S5554 Beyond Genetics: Diagnosing Wilson Disease Amidst Phenotypic Variability and Negative ATP7B Testing

Introduction: Wilson disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, leading to impaired copper metabolism and accumulation in the liver, brain, and other organs. WD has an extremely high fatality rate. Early diagnosis and medical therapy are of great importance for WD patients. Clinical manifestations are highly variable, ranging from hepatic dysfunction to neuropsychiatric symptoms, and genetic testing does not always confirm the diagnosis due to phenotypic and genotypic heterogeneity. Case Description/Methods: We report a 30-year-old man with a history of hypertension and melanoma presenting with 6 months of lower extremity numbness and paresthesias that progressed with some difficulty with gait, along with tremors and eventually seizure. Workup notable for thrombocytopenia and elevated liver enzymes prompting further workup, including serum ceruloplasmin, which was low at 6, and 24-hour urine copper, which was elevated at 64 (Uln 38). Eye examination with fundus oculi negative for Kayser-Fleischer rings. Magnetic resonance imaging of the brain is normal. Despite extensive ATP7B gene analysis, no pathogenic mutations were identified. Liver biopsy demonstrated macrovesicular steatosis and mild inflammation. Based on wide constellation of findings to date including neurological (paresthesia, tremors, seizure, insomnia, anxiety), gastrointestinal (mild aspartate aminotransferase > alanine aminotransferase elevation, indirect hyperbilirubinemia from hemolysis, thrombocytopenia and leukopenia concern for cirrhosis), Renal (Fanconi like picture with hypokalemia causing muscle weakness and hypouricemia), Heme (nonimmune hemolytic anemia with LDH elevated 419, haptoglobin low <8, indirect hyperbilirubinemia), the diagnosis was supported clinically and biochemically, highlighting the complexity of WD diagnosis in cases with negative genetic testing. Quantitative copper analysis in liver biopsy is still pending the result to ultimately guide treatment. Discussion: Wilson's Disease presents a broad spectrum of clinical phenotypes that can complicate timely diagnosis. This case underscores the phenotypic variability of WD and challenges in diagnosis, particularly when genetic testing is inconclusive. Modifier genes, environmental factors, and undiscovered mutations likely contribute to this variability. Advances in genetic sequencing and understanding of modifier factors hold promise for better diagnostic accuracy and individualized treatment.