Instead of a conventional high starting dose of penicillamine, the clinicians used an ultra-conservative regimen: 125 milligrams per day, increased stepwise by 125 milligrams at one, three and six months. All patients also received zinc gluconate. Neurological status was tracked with the Unified Wilson’s Disease Rating Scale neurological subscale, and the researchers measured 24-hour urinary copper, exchangeable copper in serum, and plasma neurofilament light chain at baseline and at one, three, six and twelve months.

Worsening was defined as an increase of more than two points on the neurological rating scale. By that criterion, nine of the 25 patients, or 36 percent, deteriorated during follow-up, and every one of those deteriorations occurred within the first three months of treatment. The remaining 16 patients showed progressive neurological improvement over the year and a sustained decline in exchangeable copper, a laboratory measure of the copper fraction in blood that is not firmly bound to proteins and is thought to reflect the potentially toxic circulating pool.

The key difference between the two groups emerged early. Patients who later worsened had a blunted rise in urinary copper at the one-month mark, while patients who remained stable showed a stronger urinary copper response.

Receiver operating characteristic analysis identified a threshold: a one-month urinary copper level above 473.85 micrograms per day was associated with a lower risk of early neurological worsening. In other words, a single routine urine test performed one month into therapy appeared to separate favourable responders from those at risk, at least in this cohort. The biomarker picture was more nuanced for the two experimental measures.

Exchangeable copper fell significantly over time only in the stable group, while the worsened patients showed no meaningful reduction. Plasma neurofilament light chain, a marker of axonal injury that has attracted growing interest in neurodegenerative disease, showed a mild transient elevation in both groups at one month. It then declined only in the stable patients, but the between-group differences for this marker did not reach statistical significance, so the authors treat it as a hypothesis-generating signal rather than a validated predictor.

The central caution of the study is that ultra-low dosing did not solve the worsening problem. Even with a starting dose of just 125 milligrams per day and a slow stepwise escalation, more than a third of patients deteriorated within three months. Several limitations frame how far these findings can travel: the analysis was retrospective, the cohort was small, and all patients came from a single centre.

The authors also note that exchangeable copper and neurofilament light chain changes parallel the clinical courses they observed but require larger studies to confirm their predictive value. By linking the magnitude of the early urinary copper response to clinical trajectory, the Guangzhou team offers a testable biomarker framework for a stubborn treatment complication. Whether a simple urine measurement one month into treatment can truly triage patients at risk will depend on the larger prospective studies that this small retrospective analysis is designed to motivate.

Subject of Research: Urinary copper as an early predictor of neurological worsening in treatment-naive Wilson's disease patients on ultra-low dose penicillamine

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

Article References: Luo, Y., Cai, M., Yang, J., Zhou, X., Wu, C., You, H., Li, X., & Chen, D. (2026). Urinary copper at 1 month predicts early neurological worsening in treatment-naïve Wilson’s disease on ultra-low dose penicillamine. Frontiers in Neurology, 17, Article 1946980. https://doi.org/10.3389/fneur.2026.1946980

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1946980

Keywords: Wilson's disease, penicillamine, urinary copper, exchangeable copper, neurofilament light chain, neurological worsening, chelation therapy, zinc gluconate, biomarker, movement disorders, retrospective study, Urinary