Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations. Diagnosis is usually straightforward in symptomatic patients, but can be challenging in children and adolescents with mild liver disease, borderline urinary copper excretion, or inconclusive genetic findings. Reduced penetrance of several ATP7B variants and the limited sensitivity of conventional biomarkers further complicate diagnostic assessment. Relative exchangeable copper (REC) has recently emerged as a highly accurate biomarker capable of distinguishing WD from other liver diseases and differentiating homozygotes from heterozygotes. We report a 14-year-old girl presenting with transient neurological symptoms and normal biochemical liver tests, except for markedly low serum ceruloplasmin. Standard urinary copper excretion was normal and only mildly increased after penicillamine challenge. Whole-genome sequencing revealed compound heterozygosity for the pathogenic ATP7B variant p.Gly626Ala and the variant of uncertain significance p.Met665Ile. Despite the inconclusive genotype, REC was markedly elevated (17.04%), indicating early impairment of copper homeostasis. Because REC is not yet validated for diagnosis in asymptomatic children, liver biopsy was performed, demonstrating steatosis and a hepatic copper content of 250 μg/g dry weight, confirming WD. This case illustrates the potential of REC as a sensitive metabolic biomarker able to detect early ATP7B dysfunction and to support diagnosis in patients with borderline biochemical findings or hypomorphic variants such as p.Met665Ile.
Nicastro et al. (Mon,) studied this question.