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The Present and Future Challenges of Wilson’s Disease Diagnosis and Treatment

The growing new knowledge about Wilson’s disease (WD) has ramifications for understanding the pathophys-iology and optimal clinical management of this rare condition. The aim of this review is to recapitulate the current understanding of the genetics of WD, explain the challenges in diagnosis and management, and appraise the pipeline of future diagnostic tests and therapies for WD. The genetic bases of WD are the autosomal recessive variants involving the ATP7B gene. The consequent hepatic and systemic copper accumulation is due to deficient biliary copper excretion and ceruloplasmin maturation within he-patocytes. The number of described mutations affecting the ATP7B gene is rapidly increasing with more than 900 variants currently reported. 1,2 The most common variant in patients of European descent is the H1069Q missense mutation that, at a molecular level, has been shown to be associated with protein misfolding and localization of the mutated protein in the endoplasmic reticulum, aberrant phosphorylation of the P- domain, and altered ATP binding orientation and affinity. 3,4 The clinical presentation of WD is varied and supports the fact that WD is a condition that affects primarily the liver and brain, but multiple organs, including heart, kidneys, and intestine, can be involved with a wide range of signs, symptoms, and tissue- specific damage. 5 Liver disease ranges from steatosis and mild elevation of liver enzymes to cirrhosis and acute liver failure with hemolysis and hepatic necrosis. Neuropsychiatric findings include speech, gait and balance disturbances, drooling, involuntary movements, dystonia, Parkinsonism, psychosis, depression, and irritability. Kayser-Fleischer (KF) rings, more commonly found in patients with