Gastroenterology | 2021
Direct Measurement of ATP7B Peptides is Highly Effective in the Diagnosis of Wilson Disease.
Abstract
BACKGROUND AND AIMS\nBoth existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson s Disease (WD) often creating ambiguities in patient identification leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot (DBS) samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared to biochemical and genetic results from individual patients.\n\n\nMETHODS\n264 samples from biorepositories at three international and two domestic academic centers and 150 normal controls were obtained after IRB approval. Genetically or clinically confirmed WD patients with a Leipzig score over 3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry.\n\n\nRESULTS\nTwo ATP7B peptides were used to measure ATP7B protein concentration. ROC curve analysis generates an AUC of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value (PPV) of 98.0%, and a negative predictive (NPV) value of 91.5%. In patients with normal ceruloplasmin concentrations (> 20 mg/dL), 14/16 (87.5%) were ATP7B deficient. In patients without clear genetic results, 94% were ATP7B deficient.\n\n\nCONCLUSIONS\nQuantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from Cp and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in non-invasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.