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Background Wilson disease (WD) is a rare inherited metabolic disorder that is often underdiagnosed. Early diagnosis, before symptoms appear (pre-symptomatic WD), leads to a better response to treatment. For universal screening in children, spot urine tests are more practical than 24-hour urine collection. We previously determined reference ranges for spot urine copper excretion indices. In this study, we evaluated their screening performance in a prospective cohort of school children.Methods Spot urine samples were collected from 193 healthy children aged 4-11 years in this prospective cohort study conducted between 2022 and 2024. Of these, 176 children also provided a 24-hour urine sample. Urine copper levels were measured using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). We assessed previously established screening cut-off values: spot urine copper ≥0.5 µmol/L, copper to osmolality ratio ≥0.00085 μmol/mOsm, and copper to creatinine ratio ≥0.1 µmol/mmol, along with a new cut-off based on urine osmolality. Children whose urine samples exceeded any of these thresholds were recalled for second-tier tests, including blood ceruloplasmin and copper levels, and underwent diagnostic sequencing of the ATP7B gene.Results Ten children (5%) underwent second-tier testing. Two children exhibited very low ceruloplasmin levels and were genetically confirmed to have WD. Both were entirely asymptomatic at diagnosis. A spot urine copper concentration of ≥0.5 µmol/L demonstrated the best screening performance with excellent sensitivity. The strong correlation between spot urine copper concentration and 24-hour urine copper excretion (R 2=0.83, p<0.01) formed the basis for screening WD using spot urine copper. Additionally, one carrier was identified among the call-back group who had normal plasma ceruloplasmin.Conclusions In this small prospective screening cohort, two patients with WD and one carrier were identified. Spot urine copper is a useful biomarker for universal WD screening in school children, which may improve outcomes and fundamentally change the natural history of WD by enabling early detection and treatment before symptom onset.