Urinary copper at 1 month predicts early neurological worsening in treatment-naïve Wilson’s disease on ultra-low dose penicillamine

Background Penicillamine can trigger early neurological worsening in patients with Wilson’s disease (WD). We evaluated a very conservative regimen, starting at 125 mg/day and increasing the does stepwise at months 1, 3, and 6, combined with zinc, focusing on clinical outcomes, urinary copper, exchangeable copper (CuEXC), and plasma neurofilament light (NfL). Methods We retrospectively analyzed 25 treatment-naïve patients with neurological WD who received penicillamine at 125 mg/day, with 125-mg/day increments at months 1, 3, and 6, plus zinc gluconate. Neurological status (UWDRS), 24-h urinary copper, CuEXC, and NfL were assessed at baseline and at 1, 3, 6, and 12 months. Neurological worsening was defined as an increase of more than 2 points in the UWDRS-N. Results Nine patients (36%) experienced neurological worsened, all within the first 3 months. Patients who remained stable ( n = 16) showed progressive improvement in UWDRS scores and a sustained decline in CuEXC. Patients who experienced worsening had a blunted increase in urinary copper at 1 month and no significant reduction in CuEXC. ROC curve analysis showed that a 1-month urinary copper level above 473.85 μg/day was associated with a lower risk of worsening. Plasma NfL showed a mild, transient elevation in both groups at 1 month, followed by a decline only in the stable groups; however, between-group differences were not statistically significant. Conclusion Neurological worsening remains frequent (36%) despite the ultra-low starting doses. A simple 1-month urinary copper threshold of 473.85 μg/day may help identify patients with more favorable outcomes. CuEXC and NfL changes parallel clinical courses but require larger validation.