Advertisement

Update on the Diagnosis and Management of Wilson Disease

  • Eve A. RobertsEmail author
Liver (S Cotler and E Kallwitz, Section Editors)
  • 441 Downloads
Part of the following topical collections:
  1. Topical Collection on Liver

Abstract

Purpose of Review

Exciting developments relating to Wilson disease (WD) have taken place with respect to both basic biological and clinical research. This review critically examines some of these findings and considers their implications for current thinking about WD. It is not a comprehensive review of WD as a clinical disorder.

Recent Findings

The structure of the gene product of ATP7B, abnormal in WD, is being worked out in detail, along with a broader description of how the protein ATP7B (Wilson ATPase) functions in cells including enterocytes, not only in relation to copper disposition but also to lipid synthesis. Recent population studies raise the possibility that WD displays incomplete penetrance. Innovative screening techniques may increase ascertainment. New strategies for diagnosing and treating WD are being developed. Several disorders have been identified which might qualify as WD-mimics.

Summary

WD can be difficult to diagnose and treat. Insights from its pathobiology are providing new options for managing WD.

Keywords

Hepatolenticular degeneration Wilson disease ATP7B Wilson ATPase Copper Hepatic Neurological Psychiatric d-penicillamine Trientine Zinc salts Bis-choline tetrathiomolybdate Methanobactin Drug-pricing 

Notes

Compliance with Ethical Standards

Conflict of Interest

Eve Roberts declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. 1.
    Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5:327–37.PubMedGoogle Scholar
  2. 2.
    Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993;5:344–50.PubMedGoogle Scholar
  3. 3.
    Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 2015;14:103–13.PubMedPubMedCentralGoogle Scholar
  4. 4.
    • Mordaunt CE, Shibata NM, Kieffer DA, Czlonkowska A, Litwin T, Weiss KH, Gotthardt DN, et al. Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease. Hum Mol Genet. 2018 Jul 16. Most recent report relating to epigenetic mechanisms in WD. Google Scholar
  5. 5.
    Jayakanthan S, Braiterman LT, Hasan NM, Unger VM, Lutsenko S. Human copper transporter ATP7B (Wilson disease protein) forms stable dimers in vitro and in cells. J Biol Chem. 2017;292:18760–74.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Pierson H, Muchenditsi A, Kim BE, Ralle M, Zachos N, Huster D, et al. The function of ATPase copper transporter ATP7B in intestine. Gastroenterology. 2018;154:168–80 e165.PubMedGoogle Scholar
  7. 7.
    Ferenci P, Steindl-Munda P, Vogel W, Jessner W, Gschwantler M, Stauber R, et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson's disease. Clin Gastroenterol Hepatol. 2005;3:811–8.PubMedGoogle Scholar
  8. 8.
    Aigner E, Strasser M, Haufe H, Sonnweber T, Hohla F, Stadlmayr A, et al. A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am J Gastroenterol. 2010;105:1978–85.PubMedGoogle Scholar
  9. 9.
    Seessle J, Gohdes A, Gotthardt DN, Pfeiffenberger J, Eckert N, Stremmel W, et al. Alterations of lipid metabolism in Wilson disease. Lipids Health Dis. 2011;10:83.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Stattermayer AF, Traussnigg S, Dienes HP, Aigner E, Stauber R, Lackner K, et al. Hepatic steatosis in Wilson disease – role of copper and PNPLA3 mutations. J Hepatol. 2015;63:156–63.PubMedGoogle Scholar
  11. 11.
    •• Muchenditsi A, Yang H, Hamilton JP, Koganti L, Housseau F, Aronov L, et al. Targeted inactivation of copper transporter Atp7b in hepatocytes causes liver steatosis and obesity in mice. Am J Physiol Gastrointest Liver Physiol. 2017;313:G39–49 Innovative, potentially important, new model for WD in mice. PubMedPubMedCentralGoogle Scholar
  12. 12.
    Zimbrean PC, Schilsky ML. Psychiatric aspects of Wilson disease: a review. Gen Hosp Psychiatry. 2014;36:53–62.PubMedGoogle Scholar
  13. 13.
    Carta MG, Farina GC, Sorbello O, Moro MF, Demelia E, Cadoni F, et al. The risk of bipolar disorders and major depressive disorders in Wilson’s disease: results of a case-control study (abstr.). Int Clin Psychopahramcol. 2012;e61:28.Google Scholar
  14. 14.
    Machado A, Chien HF, Deguti MM, Cancado E, Azevedo RS, Scaff M, et al. Neurological manifestations in Wilson’s disease: report of 119 cases. Mov Disord. 2006;21:2192–6.PubMedGoogle Scholar
  15. 15.
    Schindler EA, Guo XM, Schrag M, Ghoshal S, Schilsky ML, Beslow LA. Neuropsychiatric presentation of Wilson disease in an adolescent male. Neuropediatrics. 2016;47:346–7.PubMedGoogle Scholar
  16. 16.
    Millard H, Zimbrean P, Martin A. Delay in diagnosis of Wilson disease in children with insidious psychiatric symptoms: a case report and review of the literature. Psychosomatics. 2015;56:700–5.PubMedGoogle Scholar
  17. 17.
    Svetel M, Potrebic A, Pekmezovic T, Tomic A, Kresojevic N, Jesic R, et al. Neuropsychiatric aspects of treated Wilson’s disease. Parkinsonism Relat Disord. 2009;15:772–5.PubMedGoogle Scholar
  18. 18.
    Medici V, Mirante VG, Fassati LR, Pompili M, Forti D, Del Gaudio M, et al. Liver transplantation for Wilson’s disease: the burden of neurological and psychiatric disorders. Liver Transpl. 2005;11:1056–63.PubMedGoogle Scholar
  19. 19.
    Sorbello O, Riccio D, Sini M, Carta M, Demelia L. Resolved psychosis after liver transplantation in a patient with Wilson’s disease. Clin Pract Epidemiol Ment Health. 2011;7:182–4.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Nevsimalova S, Buskova J, Bruha R, Kemlink D, Sonka K, Vitek L, et al. Sleep disorders in Wilson's disease. Eur J Neurol. 2011;18:184–90.PubMedGoogle Scholar
  21. 21.
    Tribl GG, Trindade MC, Bittencourt T, Lorenzi-Filho G, Cardoso Alves R, Ciampi de Andrade D, et al. Wilson's disease with and without rapid eye movement sleep behavior disorder compared to healthy matched controls. Sleep Med. 2016;17:179–85.PubMedGoogle Scholar
  22. 22.
    Tribl GG, Trindade MC, Schredl M, Pires J, Reinhard I, Bittencourt T, et al. Dream recall frequencies and dream content in Wilson’s disease with and without REM sleep behaviour disorder: a neurooneirologic study. Behav Neurol. 2016;2016:2983205.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Trindade MC, Bittencourt T, Lorenzi-Filho G, Alves RC, de Andrade DC, Fonoff ET, et al. Restless legs syndrome in Wilson's disease: frequency, characteristics, and mimics. Acta Neurol Scand. 2017;135:211–8.PubMedGoogle Scholar
  24. 24.
    Hefter H, Weiss P, Wesch H, Stremmel W, Feist D, Freund HJ. Late diagnosis of Wilson’s disease in a case without onset of symptoms. Acta Neurol Scand. 1995;91:302–5.PubMedGoogle Scholar
  25. 25.
    Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in septuagenarian siblings: raising the bar for diagnosis. Hepatology. 2005;41:668–70.PubMedGoogle Scholar
  26. 26.
    Czlonkowska A, Rodo M, Gromadzka G. Late onset Wilson’s disease: therapeutic implications. Mov Disord. 2008;23:896–8.PubMedGoogle Scholar
  27. 27.
    Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepatic Wilson’s disease in preschool-aged children. J Pediatr. 2000;137:719–22.PubMedGoogle Scholar
  28. 28.
    Wiernicka A, Dadalski M, Janczyk W, Kaminska D, Naorniakowska M, Husing-Kabar A, et al. Early onset of Wilson disease: diagnostic challenges. J Pediatr Gastroenterol Nutr. 2017;65:555–60.PubMedGoogle Scholar
  29. 29.
    Kim JW, Kim JH, Seo JK, Ko JS, Chang JY, Yang HR, et al. Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases. World J Hepatol. 2013;5:156–9.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Abuduxikuer K, Li LT, Qiu YL, Wang NL, Wang JS. Wilson disease with hepatic presentation in an eight-month-old boy. World J Gastroenterol. 2015;21:8981–4.PubMedPubMedCentralGoogle Scholar
  31. 31.
    •• Socha P, Janczyk W, Dhawan A, Baumann U, D'Antiga L, Tanner S, 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. 2018;66:334–44 General overview of pediatric WD. PubMedGoogle Scholar
  32. 32.
    Coffey AJ, Durkie M, Hague S, McLay K, Emmerson J, Lo C, et al. A genetic study of Wilson’s disease in the United Kingdom. Brain. 2013;136:1476–87.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Dufernez F, Lachaux A, Chappuis P, De Lumley L, Bost M, Woimant F, et al. Wilson disease in offspring of affected patients: report of four French families. Clin Res Hepatol Gastroenterol. 2013;37:240–5.PubMedGoogle Scholar
  34. 34.
    Loudianos G, Zappu A, Lepori MB, Incollu S, Dessi V, Mameli E, et al. Wilson’s disease in two consecutive generations: the detection of three mutated alleles in the ATP7B gene in two Sardinian families. Dig Liver Dis. 2013;45:342–5.PubMedGoogle Scholar
  35. 35.
    Bennett JT, Schwarz KB, Swanson PD, Hahn SH. An exceptional family with three consecutive generations affected by Wilson disease. JIMD Rep. 2013;10:1–4.PubMedGoogle Scholar
  36. 36.
    •• Jung S, Whiteaker JR, Zhao L, Yoo HW, Paulovich AG, Hahn SH. Quantification of ATP7B protein in dried blood spots by peptide immuno-SRM as a potential screen for Wilson’s disease. J Proteome Res. 2017;16:862–71 Innovative technique for general population screening. PubMedGoogle Scholar
  37. 37.
    McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the NOTCH signaling pathway. Am J Hum Genet. 2006;79:169–73.PubMedPubMedCentralGoogle Scholar
  38. 38.
    • Martinelli D, Travaglini L, Drouin CA, Ceballos-Picot I, Rizza T, Bertini E, et al. MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy. Brain. 2013;136:872–81 Most convincing candidate as a WD-mimic disorder on mechanistic basis. PubMedGoogle Scholar
  39. 39.
    Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, et al. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012;90:457–66.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, et al. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012;90:467–77.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Stamelou M, Tuschl K, Chong WK, Burroughs AK, Mills PB, Bhatia KP, et al. Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: a new treatable disorder. Mov Disord. 2012;27:1317–22.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Tuschl K, Meyer E, Valdivia LE, Zhao N, Dadswell C, Abdul-Sada A, et al. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun. 2016;7:11601.PubMedPubMedCentralGoogle Scholar
  43. 43.
    • Rodan LH, Hauptman M, D'Gama AM, Qualls AE, Cao S, Tuschl K, et al. Novel founder intronic variant in SLC39A14 in two families causing manganism and potential treatment strategies. Mol Genet Metab. 2018;124:161–7 Includes an overview of the manganism disorders. PubMedGoogle Scholar
  44. 44.
    Socha P, Vajro P, Lefeber D, Adamowicz M, Tanner S. Search for rare liver diseases: the case of glycosylation defects mimicking Wilson disease. Clin Res Hepatol Gastroenterol. 2014;38:403–6.PubMedGoogle Scholar
  45. 45.
    Goez HR, Jacob FD, Fealey RD, Patterson MC, Ramaswamy V, Persad R, et al. An unusual presentation of copper metabolism disorder and a possible connection with Niemann-pick type C. J Child Neurol. 2011;26:518–21.PubMedGoogle Scholar
  46. 46.
    Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23:139–42.PubMedGoogle Scholar
  47. 47.
    Xuan A, Bookman I, Cox DW, Heathcote J. Three atypical cases of Wilson disease: assessment of the Leipzig scoring system in making a diagnosis. J Hepatol. 2007;47:428–33.PubMedGoogle Scholar
  48. 48.
    Tatsumi Y, Shinohara T, Imoto M, Wakusawa S, Yano M, Hayashi K, et al. Potential of the international scoring system for the diagnosis of Wilson disease to differentiate Japanese patients who need anti-copper treatment. Hepatol Res. 2011;41:887–96.PubMedGoogle Scholar
  49. 49.
    Nicastro E, Ranucci G, Vajro P, Vegnente A, Iorio R. Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology. 2010;52:1948–56.PubMedGoogle Scholar
  50. 50.
    Martins da Costa C, Baldwin D, Portmann B, Lolin Y, Mowat AP, Mieli-Vergani G. Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson’s disease. Hepatology. 1992;15:609–15.PubMedGoogle Scholar
  51. 51.
    Vieira J, Oliveira PV, Juliano Y, Warde KR, Deguti MM, Barbosa ER, et al. Urinary copper excretion before and after oral intake of d-penicillamine in parents of patients with Wilson’s disease. Dig Liver Dis. 2012;44:323–7.PubMedGoogle Scholar
  52. 52.
    Anheim M, Chamouard P, Rudolf G, Ellero B, Vercueil L, Goichot B, et al. Unexpected combination of inherited chorea-acanthocytosis with MDR3 (ABCB4) defect mimicking Wilson’s disease. Clin Genet. 2010;78:294–5.PubMedGoogle Scholar
  53. 53.
    Shneider BL. ABCB4 disease presenting with cirrhosis and copper overload-potential confusion with Wilson disease. J Clin Exp Hepatol. 2011;1:115–7.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Ramraj R, Finegold MJ, Karpen SJ. Progressive familial intrahepatic cholestasis type 3: overlapping presentation with Wilson disease. Clin Pediatr (Phila). 2012;51:689–91.Google Scholar
  55. 55.
    Boga S, Jain D, Schilsky ML. Presentation of progressive familial intrahepatic cholestasis type 3 mimicking Wilson disease: molecular genetic diagnosis and response to treatment. Pediatr Gastroenterol Hepatol Nutr. 2015;18:202–8.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O'Halloran TV. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science. 1999;284:805–8.PubMedGoogle Scholar
  57. 57.
    • Duncan A, Yacoubian C, Beetham R, Catchpole A, Bullock D. The role of calculated non-caeruloplasmin-bound copper in Wilson’s disease. Ann Clin Biochem. 2017;54:649–54 Comprehensive review of inadequacies of this estimate. PubMedGoogle Scholar
  58. 58.
    El Balkhi S, Trocello JM, Poupon J, Chappuis P, Massicot F, Girardot-Tinant N, et al. Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson’s disease diagnosis. Clin Chim Acta. 2011;412:2254–60.PubMedGoogle Scholar
  59. 59.
    Trocello JM, El Balkhi S, Woimant F, Girardot-Tinant N, Chappuis P, Lloyd C, et al. Relative exchangeable copper: a promising tool for family screening in Wilson disease. Mov Disord. 2014;29:558–62.PubMedGoogle Scholar
  60. 60.
    Guillaud O, Brunet AS, Mallet I, Dumortier J, Pelosse M, Heissat S, et al. Relative exchangeable copper: a valuable tool for the diagnosis of Wilson disease. Liver Int. 2018;38:350–7.PubMedGoogle Scholar
  61. 61.
    Poujois A, Trocello JM, Djebrani-Oussedik N, Poupon J, Collet C, Girardot-Tinant N, et al. Exchangeable copper: a reflection of the neurological severity in Wilson’s disease. Eur J Neurol. 2017;24:154–60.PubMedGoogle Scholar
  62. 62.
    Korman JD, Volenberg I, Balko J, Webster J, Schiodt FV, Squires RH Jr, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48:1167–74.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Avan A, de Bie RMA, Hoogenraad TU. Wilson’s disease should be treated with zinc rather than trientine or penicillamine. Neuropediatrics. 2017;48:394–5.PubMedGoogle Scholar
  64. 64.
    Santiago R, Gottrand F, Debray D, Bridoux L, Lachaux A, Morali A, et al. Zinc therapy for Wilson disease in children in French pediatric centers. J Pediatr Gastroenterol Nutr. 2015;61:613–8.PubMedGoogle Scholar
  65. 65.
    Wiernicka A, Janczyk W, Dadalski M, Avsar Y, Schmidt H, Socha P. Gastrointestinal side effects in children with Wilson’s disease treated with zinc sulphate. World J Gastroenterol. 2013;19:4356–62.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Sturm E, Piersma FE, Tanner MS, Socha P, Roberts EA, Shneider BL. Controversies and variation in diagnosing and treating children with Wilson disease: results of an international survey. J Pediatr Gastroenterol Nutr. 2016;63:82–7.PubMedGoogle Scholar
  67. 67.
    Pfeiffenberger J, Mogler C, Gotthardt DN, Schulze-Bergkamen H, Litwin T, Reuner U, et al. Hepatobiliary malignancies in Wilson disease. Liver Int. 2015;35:1615–22.PubMedGoogle Scholar
  68. 68.
    •• Pfeiffenberger J, Beinhardt S, Gotthardt DN, Haag N, Freissmuth C, Reuner U, et al. Pregnancy in Wilson’s disease: management and outcome. Hepatology. 2018;67:1261–9 Large retrospective study of pregnancy in women with WD. PubMedGoogle Scholar
  69. 69.
    Fox AN, Schilsky M. Once daily trientine for maintenance therapy of Wilson disease. Am J Gastroenterol. 2008;103:494–5.PubMedGoogle Scholar
  70. 70.
    Ala A, Aliu E, Schilsky ML. Prospective pilot study of a single daily dosage of trientine for the treatment of Wilson disease. Dig Dis Sci. 2015;60:1433–9.PubMedPubMedCentralGoogle Scholar
  71. 71.
    •• Weiss KH, Askari FK, Czlonkowska A, Ferenci P, Bronstein JM, Bega D, et al. Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study. Lancet Gastroenterol Hepatol. 2017;2:869–76 New drug (oral chelator) treatment for WD. PubMedGoogle Scholar
  72. 72.
    Weiss KH, Czlonkowska A, Hedera P, Ferenci P. WTX101 - an investigational drug for the treatment of Wilson disease. Expert Opin Investig Drugs. 2018;27:561–7.PubMedGoogle Scholar
  73. 73.
    Kim HJ, Graham DW, DiSpirito AA, Alterman MA, Galeva N, Larive CK, et al. Methanobactin, a copper-acquisition compound from methane-oxidizing bacteria. Science. 2004;305:1612–5.PubMedGoogle Scholar
  74. 74.
    DiSpirito AA, Semrau JD, Murrell JC, Gallagher WH, Dennison C, Vuilleumier S. Methanobactin and the link between copper and bacterial methane oxidation. Microbiol Mol Biol Rev. 2016;80:387–409.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Lichtmannegger J, Leitzinger C, Wimmer R, Schmitt S, Schulz S, Kabiri Y, et al. Methanobactin reverses acute liver failure in a rat model of Wilson disease. J Clin Invest. 2016;126:2721–35.PubMedPubMedCentralGoogle Scholar
  76. 76.
    • Chesi G, Hegde RN, Iacobacci S, Concilli M, Parashuraman S, Festa BP, et al. Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants. Hepatology. 2016;63:1842–59 Possibility of rescuing some mutant versions of the Wilson ATPase. PubMedPubMedCentralGoogle Scholar
  77. 77.
    Hamilton JP, Koganti L, Muchenditsi A, Pendyala VS, Huso D, Hankin J, et al. Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7b −/− (Wilson Disease) (Wilson disease) mice. Hepatology. 2016;63:1828–41.Google Scholar
  78. 78.
    Wooton-Kee CR, Jain AK, Wagner M, Grusak MA, Finegold MJ, Lutsenko S, et al. Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. J Clin Invest. 2015;125:3449–60.PubMedPubMedCentralGoogle Scholar
  79. 79.
    • Murillo O, Luqui DM, Gazquez C, Martinez-Espartosa D, Navarro-Blasco I, Monreal JI, et al. Long-term metabolic correction of Wilson's disease in a murine model by gene therapy. J Hepatol. 2016;64:419–26 Investigation of gene replacement therapy in WD. PubMedGoogle Scholar
  80. 80.
    Moreno D, Murillo O, Gazquez C, Hernandez-Alcoceba R, Uerlings R, Gonzalez-Aseguinolaza G, et al. Visualization of the therapeutic efficacy of a gene correction approach in Wilson's disease by laser-ablation inductively coupled mass spectrometry. J Hepatol. 2018;68:1088–90.PubMedGoogle Scholar
  81. 81.
    Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol. 2018.Google Scholar
  82. 82.
    Beinhardt S, Leiss W, Stattermayer AF, Graziadei I, Zoller H, Stauber R, et al. Long-term outcomes of patients with Wilson disease in a large Austrian cohort. Clin Gastroenterol Hepatol. 2014;12:683–9.PubMedGoogle Scholar
  83. 83.
    Chandok N, Roberts EA. The trientine crisis in Canada: a call to advocacy. Can J Gastroenterol Hepatol. 2014;28:184.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Roberts EA, Herder M, Hollis A. Fair pricing of “old” orphan drugs: considerations for Canada’s orphan drug policy. CMAJ. 2015;187:422–5.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Schilsky ML, Roberts EA, Hahn S, Askari F. Costly choices for treating Wilson’s disease. Hepatology. 2015;61:1106–8.PubMedGoogle Scholar
  86. 86.
    Gupta P, Choksi M, Goel A, Zachariah U, Sajith KG, Ramachandran J, et al. Maintenance zinc therapy after initial penicillamine chelation to treat symptomatic hepatic Wilson’s disease in resource constrained setting. Indian J Gastroenterol. 2018;37:31–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Paediatrics, Medicine, and Pharmacology & ToxicologyUniversity of TorontoTorontoCanada
  2. 2.History of Science and Technology ProgrammeUniversity of King’s CollegeHalifaxUSA
  3. 3.Division of Gastroenterology, Hepatology, and NutritionThe Hospital for Sick ChildrenTorontoCanada

Personalised recommendations