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Wilson's disease: an update

Abstract

Wilson's disease (WD) is an inborn error of copper metabolism caused by a mutation to the copper-transporting gene ATP7B. The disease has an autosomal recessive mode of inheritance, and is characterized by excessive copper deposition, predominantly in the liver and brain. Diagnosis of the condition depends primarily on clinical features, biochemical parameters and the presence of the Kayser–Fleischer ring, and a new diagnostic scoring system has recently been proposed. Mutations in ATP7B can occur anywhere along the entire 21 exons, which makes the identification of gene defects particularly challenging. Identification of carriers and presymptomatic family members of affected individuals is achieved by polymerase-chain-reaction-based marker analysis. The traditional treatment for WD is based on copper chelation with agents such as D-penicillamine, but use of this drug has been questioned because of reported side effects. The use of agents such as trientine and ammonium tetrathiomolybdate has been advocated, although results of long-term trials are awaited. In selected cases, orthotropic hepatic transplantation can reverse the basic metabolic abnormality in WD and improve both hepatic and neurological symptoms. Studies of the underlying defects in ATP7B and its suspected modifiers ATOX1 and COMMD1 are expected to unravel the disease's genotype–phenotype correlation, and should lead to the design of improved drugs for ameliorating the suffering of patients.

Key Points

  • Wilson's disease is an inborn error of copper metabolism caused by a mutation to the copper-transporting gene ATP7B

  • Epidemiologic clustering of mutations to the ATP7B gene based on ethnicity have been observed

  • Diagnosis of the condition is made primarily on the basis of clinical findings, presence of the Kayser–Fleischer ring, and biochemical parameters

  • A new scoring system for diagnosis of the condition was proposed at the 8th International Conference on Wilson Disease and Menkes Disease, 2001

  • Treatment involves the use of a chelating agent, the most commonly used being D-penicillamine, and both symptomatic and presymptomatic affected individuals can be treated

  • Liver transplantation can be used for complete reversal of the metabolic abnormality

  • Early detection of presymptomatic individuals in affected families can be achieved by polymerase-chain-reaction-based linkage analysis using microsatellite markers

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Figure 1: Schematic representation of copper metabolism within a liver cell.
Figure 2: The Kayser–Fleischer ring around the periphery of the cornea caused by deposition of copper in Descemet's membrane.
Figure 3: The 'vacuous smile' typified by mask facies with an open mouth caused by dystonia of the facial and mandibular muscles.
Figure 4: Hyperintensities in the bilateral basal ganglia and thalami shown by T2-weighted MRI of the brain.
Figure 5: The typical 'face of the giant panda' seen in the midbrain on T2-weighted MRI of the brain.

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Acknowledgements

We would like to thank the patient for allowing publication of Figure 3, for which his written consent was obtained. We would like to extend our sincere thanks to Dr O Suchowersky, Director of the Movement Disorder Clinic, Department of Clinical Neurosciences, University of Calgary, Alberta, Canada for reviewing this paper and providing useful suggestions. We also gratefully acknowledge the help of Dr MK Roy, Dr S Biswas, Mr A Gupta and Mr A Biswas for literary support, Dr P Verma for assistance in photography, Miss S Das for editorial help and Miss N Roy for secretarial assistance.

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Correspondence to Shyamal K Das.

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Das, S., Ray, K. Wilson's disease: an update. Nat Rev Neurol 2, 482–493 (2006). https://doi.org/10.1038/ncpneuro0291

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