Objective: We aim to address the uncertainties surrounding the genotype-phenotype correlation in ATP7B pathogenic mutations, particularly with a focus on heterozygous carriers, challenging the traditionally understood autosomal recessive inheritance of Wilson’s disease (WD). It also highlights the role of objective, quantitative measures in assessing motor dysfunction in borderline cases.

Background: Over 600 ATP7B mutations have been identified with most affected individuals being compound heterozygotes, making it difficult to determine the pathogenicity of specific mutations or the functional impact of paired variants. While heterozygous carriers are not expected to develop copper overload, studies suggest they may have lower ceruloplasmin levels. Growing number of case reports have also linked ATP7B heterozygosity to dystonia, early-onset Parkinson’s disease, and basal ganglia metabolic changes detected by MRS.

Method: A 35-yo Portuguese male presented with a delayed abnormal posturing of the left leg during running, progressive lower extremity stiffness, right shoulder stiffness, left shoulder elevation, and mild truncal flexion. Neurological exam revealed mild postural tremor, bradykinesia, and increased left-sided tone. Family history included unspecified hand twitching in his father and brother. A dystonia-parkinsonism genetic panel was pursued.

Results: Genetic testing identified a single pathogenic ATP7B variant (p. Met645Arg, c.1934T>G, exon 6), confirming at least carrier status. Laboratory results showed low ceruloplasmin and serum copper but normal 24-hour urine copper. Brain MRI and slit-lamp exam were unremarkable. The Leipzig score of 3 suggested a possible WD diagnosis. To further quantify motor dysfunction, we employed Quantitative Digitography (QDG), a digital tool for movement analysis. Genome sequencing and hepatology consultation are currently in progress.

Conclusion: This case highlights the diagnostic uncertainty of heterozygous ATP7B mutations and their potential neurological impact. Three possibilities are considered: 1) an undetected second ATP7B mutation, 2) a symptomatic heterozygous ATP7B variant contributing to movement dysfunction, or 3) an incidental ATP7B finding unrelated to symptoms. Validated, quantitative assessments like QDG were instrumental in objectively establishing motor dysfunction for him, prompting a broader diagnostic approach including DaTscan and MRS. A low-copper diet was recommended while awaiting further results.

QDG

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-diagnostic-dilemma-in-atp7b-heterozygosity/