Blood Based Biomarkers of Central Nervous System Involvement in Wilson’s Disease

Abstract

Wilson’s disease (WD) is an inherited disorder of copper metabolism with clinical symptoms related to pathological copper accumulation, which are mainly hepatic and/or neuropsychiatric. The disease is potentially treatable with pharmacological agents (chelators or zinc salts). As such, key factors for a favorable treatment outcome are early diagnosis and anti-copper treatment initiation as well as appropriate treatment monitoring for safety and efficacy. Despite the generally favorable outcome in most treated patients, almost 10% of the general population of WD patients and about 25% of patients in the group with initial neurological phenotype of disease experience early neurological deterioration. In almost 50% of patients with neurological symptoms, the symptoms persist. A search for new treatment modalities (e.g., gene therapy, molybdenum salts) aims to prevent early neurological deterioration as well as improve treatment outcomes. In addition to evaluating the clinical signs and symptoms of the disease, serum biomarkers for diagnosis and treatment monitoring are very important for WD management. Sensitive serum biomarkers of copper metabolism and liver injury are well described. However, there is a need to establish blood-based biomarkers of central nervous system (CNS) injury to help identify patients at risk of early neurological deterioration and aid in their monitoring. Based on the available literature and studies of WD patients, the authors reviewed serum biomarkers of CNS involvement in WD, as well as their potential clinical significance.

Early neurological deterioration in Wilson’s disease: a systematic literature review and meta-analysis

“…The early neurological deteriorations in WD occur less frequently than previously reported; however, it is still present in around 14% of WD patients and almost one quarter of patients with initial neurological phenotype of WD. Further studies are required to distinguish the natural progression of the disease from an early neurological deterioration, including considerations of “therapeutic lag” [ 47 ] as well as brain MRI studies [ 66 ], and biomarkers of central nervous system involvement [ 66 ]. Results of such studies may help develop an evidence-based definition for an early neurological deterioration.…”

Copper Deficiency as Wilson’s Disease Overtreatment: A Systematic Review

“…In addition, analysis of Cp was conducted using different methods (immunologic and enzymatic assay), which did not allow us to calculate NCC across the whole group of patients [4,5].…”

“…Direct methods to measure NCC are under investigation [2,4]. The most promising is direct quantification of copper pools from human plasma by combining Cp immunocapture, chelation and filtered inductively coupled plasma mass spectrometry (ICP-MS) to permit quantitative analysis of Cp-copper and directly measured NCC; however, this method currently requires validation before introduction into WD management [2,4,5].…”

Gandouling alleviates nerve injury through PI3K/Akt/FoxO1 and Sirt1/FoxO1 signaling pathway to inhibit autophagy in the rats model of Wilson's disease

“…Neurological impairment is the most important clinical manifestation of WD disease, accounting for over 50% of the total cases (Dusek et al., 2019 ; Litwin et al., 2019 ). Anti‐copper treatment for WD requires treatment monitoring of patients to prevent serious adverse events, especially early neurological deterioration (Antos et al., 2023 ). The monitoring and evaluation of neurological symptoms using the Unified Wilson's Disease Rating Scale or the Global Assessment Scale for WD, as well as quantitative monitoring of blood biomarkers for central nervous system injury in WD (such as neurofilament proteins, glial fiber acid protein, tau proteins, and ubiquitin carboxyl terminal hydrolase L1), are effective methods for preventing early neurological deterioration (Ziemssen et al., 2022 , 2023 ).…”