GENDER DIFFERENCES IN CLINICAL MANIFESTATIONS AND DIAGNOSTIC LATENCY OF WILSON'S DISEASE IN CHINA: A SYSTEMATIC REVIEW

Wilson’s Disease (WD) is a complex autosomal recessive disorder of copper metabolism in China, where recent
multi-center cohort data highlights biological sex as an independent predictor for phenotypic expression, severity,
and clinical progression. This systematic review synthesizes localized literature across Chinese and international
electronic databases up to June 2026 to evaluate the impact of sex on age profiles, clinical manifestations, and
diagnostic latency gaps, while examining the influence of pathogenic ATP7B variant hotspots and the efficacy of
familial screening frameworks. Following PRISMA 2020 guidelines, peer-reviewed primary studies detailing sexstratified clinical profiles and quantified diagnostic timelines were reviewed. Analysis reveals a consistent maleto-female ratio of ~1.3:1 to 1.4:1. Male patients demonstrate earlier clinical onset (median: 11.4–13.2 years) and
a strong predominance toward progressive neuropsychiatric phenotypes characterized by motor signs and basal
ganglia structural alterations. Conversely, female patients display a delayed presentation (median: 14.8–16.5
years)—potentially buffered by the protective effects of endogenous estrogen—manifesting predominantly with
hepatic tracts or atypical bone and joint anomalies. Diagnostic latency is heavily phenotype-dependent, averaging
8.0 months for hepatic tracks but reaching 28.0 months for neurological phenotypes. Due to insidious
presentations, over 45% of symptomatic females experience severe diagnostic delays, averaging up to 38.4 months
due to initial misidentification as autoimmune hepatitis or joint disease. Genetically, the p.R778L hotspot variant
(20%–40% frequency) steers early pediatric hepatic phenotypes, while the p.P992L mutation drives delayed adult
neurological degradation. Notably, while sporadic care-seeking results in severe diagnostic delays averaging 18.2
months, family cascade screening eliminates the latency window entirely to 0 months. In conclusion, biological
sex significantly modulates the phenotypic trajectories and diagnostic timelines of Wilson’s Disease in China.
Expanding proactive family tracking networks and reducing clinical blind spots regarding atypical female
presentations are vital to prevent irreversible systemic copper damage.

Wilson's Disease, Gender Differences, Diagnostic Latency, Phenotypes, ATP7B Variants, Family Screening, China