Wilson Disease Neurodegeneration: Mechanism and Therapeutic Response

SUMMARY

# Wilson Disease Neurodegeneration: Mechanism and Therapeutic Response ## Background and Rationale Wilson Disease presents a unique paradigm in neurodegeneration where identical ATP7B mutations can result in dramatically different clinical presentations - from isolated hepatic dysfunction to severe neurological deterioration involving movement disorders and cognitive decline. This clinical heterogeneity has puzzled physicians and researchers for decades, representing a critical knowledge gap tha

METHODOLOGY NOTES

**Phase 1: Multi-Center Patient Recruitment and Phenotyping (Months 1-6)** Recruit 300 Wilson Disease patients across 3 medical centers: 150 with neurological symptoms (tremor, dystonia, dysarthria, choreoathetosis) and 150 with hepatic-only presentation. Include 50 asymptomatic siblings with ATP7B mutations as controls. Perform comprehensive clinical assessment including Unified Wilson Disease Rating Scale (UWDRS), brain MRI with T1/T2/FLAIR/DWI sequences, liver function tests, and 24-hour urinary copper excretion. Genotype all participants for ATP7B mutations using targeted sequencing and MLPA analysis. Collect plasma, serum, CSF (when clinically indicated), and peripheral blood for biomarker analysis. **Phase 2: Neuroimaging and Biomarker Analysis (Months 7-12)** Perform quantitative brain MRI analysis including volumetric assessment of basal ganglia, thalamus, brainstem, and cerebellum using FreeSurfer and FSL. Conduct DTI analysis to assess white matter integrity in corticospin