ArticleJournal of the peripheral nervous system : JPNS2026
Biallelic SCO2 Variants Presenting as Motor-Predominant Axonal Neuropathy With Complex IV Deficiency.
Article in Journal of the peripheral nervous system : JPNS, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Pathogenic variants of the mitochondrial copper chaperones SCO1 and SCO2 reshape their respective interactomes and disrupt cellular phospholipid metabolism.bioRxiv : the preprint server for biology · 2026Article
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6 authors.
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Abstract
BACKGROUND AND
aimsSCO2 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.
methodsClinical, 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.
resultsThe 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.
interpretationThese 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.
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