S. G. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 14, 103–113 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Ferenci, P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum. Genet. 120, 151–159 (2006).

    CAS  Google Scholar 

  3. 3.

    DzieŻyc, K., Karliński, M., Litwin, T. & Członkowska, A. Compliant treatment with anti-copper agents prevents clinically overt Wilson’s disease in pre-symptomatic patients. Eur. J. Neurol. 21, 332–337 (2013).

    Google Scholar 

  4. 4.

    European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson’s disease. J. Hepatol. 56, 671–685 (2012). These guidelines are the current best practice for the management of WD from the EASL.

    Google Scholar 

  5. 5.

    Roberts, E. A. & Schilsky, M. L. Diagnosis and treatment of Wilson disease: an update. Hepatology 47, 2089–2111 (2008). These guidelines are the current best practice for the diagnosis and treatment of WD from the AASLD.

    CAS  Google Scholar 

  6. 6.

    Socha, P. et al. Wilson’s disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 66, 334–344 (2018).

    Google Scholar 

  7. 7.

    Saito, T. An assessment of efficiency in potential screening for Wilson’s disease. J. Epidemiol. Community Health 35, 274–280 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bachmann, H., Lössner, J. & Biesold, D. Wilson’s disease in the German Democratic Republic. I. Genetics and epidemiology [German]. Z. Gesamte Inn. Med. 34, 744–748 (1979).

    CAS  Google Scholar 

  9. 9.

    Scheinberg, I. H. & Sternlieb, I. Wilson’s disease (a volume in the major problems in internal medicine series). Ann. Neurol. 16, 626–626 (1984).

    Google Scholar 

  10. 10.

    Xie, J.-J. & Wu, Z.-Y. Wilson’s disease in China. Neurosci. Bull. 33, 323–330 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Lo, C. & Bandmann, O. Epidemiology and introduction to the clinical presentation of Wilson disease. Handb Clin. Neurol. 142, 7–17 (2017). This recent review describes population studies on WD epidemiology and highlights the different patterns of presentation that are commonly observed with WD.

    Google Scholar 

  12. 12.

    Coffey, A. J. et al. A genetic study of Wilson’s disease in the United Kingdom. Brain 136, 1476–1487 (2013).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Członkowska, A., Tarnacka, B., Litwin, T., Gajda, J. & Rodo, M. Wilson’s disease — cause of mortality in 164 patients during 1992–2003 observation period. J. Neurol. 252, 698–703 (2005).

    Google Scholar 

  14. 14.

    Svetel, M. et al. Long-term outcome in Serbian patients with Wilson disease. Eur. J. Neurol. 16, 852–857 (2009).

    CAS  Google Scholar 

  15. 15.

    Beinhardt, S. et al. Long-term outcomes of patients with Wilson disease in a large Austrian cohort. Clin. Gastroenterol. Hepatol. 12, 683–689 (2014).

    Google Scholar 

  16. 16.

    Cooper, D. N. et al. The Human Gene Mutation Database. QIAGEN http://www.hgmd.cf.ac.uk/ac/index.php (2018).

  17. 17.

    Stenson, P. D. et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum. Genet. 136, 665–677 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Huster, D. et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology 142, 947–956 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Ferenci, P. & Roberts, E. A. Defining Wilson disease phenotypes: from the patient to the bench and back again. Gastroenterology 142, 692–696 (2012).

    Google Scholar 

  20. 20.

    Caca, K. et al. High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype–genotype analysis. J. Hepatol. 35, 575–581 (2001).

    CAS  Google Scholar 

  21. 21.

    Gromadzka, G. et al. p.H1069Q mutation in ATP7B and biochemical parameters of copper metabolism and clinical manifestation of Wilson’s disease. Mov. Disord. 21, 245–248 (2006).

    Google Scholar 

  22. 22.

    Nicastro, E. et al. Genotype-phenotype correlation in Italian children with Wilson’s disease. J. Hepatol. 50, 555–561 (2009).

    CAS  Google Scholar 

  23. 23.

    Ferenci, P. Phenotype-genotype correlations in patients with Wilson’s disease. Ann. NY Acad. Sci. 1315, 1–5 (2014).

    CAS  Google Scholar 

  24. 24.

    Merle, U. et al. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol. 10, 8 (2010).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Okada, T. et al. High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson’s disease. Scand. J. Gastroenterol. 45, 1232–1237 (2010).

    CAS  Google Scholar 

  26. 26.

    Usta, J. et al. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype. PLOS ONE 9, e109727 (2014).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    CocoŞ, R. et al. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson’s disease: genetic and clinical homogeneity. PLOS ONE 9, e98520 (2014).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Mukherjee, S. et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat. Disord. 20, 75–81 (2014).

    Google Scholar 

  29. 29.

    Stättermayer, A. F. et al. Hepatic steatosis in Wilson disease — Role of copper and PNPLA3 mutations. J. Hepatol. 63, 156–163 (2015).

    Google Scholar 

  30. 30.

    Pingitore, P. et al. Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochim. Biophys. Acta 1841, 574–580 (2014).

    CAS  Google Scholar 

  31. 31.

    Schiefermeier, M. The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson’s disease. Brain 123, 585–590 (2000).

    Google Scholar 

  32. 32.

    Litwin, T., Gromadzka, G. & Członkowska, A. Apolipoprotein E gene (APOE) genotype in Wilson’s disease: impact on clinical presentation. Parkinsonism Relat. Disord. 18, 367–369 (2012).

    CAS  Google Scholar 

  33. 33.

    Stuehler, B., Reichert, J., Stremmel, W. & Schaefer, M. Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients. J. Mol. Med. 82, 629–634 (2004).

    CAS  Google Scholar 

  34. 34.

    Lovicu, M. et al. The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease. J. Gastroenterol. 41, 582–587 (2006).

    CAS  Google Scholar 

  35. 35.

    Wu, Z.-Y. et al. Mutation analysis of 218 Chinese patients with Wilson disease revealed no correlation between the canine copper toxicosis gene MURR1 and Wilson disease. J. Mol. Med. 84, 438–442 (2006).

    CAS  Google Scholar 

  36. 36.

    Yu, C. H. et al. The metal chaperone Atox1 regulates the activity of the human copper transporter ATP7B by modulating domain dynamics. J. Biol. Chem. 292, 18169–18177 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Simon, I., Schaefer, M., Reichert, J. & Stremmel, W. Analysis of the human Atox 1 homologue in Wilson patients. World J. Gastroenterol. 14, 2383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Lee, B. H. et al. Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson’s disease cohort. Liver Int. 31, 831–839 (2011).

    CAS  Google Scholar 

  39. 39.

    Bost, M., Piguet-Lacroix, G., Parant, F. & Wilson, C. M. R. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J. Trace Elem. Med. Biol. 26, 97–101 (2012).

    CAS  Google Scholar 

  40. 40.

    Gromadzka, G. et al. Gene variants encoding proteins involved in antioxidant defense system and the clinical expression of Wilson disease. Liver Int. 35, 215–222 (2014).

    Google Scholar 

  41. 41.

    Gromadzka, G., Rudnicka, M., Chabik, G., Przybyłkowski, A. & Członkowska, A. Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson’s disease. J. Hepatol. 55, 913–919 (2011).

    CAS  Google Scholar 

  42. 42.

    Senzolo, M. et al. Different neurological outcome of liver transplantation for Wilson’s disease in two homozygotic twins. Clin. Neurol. Neurosurg. 109, 71–75 (2007).

    Google Scholar 

  43. 43.

    Członkowska, A., Gromadzka, G. & Chabik, G. Monozygotic female twins discordant for phenotype of Wilson’s disease. Mov. Disord. 24, 1066–1069 (2009).

    Google Scholar 

  44. 44.

    Kegley, K. M. et al. Fulminant Wilson’s disease requiring liver transplantation in one monozygotic twin despite identical genetic mutation. Am. J. Transplant. 10, 1325–1329 (2010).

    CAS  Google Scholar 

  45. 45.

    Bethin, K. E., Cimato, T. R. & Ettinger, M. J. Copper binding to mouse liver S-adenosylhomocysteine hydrolase and the effects of copper on its levels. J. Biol. Chem. 270, 20703–20711 (1995).

    CAS  Google Scholar 

  46. 46.

    Delgado, M. et al. Early effects of copper accumulation on methionine metabolism. Cell. Mol. Life Sci. 65, 2080–2090 (2008).

    CAS  Google Scholar 

  47. 47.

    Medici, V. et al. Wilson’s disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology 57, 555–565 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Medici, V. et al. Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. Epigenetics 9, 286–296 (2013).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Ma, J. & Betts, N. M. Zinc and copper intakes and their major food sources for older adults in the 1994–1996 continuing survey of food intakes by individuals (CSFII). J. Nutr. 130, 2838–2843 (2000).

    CAS  Google Scholar 

  50. 50.

    Russell, K., Gillanders, L. K., Orr, D. W. & Plank, L. D. Dietary copper restriction in Wilson’s disease. Eur. J. Clin. Nutr. 72, 326–331 (2018).

    CAS  Google Scholar 

  51. 51.

    Maryon, E. B., Molloy, S. A. & Kaplan, J. H. Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1. Am. J. Physiol. Cell Physiol. 304, C768–C779 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Llanos, R. M. et al. Copper transport during lactation in transgenic mice expressing the human ATP7A protein. Biochem. Biophys. Res. Commun. 372, 613–617 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Hatori, Y. et al. Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway. Nat. Commun. 7, 10640 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Baker, Z. N., Cobine, P. A. & Leary, S. C. The mitochondrion: a central architect of copper homeostasis. Metallomics 9, 1501–1512 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Xiao, Z. et al. Unification of the copper(I) binding affinities of the metallo-chaperones Atx1, Atox1, and related proteins. J. Biol. Chem. 286, 11047–11055 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Liggi, M. et al. The relationship between copper and steatosis in Wilson’s disease. Clin. Res. Hepatol. Gastroenterol. 37, 36–40 (2013).

    CAS  Google Scholar 

  57. 57.

    Muchenditsi, A. et al. Targeted inactivation of copper transporter Atp7b in hepatocytes causes liver steatosis and obesity in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G39–G49 (2017).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Aigner, E. et al. A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am. J. Gastroenterol. 105, 1978–1985 (2010).

    CAS  Google Scholar 

  59. 59.

    Zhang, H. et al. Alterations of serum trace elements in patients with type 2 diabetes. J. Trace Elem. Med. Biol. 40, 91–96 (2017).

    CAS  Google Scholar 

  60. 60.

    Stättermayer, A. F. et al. Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome. J. Trace Elem. Med. Biol. 39, 100–107 (2017).

    Google Scholar 

  61. 61.

    Pierson, H. et al. The function of ATPase copper transporter ATP7B in intestine. Gastroenterology 154, 168–180 (2018).

    CAS  Google Scholar 

  62. 62.

    Das, A. et al. Endothelial antioxidant-1: a key mediator of copper-dependent wound healing in vivo. Sci. Rep. 6, 33783 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Jurevics, H. et al. Cerebroside synthesis as a measure of the rate of remyelination following cuprizone-induced demyelination in brain. J. Neurochem. 77, 1067–1076 (2001).

    CAS  Google Scholar 

  64. 64.

    Urso, E. & Maffia, M. Behind the link between copper and angiogenesis: established mechanisms and an overview on the role of vascular copper transport systems. J. Vasc. Res. 52, 172–196 (2015).

    CAS  Google Scholar 

  65. 65.

    Jain, S. et al. Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Ann. Oncol. 24, 1491–1498 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Cumings, J. N. The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration. Brain 71, 410–415 (1948).

    CAS  Google Scholar 

  67. 67.

    Lin, C., Zhang, Z., Wang, T., Chen, C. & James Kang, Y. Copper uptake by DMT1: a compensatory mechanism for CTR1 deficiency in human umbilical vein endothelial cells. Metallomics 7, 1285–1289 (2015).

    CAS  Google Scholar 

  68. 68.

    Lang, P. A. et al. Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat. Med. 13, 164–170 (2007).

    CAS  Google Scholar 

  69. 69.

    Letelier, M. E., Sánchez-Jofré, S., Peredo-Silva, L., Cortés-Troncoso, J. & Aracena-Parks, P. Mechanisms underlying iron and copper ions toxicity in biological systems: pro-oxidant activity and protein-binding effects. Chem. Biol. Interact. 188, 220–227 (2010).

    CAS  Google Scholar 

  70. 70.

    Mufti, A. R. et al. XIAP is a copper binding protein deregulated in Wilson’s disease and other copper toxicosis disorders. Mol. Cell 21, 775–785 (2006).

    CAS  Google Scholar 

  71. 71.

    Huster, D. et al. Consequences of copper accumulation in the livers of the Atp7b−/− (Wilson disease gene) knockout mice. Am. J. Pathol. 168, 423–434 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Borchard, S. et al. The exceptional sensitivity of brain mitochondria to copper. Toxicol. In Vitro 51, 11–22 (2018).

    CAS  Google Scholar 

  73. 73.

    Mounajjed, T., Oxentenko, A. S., Qureshi, H. & Smyrk, T. C. Revisiting the topic of histochemically detectable copper in various liver diseases with special focus on venous outflow impairment. Am. J. Clin. Pathol. 139, 79–86 (2013).

    Google Scholar 

  74. 74.

    Huster, D. Structural and metabolic changes in Atp7b−/− mouse liver and potential for new interventions in Wilson’s disease. Ann. NY Acad. Sci. 1315, 37–44 (2014).

    CAS  Google Scholar 

  75. 75.

    Sternlieb, I. Mitochondrial and fatty changes in hepatocytes of patients with Wilson’s disease. Gastroenterology 55, 354–367 (1968).

    CAS  Google Scholar 

  76. 76.

    Peng, F. Positron emission tomography for measurement of copper fluxes in live organisms. Ann. NY Acad. Sci. 1314, 24–31 (2014).

    CAS  Google Scholar 

  77. 77.

    Scheiber, I. F., Brůha, R. & Dušek, P. Pathogenesis of Wilson disease. Handb Clin. Neurol. 142, 43–55 (2017).

    Google Scholar 

  78. 78.

    Mikol, J. et al. Extensive cortico-subcortical lesions in Wilson’s disease: clinico-pathological study of two cases. Acta Neuropathol. 110, 451–458 (2005).

    Google Scholar 

  79. 79.

    Horoupian, D. S., Sternlieb, I. & Scheinberg, I. H. Neuropathological findings in penicillamine-treated patients with Wilson’s disease. Clin. Neuropathol. 7, 62–67 (1988).

    CAS  Google Scholar 

  80. 80.

    Scheiber, I. F. & Dringen, R. Copper-treatment increases the cellular GSH content and accelerates GSH export from cultured rat astrocytes. Neurosci. Lett. 498, 42–46 (2011).

    CAS  Google Scholar 

  81. 81.

    Bertrand, E. et al. Neuropathological analysis of pathological forms of astroglia in Wilson’s disease. Folia Neuropathol. 39, 73–79 (2001).

    CAS  Google Scholar 

  82. 82.

    Pal, A. & Prasad, R. Recent discoveries on the functions of astrocytes in the copper homeostasis of the brain: a brief update. Neurotox. Res. 26, 78–84 (2014).

    CAS  Google Scholar 

  83. 83.

    Dusek, P. et al. Brain iron accumulation in Wilson disease: a post mortem 7 Tesla MRI — histopathological study. Neuropathol. Appl. Neurobiol. 43, 514–532 (2016).

    Google Scholar 

  84. 84.

    Meenakshi-Sundaram, S. et al. Wilson’s disease: a clinico-neuropathological autopsy study. J. Clin. Neurosci. 15, 409–417 (2008).

    CAS  Google Scholar 

  85. 85.

    Dusek, P. et al. Brain iron accumulation in Wilson’s disease: a longitudinal imaging case study during anticopper treatment using 7.0T MRI and transcranial sonography. J. Magn. Reson. Imaging 47, 282–285 (2018).

    Google Scholar 

  86. 86.

    Svetel, M. et al. Dystonia in Wilson’s disease. Mov. Disord. 16, 719–723 (2001).

    CAS  Google Scholar 

  87. 87.

    Iwański, S., Seniów, J., Leśniak, M., Litwin, T. & Członkowska, A. Diverse attention deficits in patients with neurologically symptomatic and asymptomatic Wilson’s disease. Neuropsychology 29, 25–30 (2015).

    Google Scholar 

  88. 88.

    Südmeyer, M. et al. Synchronized brain network underlying postural tremor in Wilson’s disease. Mov. Disord. 21, 1935–1940 (2006).

    Google Scholar 

  89. 89.

    Prashanth, L. K. et al. Spectrum of epilepsy in Wilson’s disease with electroencephalographic, MR imaging and pathological correlates. J. Neurol. Sci. 291, 44–51 (2010).

    CAS  Google Scholar 

  90. 90.

    Langwińska-Wośko, E., Litwin, T., Szulborski, K. & Członkowska, A. Optical coherence tomography and electrophysiology of retinal and visual pathways in Wilson’s disease. Metab. Brain Dis. 31, 405–415 (2016).

    Google Scholar 

  91. 91.

    Langwińska-Wośko, E., Litwin, T., DzieŻyc, K., Karlinski, M. & Członkowska, A. Optical coherence tomography as a marker of neurodegeneration in patients with Wilson’s disease. Acta Neurol. Belg. 117, 867–871 (2017).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Walshe, J. M. The acute haemolytic syndrome in Wilson’s disease — a review of 22 patients. QJM 106, 1003–1008 (2013).

    CAS  Google Scholar 

  93. 93.

    Forman, S. J., Kumar, K. S., Redeker, A. G. & Hochstein, P. Hemolytic anemia in wilson disease: clinical findings and biochemical mechanisms. Am. J. Hematol. 9, 269–275 (1980).

    CAS  Google Scholar 

  94. 94.

    Benders, A. A. et al. Copper toxicity in cultured human skeletal muscle cells: the involvement of Na+/K+-ATPase and the Na+/Ca2+-exchanger. Pflugers Arch. 428, 461–467 (1994).

    CAS  Google Scholar 

  95. 95.

    Hogland, H. C. & Goldstein, N. P. Hematologic (cytopenic) manifestations of Wilson’s disease (hepatolenticular degeneration). Mayo Clin. Proc. 53, 498–500 (1978).

    CAS  Google Scholar 

  96. 96.

    DzieŻyc, K., Litwin, T. & Członkowska, A. Other organ involvement and clinical aspects of Wilson disease. Handb Clin. Neurol. 142, 157–169 (2017).

    Google Scholar 

  97. 97.

    Zhuang, X.-H., Mo, Y., Jiang, X.-Y. & Chen, S.-M. Analysis of renal impairment in children with Wilson’s disease. World J. Pediatr. 4, 102–105 (2008).

    Google Scholar 

  98. 98.

    Weiss, K. H. et al. Bone demineralisation in a large cohort of Wilson disease patients. J. Inherit. Metab. Dis. 38, 949–956 (2015).

    Google Scholar 

  99. 99.

    Menerey, K. A. et al. The arthropathy of Wilson’s disease: clinical and pathologic features. J. Rheumatol. 15, 331–337 (1988).

    CAS  Google Scholar 

  100. 100.

    Buksińska-Lisik, M., Litwin, T., Pasierski, T. & Członkowska, A. Cardiac assessment in Wilson’s disease patients based on electrocardiography and echocardiography examination. Arch. Med. Sci. https://doi.org/10.5114/aoms.2017.69728 (2017).

  101. 101.

    Brewer, G. J. & Askari, F. K. Wilson’s disease: clinical management and therapy. J. Hepatol. 42, S13–S21 (2005).

    Google Scholar 

  102. 102.

    Dalvi, A. Wilson’s disease: neurological and psychiatric manifestations. Dis. Mon. 60, 460–464 (2014).

    Google Scholar 

  103. 103.

    Dusek, P., Litwin, T. & Czlonkowska, A. Wilson disease and other neurodegenerations with metal accumulations. Neurol. Clin. 33, 175–204 (2015).

    Google Scholar 

  104. 104.

    Weiss, K. H. Wilson Disease. GeneReviews (Univ. of Washington, Seattle, 1993).

    Google Scholar 

  105. 105.

    Medici, V. & Weiss, K.-H. Genetic and environmental modifiers of Wilson disease. Handb Clin. Neurol. 142, 35–41 (2017). This recent review describes what is currently known about genetic factors and environmental factors involved in the pathogenesis of WD.

    Google Scholar 

  106. 106.

    Boga, S., Ala, A. & Schilsky, M. L. Hepatic features of Wilson disease. Handb Clin. Neurol. 142, 91–99 (2017). This recent review describes the range of hepatic manifestations observed in patients with WD.

    Google Scholar 

  107. 107.

    Dhawan, A. et al. Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation. Liver Transpl. 11, 441–448 (2005).

    Google Scholar 

  108. 108.

    Kamath, P. S. & Kim, W. R. The model for end-stage liver disease (MELD). Hepatology 45, 797–805 (2007).

    Google Scholar 

  109. 109.

    Pugh, R. N. Pugh’s grading in the classification of liver decompensation. Gut 33, 1583 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Karlas, T. et al. Non-invasive evaluation of hepatic manifestation in Wilson disease with transient elastography, ARFI, and different fibrosis scores. Scand. J. Gastroenterol. 47, 1353–1361 (2012).

    Google Scholar 

  111. 111.

    Pfeiffenberger, J. et al. Hepatobiliary malignancies in Wilson disease. Liver Int. 35, 1615–1622 (2015).

    Google Scholar 

  112. 112.

    Pfeiffer, R. Wilson’s disease. Semin. Neurol. 27, 123–132 (2007).

    Google Scholar 

  113. 113.

    Lorincz, M. T. Neurologic Wilson’s disease. Ann. NY Acad. Sci. 1184, 173–187 (2009).

    Google Scholar 

  114. 114.

    Litwin, T., DzieŻyc, K., Karliński, M., Szafrański, T. & Członkowska, A. Psychiatric disturbances as a first clinical symptom of Wilson’s disease — case report. Psychiatr. Pol. 50, 337–344 (2016).

    Google Scholar 

  115. 115.

    Członkowska, A. & Litwin, T. Wilson disease — currently used anticopper therapy. Handb Clin. Neurol. 142, 181–191 (2017).

    Google Scholar 

  116. 116.

    Członkowska, A. et al. Characteristics of a newly diagnosed Polish cohort of patients with neurological manifestations of Wilson disease evaluated with the Unified Wilson’s Disease Rating Scale. BMC Neurol. 18, 34 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Członkowska, A. et al. Unified Wilson’s Disease Rating Scale — a proposal for the neurological scoring of Wilson’s disease patients. Neurol. Neurochir. Pol. 41, 1–12 (2007). This paper describes a novel WD-specific clinical rating scale based on neurological manifestations.

    Google Scholar 

  118. 118.

    Trocello, J.-M. et al. Hypersialorrhea in Wilson’s disease. Dysphagia 30, 489–495 (2015).

    Google Scholar 

  119. 119.

    da Silva-Júnior, F. P. et al. Swallowing dysfunction in Wilson’s disease: a scintigraphic study. Neurogastroenterol. Motil. 20, 285–290 (2008).

    Google Scholar 

  120. 120.

    Boyce, H. W. & Bakheet, M. R. Sialorrhea: a review of a vexing, often unrecognized sign of oropharyngeal and esophageal disease. J. Clin. Gastroenterol. 39, 89–97 (2005).

    Google Scholar 

  121. 121.

    Dening, T. R., Berrios, G. E. & Walshe, J. M. Wilson’s disease and epilepsy. Brain 111, 1139–1155 (1988).

    Google Scholar 

  122. 122.

    Pestana Knight, E. M., Gilman, S. & Selwa, L. Status epilepticus in Wilson’s disease. Epileptic Disord. 11, 138–143 (2009).

    Google Scholar 

  123. 123.

    Aikath, D. et al. Subcortical white matter abnormalities related to drug resistance in Wilson disease. Neurology 67, 878–880 (2006).

    CAS  Google Scholar 

  124. 124.

    Benbir, G., Gunduz, A., Ertan, S. & Ozkara, C. Partial status epilepticus induced by hypocupremia in a patient with Wilson’s disease. Seizure 19, 602–604 (2010).

    Google Scholar 

  125. 125.

    Barbosa, E. R. et al. Wilson’s disease with myoclonus and white matter lesions. Parkinsonism Relat. Disord. 13, 185–188 (2007).

    Google Scholar 

  126. 126.

    Machado, A. et al. Neurological manifestations in Wilson’s disease: report of 119 cases. Mov. Disord. 21, 2192–2196 (2006).

    Google Scholar 

  127. 127.

    Trindade, M. C. et al. Restless legs syndrome in Wilson’s disease: frequency, characteristics, and mimics. Acta Neurol. Scand. 135, 211–218 (2016).

    Google Scholar 

  128. 128.

    Tribl, G. G. et al. Wilson’s disease with and without rapid eye movement sleep behavior disorder compared to healthy matched controls. Sleep Med. 17, 179–185 (2016).

    Google Scholar 

  129. 129.

    Ingster-Moati, I. et al. Ocular motility and Wilson’s disease: a study on 34 patients. J. Neurol. Neurosurg. Psychiatry 78, 1199–1201 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Litwin, T., Dusek, P. & Czlonkowska, A. Neurological manifestations in Wilson’s disease — possible treatment options for symptoms. Expert Opin. Orphan Drugs 4, 719–728 (2016). This review describes the most frequent neurological symptoms associated with WD and their possible treatments.

    CAS  Google Scholar 

  131. 131.

    Hermann, W. Morphological and functional imaging in neurological and non-neurological Wilson’s patients. Ann. NY Acad. Sci. 1315, 24–29 (2014).

    CAS  Google Scholar 

  132. 132.

    King, A. D. et al. Cranial MR imaging in Wilson’s disease. Am. J. Roentgenol. 167, 1579–1584 (1996).

    CAS  Google Scholar 

  133. 133.

    Prayer, L. et al. Cranial MRI in Wilson’s disease. Neuroradiology 32, 211–214 (1990).

    CAS  Google Scholar 

  134. 134.

    Sinha, S. et al. Sequential MRI changes in Wilson’s disease with de-coppering therapy: a study of 50 patients. Br. J. Radiol. 80, 744–749 (2007).

    CAS  Google Scholar 

  135. 135.

    Kozic, D. et al. MR imaging of the brain in patients with hepatic form of Wilson’s disease. Eur. J. Neurol. 10, 587–592 (2003).

    CAS  Google Scholar 

  136. 136.

    MiletiĆ, V., OzretiĆ, D. & Relja, M. Parkinsonian syndrome and ataxia as a presenting finding of acquired hepatocerebral degeneration. Metab. Brain Dis. 29, 207–209 (2014).

    Google Scholar 

  137. 137.

    Litwin, T. et al. Early neurological worsening in patients with Wilson’s disease. J. Neurol. Sci. 355, 162–167 (2015).

    Google Scholar 

  138. 138.

    Walter, U. et al. Lenticular nucleus hyperechogenicity in Wilson’s disease reflects local copper, but not iron accumulation. J. Neural Transm. 121, 1273–1279 (2014).

    CAS  Google Scholar 

  139. 139.

    Wiebers, D. O., Hollenhorst, R. W. & Goldstein, N. P. The ophthalmologic manifestations of Wilson’s disease. Mayo Clin. Proc. 52, 409–416 (1977).

    CAS  Google Scholar 

  140. 140.

    Sridhar, M. S. Advantages of anterior segment optical coherence tomography evaluation of the Kayser–Fleischer ring in Wilson disease. Cornea 36, 343–346 (2017).

    Google Scholar 

  141. 141.

    Zimbrean, P. C. & Schilsky, M. L. Psychiatric aspects of Wilson disease: a review. Gen. Hosp. Psychiatry 36, 53–62 (2014). This article describes the psychiatric manifestations of WD.

    Google Scholar 

  142. 142.

    Akil, M. & Brewer, G. J. Psychiatric and behavioral abnormalities in Wilson’s disease. Adv. Neurol. 65, 171–178 (1995).

    CAS  Google Scholar 

  143. 143.

    Azova, S., Rice, T., Garcia-Delgar, B. & Coffey, B. J. New-onset psychosis in an adolescent with Wilson’s disease. J. Child Adolesc. Psychopharmacol. 26, 301–304 (2016).

    Google Scholar 

  144. 144.

    Srinivas, K. et al. Dominant psychiatric manifestations in Wilson’s disease: a diagnostic and therapeutic challenge! J. Neurol. Sci. 266, 104–108 (2008).

    CAS  Google Scholar 

  145. 145.

    Svetel, M. et al. Neuropsychiatric aspects of treated Wilson’s disease. Parkinsonism Relat. Disord. 15, 772–775 (2009).

    Google Scholar 

  146. 146.

    Carta, M. G. et al. Bipolar disorders and Wilson’s disease. BMC Psychiatry 12, 52 (2012).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Chung, Y. S., Ravi, S. D. & Borge, G. F. Psychosis in Wilson’s disease. Psychosomatics 27, 65–66 (1986).

    CAS  Google Scholar 

  148. 148.

    Demily, C. et al. Screening of Wilson’s disease in a psychiatric population: difficulties and pitfalls. A preliminary study. Ann. Gen. Psychiatry 16, 19 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Litwin, T. et al. Psychiatric manifestations in Wilson’s disease: possibilities and difficulties for treatment. Ther. Adv. Psychopharmacol. 8, 199–211 (2018).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Portala, K., Westermark, K., von Knorring, L. & Ekselius, L. Psychopathology in treated Wilson’s disease determined by means of CPRS expert and self-ratings. Acta Psychiatr. Scand. 101, 104–109 (2000).

    CAS  Google Scholar 

  151. 151.

    Gwirtsman, H. E., Prager, J. & Henkin, R. Case report of anorexia nervosa associated with Wilson’s disease. Int. J. Eat. Disord. 13, 241–244 (1993).

    CAS  Google Scholar 

  152. 152.

    Kumawat, B. L., Sharma, C. M., Tripathi, G., Ralot, T. & Dixit, S. Wilson’s disease presenting as isolated obsessive-compulsive disorder. Indian J. Med. Sci. 61, 607 (2007).

    CAS  Google Scholar 

  153. 153.

    Steindl, P. et al. Wilson’s disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 113, 212–218 (1997).

    CAS  Google Scholar 

  154. 154.

    Cauza, E. et al. Screening for Wilson’s disease in patients with liver diseases by serum ceruloplasmin. J. Hepatol. 27, 358–362 (1997).

    CAS  Google Scholar 

  155. 155.

    Korman, J. D. et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 48, 1167–1174 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Merle, U., Eisenbach, C., Weiss, K. H., Tuma, S. & Stremmel, W. Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson’s disease. J. Hepatol. 51, 925–930 (2009).

    CAS  Google Scholar 

  157. 157.

    Walshe, J. M. Serum ‘free’ copper in Wilson disease. QJM 105, 419–423 (2011).

    Google Scholar 

  158. 158.

    Poujois, A. et al. Exchangeable copper: a reflection of the neurological severity in Wilson’s disease. Eur. J. Neurol. 24, 154–160 (2016).

    Google Scholar 

  159. 159.

    Müller, T. et al. Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson’s disease in children. J. Hepatol. 47, 270–276 (2007).

    Google Scholar 

  160. 160.

    Schilsky, M. L. Non-invasive testing for Wilson disease: revisiting the d-penicillamine challenge test. J. Hepatol. 47, 172–173 (2007).

    CAS  Google Scholar 

  161. 161.

    Członkowska, A., Rodo, M., Wierzchowska-Ciok, A., Smolinski, L. & Litwin, T. Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease. Liver Int. https://doi.org/10.1111/liv.13715 (2018).

  162. 162.

    Yang, X. et al. Prospective evaluation of the diagnostic accuracy of hepatic copper content, as determined using the entire core of a liver biopsy sample. Hepatology 62, 1731–1741 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Ferenci, P. et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson’s disease. Clin. Gastroenterol. Hepatol. 3, 811–818 (2005).

    CAS  Google Scholar 

  164. 164.

    Song, Y.-M. & Chen, M.-D. A single determination of liver copper concentration may misdiagnose Wilson’s disease. Clin. Biochem. 33, 589–590 (2000).

    CAS  Google Scholar 

  165. 165.

    Roberts, E. A. & Cox, D. W. 3 Wilson disease. Baillieres. Clin. Gastroenterol. 12, 237–256 (1998).

    CAS  Google Scholar 

  166. 166.

    Ferenci, P. Wilson’s Disease. Clin. Gastroenterol. Hepatol. 3, 726–733 (2005).

    CAS  Google Scholar 

  167. 167.

    Ferenci, P. et al. Diagnosis and phenotypic classification of Wilson disease1. Liver Int. 23, 139–142 (2003). This important paper discusses phenotypic classification and presents a widely used WD diagnosis algorithm.

    Google Scholar 

  168. 168.

    Ferenci, P. Diagnosis of Wilson disease. Hand. Clin. Neurol. 142, 171–180 (2017).

    Google Scholar 

  169. 169.

    DzieŻyc, K., Litwin, T., Chabik, G., Gramza, K. & Członkowska, A. Families with Wilson’s disease in subsequent generations: clinical and genetic analysis. Mov. Disord. 29, 1828–1832 (2014).

    Google Scholar 

  170. 170.

    Brunet, A.-S., Marotte, S., Guillaud, O. & Lachaux, A. Familial screening in Wilson’s disease: think at the previous generation! J. Hepatol. 57, 1394–1395 (2012).

    Google Scholar 

  171. 171.

    Graper, M. L. & Schilsky, M. L. Patient support groups in the management of Wilson disease. Handb Clin. Neurol. 142, 231–240 (2017).

    Google Scholar 

  172. 172.

    Ahmad, A., Torrazza-Perez, E. & Schilsky, M. L. Liver transplantation for Wilson disease. Handb Clin. Neurol. 142, 193–204 (2017).

    Google Scholar 

  173. 173.

    Bruha, R. et al. Long-term follow-up of Wilson disease: natural history, treatment, mutations analysis and phenotypic correlation. Liver Int. 31, 83–91 (2010).

    Google Scholar 

  174. 174.

    Członkowska, A. et al. D-Penicillamine versus zinc sulfate as first-line therapy for Wilson’s disease. Eur. J. Neurol. 21, 599–606 (2014).

    Google Scholar 

  175. 175.

    Masełbas, W., Chabik, G. & Członkowska, A. Persistence with treatment in patients with Wilson disease. Neurol. Neurochir. Pol. 44, 260–263 (2010).

    Google Scholar 

  176. 176.

    Brewer, G. J., Terry, C. A., Aisen, A. M. & Hill, G. M. Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch. Neurol. 44, 490–493 (1987).

    CAS  Google Scholar 

  177. 177.

    Chen, D.-B. et al. Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. PLOS ONE 7, e37709 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Ranucci, G., Di Dato, F., Spagnuolo, M., Vajro, P. & Iorio, R. Zinc monotherapy is effective in Wilson’s disease patients with mild liver disease diagnosed in childhood: a retrospective study. Orphanet J. Rare Dis. 9, 41 (2014).

    PubMed  PubMed Central  Google Scholar 

  179. 179.

    Weiss, K. H. et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin. Gastroenterol. Hepatol. 11, 1028–1035 (2013).

    CAS  Google Scholar 

  180. 180.

    Weiss, K. H. et al. Outcome and development of symptoms after orthotopic liver transplantation for Wilson disease. Clin. Transplant. 27, 914–922 (2013).

    Google Scholar 

  181. 181.

    Pfeiffenberger, J., Weiss, K.-H. & Stremmel, W. Wilson disease: symptomatic liver therapy. Handb Clin. Neurol. 142, 205–209 (2017).

    Google Scholar 

  182. 182.

    Litwin, T., Dušek, P. & Członkowska, A. Symptomatic treatment of neurologic symptoms in Wilson disease. Handb Clin. Neurol. 142, 211–223 (2017).

    Google Scholar 

  183. 183.

    Tarnacka, B., Rodo, M., Cichy, S. & Czlonkowska, A. Procreation ability in Wilson’s disease. Acta Neurol. Scand. 101, 395–398 (2000).

    CAS  Google Scholar 

  184. 184.

    Sinha, S., Taly, A. B., Prashanth, L. K., Arunodaya, G. R. & Swamy, H. S. Successful pregnancies and abortions in symptomatic and asymptomatic Wilson’s disease. J. Neurol. Sci. 217, 37–40 (2004).

    Google Scholar 

  185. 185.

    Klee, J. G. Undiagnosed Wilson’s disease as cause of unexplained miscarriage. Lancet 2, 423 (1979).

    CAS  Google Scholar 

  186. 186.

    Pfeiffenberger, J. et al. Pregnancy in Wilson’s disease: management and outcome. Hepatology 67, 1261–1269 (2018).

    CAS  Google Scholar 

  187. 187.

    Aggarwal, N., Negi, N., Aggarwal, A., Bodh, V. & Dhiman, R. K. Pregnancy with portal hypertension. J. Clin. Exp. Hepatol. 4, 163–171 (2014).

    PubMed  PubMed Central  Google Scholar 

  188. 188.

    Gambling, L. & McArdle, H. J Iron and copper and fetal development. Proc. Nutr. Soc. 63, 553–562 (2004).

    CAS  Google Scholar 

  189. 189.

    Zimbrean, P. C. & Schilsky, M. L. The spectrum of psychiatric symptoms in Wilson’s disease: treatment and prognostic considerations. Am. J. Psychiatry 172, 1068–1072 (2015).

    Google Scholar 

  190. 190.

    Avasthi, A., Sahoo, M., Modi, M., Biswas, P. & Sahoo, M. Psychiatric manifestations of wilson’s disease and treatment with electroconvulsive therapy. Indian J. Psychiatry 52, 66 (2010).

    PubMed  PubMed Central  Google Scholar 

  191. 191.

    Bleakley, S. Identifying and reducing the risk of antipsychotic drug interactions. Prog. Neurol. Psychiatry 16, 20–24 (2012).

    Google Scholar 

  192. 192.

    Rybakowski, J., Litwin, T., Chlopocka-Wozniak, M. & Czlonkowska, A. Lithium treatment of a bipolar patient with Wilson’s disease: a case report. Pharmacopsychiatry 46, 120–121 (2012).

    Google Scholar 

  193. 193.

    Kulaksizoglu, I. B. & Polat, A. Quetiapine for mania With Wilson’s disease. Psychosomatics 44, 438–439 (2003).

    Google Scholar 

  194. 194.

    Svetel, M. et al. Quality of life in patients with treated and clinically stable Wilson’s disease. Mov. Disord. 26, 1503–1508 (2011).

    Google Scholar 

  195. 195.

    Sutcliffe, R. P. et al. Liver transplantation for Wilson’s disease: long-term results and quality-of-life assessment. Transplantation 75, 1003–1006 (2003).

    Google Scholar 

  196. 196.

    Taly, A. B. et al. Quality of life inWilson’s disease. Ann. Indian Acad. Neurol. 11, 37 (2008).

    PubMed  PubMed Central  Google Scholar 

  197. 197.

    Schaefer, M. et al. Wilson disease: health-related quality of life and risk for depression. Clin. Res. Hepatol. Gastroenterol. 40, 349–356 (2016).

    Google Scholar 

  198. 198.

    Schilsky, M. L. Long-term outcome for Wilson disease: 85% good. Clin. Gastroenterol. Hepatol. 12, 690–691 (2014).

    Google Scholar 

  199. 199.

    Weiss, K. H. et al. Bis-choline tetrathiomolybdate in patients with Wilson’s disease: an open-label, multicentre, phase 2 study. Lancet Gastroenterol. Hepatol. 2, 869–876 (2017). This recent original paper presents data on a potential new treatment for WD, which may address some unmet needs associated with currently available therapies.

    Google Scholar 

  200. 200.

    Roy-Chowdhury, J. & Schilsky, M. L. Gene therapy of Wilson disease: a ‘golden’ opportunity using rAAV on the 50th anniversary of the discovery of the virus. J. Hepatol. 64, 265–267 (2016).

    Google Scholar 

  201. 201.

    Hamilton, J. P. et al. Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease inAtp7B−/−(Wilson disease) mice. Hepatology 63, 1828–1841 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Jung, S. et al. Quantification of ATP7B protein in dried blood spots by peptide immuno-SRM as a potential screen for Wilson’s disease. J. Proteome Res. 16, 862–871 (2017).

    CAS  Google Scholar 

  203. 203.

    Ala, A. & Schilsky, M. Genetic modifiers of liver injury in hereditary liver disease. Semin. Liver Dis. 31, 208–214 (2011).

    CAS  Google Scholar 

  204. 204.

    Le, A. et al. Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease. Int. J. Mol. Sci. 15, 8004–8023 (2014).

    PubMed  PubMed Central  Google Scholar 

  205. 205.

    Fritzsch, D. et al. Seven-tesla magnetic resonance imaging in Wilson disease using quantitative susceptibility mapping for measurement of copper accumulation. Invest. Radiol. 49, 299–306 (2014).

    Google Scholar 

  206. 206.

    Tarnacka, B., Szeszkowski, W., Golebiowski, M. & Czlonkowska, A. MR spectroscopy in monitoring the treatment of Wilson’s disease patients. Mov. Disord. 23, 1560–1566 (2008).

    Google Scholar 

  207. 207.

    Chang, I. J. & Hahn, S. H. The genetics of Wilson disease. Handb Clin. Neurol. 142, 19–34 (2017).

    PubMed  PubMed Central  Google Scholar 

  208. 208.

    Girard, M. et al. CCDC115-CDG: a new rare and misleading inherited cause of liver disease. Mol. Genet. Metab. 124, 228–235 (2018).

    CAS  Google Scholar 

  209. 209.

    Walshe, J. M. History of Wilson disease. Handb Clin. Neurol. 142, 1–5 (2017).

    Google Scholar 

  210. 210.

    Nazer, H., Ede, R. J., Mowat, A. P. & Williams, R. Wilson’s disease: clinical presentation and use of prognostic index. Gut 27, 1377–1381 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the following grant support: A.C. and T.L. (NCN 2013/11/B and NZ2/00130); S.L. (US NIH grant DK071865), P.D. (Czech Ministry of Health, nr.15-25602A) and V.M. (US NIH grant DK104770-02). Assistance with administration, reference management and English language provided by E. Marshman, which was funded by the Institute of Psychiatry and Neurology (Poland) as a statutory activity.

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Nature Reviews Disease Primers thanks P. Wittung-Stafshede, M. Svetel, R.H.J.H. Houwen, R. Iorio and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Contributions

Introduction (A.C. and T.L.); Epidemiology (A.C. and T.L.); Mechanisms/pathophysiology (S.L., V.M. and P.D.); Diagnosis, screening and prevention (K.H.W., T.L., A.C., J.K.R. and P.F.); Management (T.L., A.C., K.H.W. and J.K.R.); Quality of life (A.C. and T.L.); Outlook (M.L.S.); overview of Primer (A.C.).

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Correspondence to Anna Członkowska.

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Competing interests

A.C. has served on advisory boards for Wilson Therapeutics, Vivet Therapeutics and GMP-Orphan SAS and has received speaker fees from EVER Pharma, Boehringer Ingelheim and Nutricia. P.F. has served on advisory boards for Wilson Therapeutics, Vivet Therapeutics and Univar and has received speaker fees from Univar. V.M. has served as a consultant for Kadmon Holdings. K.H.W. is on the speakers bureaus of AbbVie, Alexion Pharmaceuticals, Bayer, Bristol-Myers Squibb, Chiesi Farmaceutici SpA, GMP-Orphan SAS, Norgine, Novartis, Univar, Wilson Therapeutics and Vivet Therapeutics and has received grants (to the institution) from Alexion Pharmaceuticals, Bayer, Bristol-Myers Squibb, Eisai, GMP-Orphan SAS, Novartis, Univar and Wilson Therapeutics. M.L.S. has served on advisory boards for Wilson Therapeutics, Vivet Therapeutics, GMP-Orphan SAS and Kadmon Holdings, is a speaker for Gilead Sciences and is on the Medical Advisory Committee of the Wilson Disease Association. All other authors declare no competing interests.

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Członkowska, A., Litwin, T., Dusek, P. et al. Wilson disease. Nat Rev Dis Primers 4, 21 (2018). https://doi.org/10.1038/s41572-018-0018-3

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