Wilson's disease and other neurological copper disorders

Abstract

The copper metabolism disorder Wilson's disease was first defined in 1912. Wilson's disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutations are increasingly available to confirm the clinical diagnosis of Wilson's disease, and results from biochemical and genetic prevalence studies suggest that Wilson's disease might be much more common than previously estimated. Early diagnosis of Wilson's disease is crucial to ensure that patients can be started on adequate treatment, but uncertainty remains about the best possible choice of medication. Furthermore, Wilson's disease needs to be differentiated from other conditions that also present clinically with hepatolenticular degeneration or share biochemical abnormalities with Wilson's disease, such as reduced serum ceruloplasmin concentrations. Disordered copper metabolism is also associated with other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations and the late-onset neurodegenerative disorders Alzheimer's disease and Parkinson's disease.

Figure 1

Normal copper metabolism and the molecular mechanisms of copper transport disease. Copper absorption occurs in the small intestine via enterocyte uptake by hCTR1, and passage into the blood mediated by ATP7A at the basolateral aspect of duodenal epithelia. Copper is conveyed to the liver via the portal circulation and excess removed by excretion into the bile at the apical aspect of hepatocytes, a process impaired by mutations in ATP7B. Copper diseases of the liver also involve the AP1S1 gene implicated in MEDNIK syndrome, an acetyl CoA transporter, SLC33A1, and a cytosolic copper chaperone, CCS. See text for details. Mutations in a manganese transporter, SLC30A10, produce hepatic cirrhosis due to manganese accumulation that can mimic Wilson disease. ATP7A and ATP7B are believed to mediate copper entry and exodus, respectively, at the blood-CSF (cerebrospinal fluid) barrier of choroid plexus epithelia. Brain copper deficiency (Menkes disease) or excess (Wilson disease), respectively, result from mutations in these essential copper transporters. The central nervous system is also affected by alterations of AP1S1, SLC33A1, CCS, and SLC30A10. Isolated motor neuron degeneration occurs in association with unique ATP7A missense mutations affecting axonal trafficking, and sensory peripheral neuropathy can be a component of Wilson disease.

Figure 2

Kayser Fleischer ring with copper deposition in Descemet’s membrane, leading to brown discolouration at the outer margin of the cornea (Reference to be added – Aftab et al., Lancet 2007 - and comment to be added “with permission by Elsevier”)

Figure 3

Two representative T2-weighted axial brain MR images showing on the left (solid white arrows) with symmetrical T2-w hyperintense lesions in the tectal midbrain on the left and in the ventromedial thalami and posterior limbs of the internal capsule on the right (kindly provided by Dr. M. Pham, Department of Neuroradiology, Heidelberg University Hospital, Germany).