Biallelic SCO2 Variants Presenting as Motor‐Predominant Axonal Neuropathy With Complex IV Deficiency
TL;DR
It is demonstrated that SCO2‐related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported.
Abstract
ABSTRACT Background and Aims SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor‐predominant axonal neuropathy presentation associated with biallelic SCO2 variants. Methods Clinical, genetic, and functional studies were performed in a 15‐year‐old female presenting with axonal neuropathy. Functional studies were conducted in patient‐derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX. Results The patient presented with a motor‐predominant axonal neuropathy consistent with Charcot‐Marie‐Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient‐derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss‐of‐function mechanism. Interpretation These findings demonstrate that SCO2‐related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.