Wilson’s disease: update on pathogenesis, biomarkers and treatments

Abstract

Wilson’s disease is an autosomal–recessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. Decoppering treatments are used to prevent disease progression and reduce symptoms, but neurological outcomes remain mixed. In this article, we review the current understanding of pathogenesis, biomarkers and treatments for Wilson’s disease from the neurological perspective, with a focus on recent advances. The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotype–phenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilson’s disease. Delayed diagnoses continue to be a major problem for patients with neurological presentations. We highlight limitations in our current approach to making a diagnosis and novel diagnostic biomarkers, including the potential for newborn screening programmes. We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilson’s disease, before discussing future directions for translational research.

Clinical and Genetic Analysis in Neurological Wilson’s Disease Patients With Neurological Worsening Following Chelator Therapy

“…However, stronger and faster anti-copper therapy, which could remove brain copper more quickly, and may could have a better clinical outcome in these patients. There are several potential new therapeutic approaches in recent years, such as novel chelating agents, gene therapy, and targeted molecular therapy ( Shribman et al, 2021b ). Bis-choline tetrathiomolybdate (TTM), a novel promising copper-protein-binding agent, is capable of rapidly controlling free copper and detoxifying circulating reactive copper in tripartite complexes due to its unique mechanism of action.…”

The Role of Zinc in the Treatment of Wilson’s Disease

“…A small number of case series support the use of penicillamine to treat severe hepatic insufficiency [ 108 ]. However, a high percentage of patients, who cannot be identified pre-treatment, suffer from ‘paradoxical’ deterioration as chelators promote a transient increase in free copper intoxication [ 2 , 109 , 110 ] ( Figure 1 c). The brain is more sensitive to increased levels of free copper [ 1 , 14 , 111 ].…”

“…Wilson’s disease (WD) is a rare hereditary impairment of copper metabolism with impaired incorporation of copper into ceruloplasmin, leading to free copper intoxication (oxidative stress) and its deposition, mainly in the liver and brain, with lesser amounts in other organs. Disease results due to the toxicity of the deposited copper and/or the oxidative stress from reactive oxygen species (ROS) formed by the non-ceruloplasmin-bound copper [ 1 , 2 , 3 ]. Presentation is initially recognized due to hepatic (30–50%), neurologic (30–40%), or psychiatric/behavioral (30–40%) disturbances [ 4 ], although ophthalmological, renal, cardiac, osteoarticular, hematologic, endocrine, and sleep disturbances can also occur [ 5 , 6 , 7 ].…”

Dystonia

“…Dystonia and liver abnormalities and/or psychiatric symptoms raise the possibility of Wilson’s disease. 17 This autosomal recessive disorder of copper metabolism has a mean age of 18 for neurological presentation, often with a mixed movement disorder. 18 Full blood count, liver function tests, and serum caeruloplasmin are useful initial investigations.…”

“… 18 Full blood count, liver function tests, and serum caeruloplasmin are useful initial investigations. 17 Twenty four hour urine copper and slit lamp examination (for Kayser-Fleischer rings) can be organised if serum caeruloplasmin is low, neuro-imaging is abnormal, or there is a high index of suspicion for Wilson’s disease. First line treatments include copper chelating agents that increase urinary copper excretion or zinc salts that inhibit the intestinal absorption of copper.…”