Background

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by pathogenic variants in the ATP7B gene. Impaired biliary copper excretion leads to progressive accumulation in the liver, brain, and other organs. Despite prevalence estimates of 1:30,000 to 1:50,000, WD remains significantly underdiagnosed due to heterogeneous clinical manifestations and the absence of pathognomonic markers. This comprehensive review aimed to describe the current evidence on WD epidemiology, molecular pathogenesis, clinical manifestations, diagnostic strategies, and therapeutic approaches, with particular emphasis on neuropsychiatric presentations that contribute substantially to diagnostic delay and disability.

Methods

We searched PubMed/MEDLINE, EMBASE, and the Cochrane Library from inception to July 2025 using MeSH terms and free-text keywords including ‘Wilson disease’, ‘ATP7B’, ‘copper metabolism’, ‘neuropsychiatric manifestations’, ‘ceruloplasmin’, ‘exchangeable copper’, ‘relative exchangeable copper’, ‘liver biopsy’, and ‘chelation therapy’. Priority was given to systematic reviews, randomized trials, clinical guidelines (EASL-ERN 2025, AASLD 2022), and large prospective or retrospective cohort studies.

Results

Clinical presentations encompass hepatic dysfunction (40–60%), neurological syndromes (30–50%), psychiatric disturbances, and ophthalmological signs, with onset from childhood to adulthood. Diagnostic delay averages 22.5 months and reaches 65 months in patients presenting predominantly with psychiatric symptoms. Emerging biomarkers—particularly relative exchangeable copper (REC) with a validated diagnostic cut-off of 14% (sensitivity 95.6%, specificity 99.8%)—now supplement established biochemical tests. Early therapeutic intervention with copper-chelating agents or zinc therapy fundamentally alters the disease trajectory.

Conclusions

Early recognition and sustained treatment adherence remain paramount. Emerging diagnostic modalities—including REC, EASL-ERN 2025 guideline-endorsed algorithms, and advances in gene therapy—offer promise for improved patient outcomes.