Challenges and Recent Advances in Diagnosing Wilson Disease

Abstract

Wilson disease (WD) is a rare autosomal recessive disorder caused by ATP7B gene mutations, leading to pathological copper accumulation that primarily affects the liver, brain, and eyes. Diagnosing WD remains a significant challenge due to its highly variable clinical presentation, which ranges from asymptomatic biochemical abnormalities to acute liver failure and severe neuropsychiatric manifestations. Traditional diagnostic markers, such as serum ceruloplasmin, urinary copper excretion, and liver biopsy, lack sufficient specificity and sensitivity, often leading to delays in diagnosis and misclassification. Additionally, the absence of a single gold-standard test and the overlap with other hepatic and neurological disorders further complicate early detection. Recent advances in diagnostic techniques offer promising solutions to overcome these limitations. Novel biomarkers, including relative exchangeable copper (REC) and ATP7B protein quantification in dried blood spots have demonstrated improved accuracy in distinguishing WD from other conditions. Advanced imaging modalities, such as anterior segment optical coherence tomography (AS-OCT), quantitative susceptibility mapping (QSM), and copper-64 positron emission tomography imaging provide noninvasive tools for detecting early disease-related changes. Furthermore, next-generation sequencing (NGS) enhances genetic screening, facilitating earlier diagnosis, and family screening. A comprehensive approach integrating conventional and emerging diagnostic methodologies is essential for improving early detection and patient outcomes. Greater awareness of the limitations of traditional tests and the incorporation of novel biomarkers and imaging techniques into clinical practice can help refine diagnostic accuracy, reduce delays, and optimize treatment strategies for WD.

Keywords: Kayser–Fleischer rings; Wilson disease; ceruloplasmin; copper; diagnostic challenges.