Cryptic Presentations of Neurologic Wilson Disease With ATP7B Peptide Assessments

Objectives: To illustrate the phenotypic variability in neurologic Wilson disease (NWD) and diagnostic value of ATP7B peptide testing in resolving WD cases. Methods: We conducted a case series analysis of 3 individuals with suspected NWD. Clinical presentation, diagnostic workup including traditional biomarkers, genetic testing, and ATP7B peptide quantification by immuno-selected reaction monitoring mass spectrometry were reviewed. Results: The 3 patients demonstrated diverse neurologic presentations: (1) an adult with coexisting Parkinson disease and WD, exhibiting parkinsonian features with partial response to dopaminergic therapy; (2) a child with early-onset dystonia and neuropsychiatric symptoms; and (3) an adult initially misdiagnosed with multiple sclerosis. In these cases, ATP7B peptide testing revealed either markedly reduced or undetectable levels, confirming WD. Discussion: These cases emphasize the diagnostic complexity of NWD. ATP7B peptide analysis via immuno-SRM-MS provided direct evidence of ATP7B protein deficiency and confirmed variant pathogenicity demonstrating its use as a rapid, noninvasive, functionally informative diagnostic adjunct. As the assay is further validated and piloted for newborn screening, it holds promise for improving early detection and clinical outcomes in WD.