What is Wilson’s Disease? | Think Wilson

What is Wilson disease?

Wilson disease is a rare, genetic disease leading to copper build-up in the brain, liver, and other tissues, and that requires lifelong management.3,5,6 Mutations in the ATP7B copper transporter result in elevated copper levels that can then lead to a range of clinical consequences, including:

  • Hepatic dysfunction: reported as the initial clinical manifestation in ~45% of patients9,10
  • Neurologic dysfunction: reported as the initial clinical manifestation in ~40–60% of patients9,11
  • Psychiatric manifestations: reported to affect 30–40% of patients at diagnosis12
  • Ophthalmologic manifestations: Kayser–Fleischer rings are the most common and are present in 10−90% of patients13







Hepatic dysfunction: reported as the initial clinical manifestation in ~45% of patients9,10

Neurologic dysfunction: reported as the initial clinical manifestation in ~40–60% of patients9,11

Psychiatric manifestations: reported to affect 30–40% of patients at diagnosis12

Ophthalmologic manifestations:
Kayser–Fleischer rings are the most common and are present in 10−90% of patients13

High liver copper levels in Wilson’s disease
Brain MRI assessment
Psychiatric symptoms & manifestations of Wilson’s disease
Excess copper can cause amber eyes (Kayser Fleischer rings) in Wilson’s disease
Michael L. Schilsky, MD, FAASLD. Professor of Medicine and Surgery, Yale University. Director of Center of Excellence for Wilson disease, Yale University. Explains the Overview of Wilson disease.

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michael schilsky - yale school of medicine, connecticut, usa

Copper builds up in the liver & brain in Wilson’s disease

Copper metabolism in Wilson disease

Copper is an essential trace element involved in a wide range of processes, including iron oxidation, cellular respiration, and neurotransmitter biosynthesis.14 Free copper can lead to toxic effects, so regulating copper balance in the body is vital.14

Dietary copper is absorbed from the proximal small intestine and transported into the liver.3 Copper is normally transported in the blood in a variety of forms:

  • The majority of copper (65−71%) in the blood is bound to ceruloplasmin (a protein involved in iron metabolism)14
  • A smaller fraction is either bound to albumin (15−19%) or transcuprein (7−15%) for transport (referred to as exchangeable or labile copper)14
  • A tiny fraction of copper (<2−5%) in the blood is “free” copper and an excess of this fraction is believed to be what causes toxicity in Wilson disease4,14

In order to maintain a normal copper balance, excess copper must be excreted. The main route of copper excretion is in the bile, which is mediated by the copper transporter ATP7B.15,16 ATP7B also plays a role in the incorporation of copper into apoceruloplasmin in the liver for transport around the body.3

In Wilson disease, mutations in the ATP7B gene and reduced ATP7B activity in the liver lead to reduced copper excretion in the bile and reduced ceruloplasmin synthesis, and increased urinary copper excretion in an attempt to compensate.13,16 Copper builds up and eventually spills out from the liver and is deposited in other organs and tissues.3,15 This accumulation of toxic free copper leads to cellular damage and the clinical Wilson disease phenotype.3,15,16

Prevalence and genetics of Wilson disease

Comparing epidemiologic and genetic prevalence data for Wilson disease suggests that the disease may be underdiagnosed.5 The true prevalence of Wilson disease is unknown given the rare nature of the disease. Historically, the diagnosed prevalence has been estimated as 1 in 30,000 globally.1,2,17 However, recent large population-based studies from France estimate prevalence to be 1 in 67,00018 and from Hong Kong as 1 in 40,000.19 In contrast, genetic disease birth prevalence has been estimated at ~1:7026 to ~1:20,000.6,20

There are numerous genetic alterations associated with Wilson disease.5 A recent study reported that 782 pathogenic variants of the ATP7B gene have been identified.5 In addition, genetic variants where the pathogenicity is uncertain have also been reported.5

From a clinical standpoint, there is a poor genotype−phenotype correlation in Wilson disease.7,8 Differences in phenotype between patients with the same mutation suggest that clinical outcomes in patients with Wilson disease are likely influenced by environmental factors, resulting in the inability to reliably predict disease severity by genetic testing.7 Also, patients with a confirmed ATP7B gene alteration may be clinically asymptomatic.5,6 This could potentially be due to the patient being pre-symptomatic or harboring a non-pathogenic ATP7B variant.5,6

Video showing Sihoun Hahn, MD, PhD Professor, Department of Pediatrics and Medicine. Former Medical Director, Biochemical Genetics Program Director, Wilson Disease Center of Excellence. University of Washington School of Medicine. From Seattle, WA, USA. Explaining the Genetics of Wilson Disease

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Sihoun Hahn – Seattle Children’s Hospital, Washington, USA

Video showing Sihoun Hahn, MD, PhD Professor, Department of Pediatrics and Medicine. Former Medical Director, Biochemical Genetics Program Director, Wilson Disease Center of Excellence. University of Washington School of Medicine. From Seattle, WA, USA. Explaining the Newborn screening for Wilson disease: active research

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THINK GENETICS SUPPLEMENT – NEWBORN SCREENING FOR WILSON DISEASE: ACTIVE RESEARCH

Sihoun Hahn – Seattle Children’s Hospital, Washington, USA

REFERENCES

  1. 1. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47: 2089-2111.
  2. 2. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56: 671-685.
  3. 3. Patil M, Sheth KA, Krishnamurthy AC et al. A review and current perspective on Wilson disease. J Clin Exp Hepatol 2013; 3: 321-336.
  4. 4. Woimant F, Djebrani-Oussedik N, Poujois A. New tools for Wilson's disease diagnosis: exchangeable copper fraction. Ann Transl Med 2019; 7: S70.
  5. 5. Gao J, Brackley S, Mann JP. The global prevalence of Wilson disease from next-generation sequencing data. Genet Med 2019; 21: 1155-1163.
  6. 6. Coffey AJ, Durkie M, Hague S et al. A genetic study of Wilson's disease in the United Kingdom. Brain 2013; 136: 1476-1487.
  7. 7. Kegley KM, Sellers MA, Ferber MJ et al. Fulminant Wilson's disease requiring liver transplantation in one monozygotic twin despite identical genetic mutation. Am J Transplant 2010; 10: 1325-1329.
  8. 8. Merle U, Schaefer M, Ferenci P et al. Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 2007; 56: 115-120.
  9. 9. Walshe JM. Wilson's disease. The presenting symptoms. Arch Dis Child 1962; 37: 253-256.
  10. 10. Woimant F, Trocello JM. Disorders of heavy metals. Handb Clin Neurol 2014; 120: 851-864.
  11. 11. Pfeiffer RF. Wilson's disease. Semin Neurol 2007; 27: 123-132.
  1. 12. Zimbrean PC, Schilsky ML. Psychiatric aspects of Wilson disease: a review. Gen Hosp Psychiatry 2014; 36: 53-62.
  2. 13. Steindl P, Ferenci P, Dienes HP et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113: 212-218.
  3. 14. Catalani S, Paganelli M, Gilberti ME et al. Free copper in serum: an analytical challenge and its possible applications. J Trace Elem Med Biol 2018; 45: 176-180.
  4. 15. Petrukhin K, Lutsenko S, Chernov I et al. Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. Hum Mol Genet 1994; 3: 1647-1656.
  5. 16. Forbes JR, Cox DW. Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Hum Mol Genet 2000; 9: 1927-1935.
  6. 17. Socha P, Janczyk W, Dhawan A 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: 334-344.
  7. 18. Poujois A, Woimant F, Samson S et al. Characteristics and prevalence of Wilson's disease: a 2013 observational population-based study in France. Clin Res Hepatol Gastroenterol 2018; 42: 57-63.
  8. 19. Cheung KS, Seto WK, Fung J et al. Epidemiology and natural history of Wilson's disease in the Chinese: a territory-based study in Hong Kong between 2000 and 2016. World J Gastroenterol 2017; 23: 7716-7726.
  9. 20. Wallace DF, Dooley JS. ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Hum Genet 2020; doi: 10.1007/s00439-020-02161-3.