Biallelic SCO2 Variants Presenting as Motor‐Predominant Axonal Neuropathy With Complex IV Deficiency

Adriana P. Rebelo; Katie Lutz; Tiffany Grider; Craig M. Zaidman; Michael E. Shy; Stephan Zuchner

doi:10.1111/jns.70150

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Biallelic SCO2 Variants Presenting as Motor‐Predominant Axonal Neuropathy With Complex IV Deficiency

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Biallelic SCO2 Variants Presenting as Motor‐Predominant Axonal Neuropathy With Complex IV Deficiency

Adriana P. Rebelo, Katie Lutz, Tiffany Grider, Craig M. Zaidman, Michael E. Shy and Stephan Zuchner

Journal of the peripheral nervous system, Vol.31(3), e70150

09/2026

DOI: 10.1111/jns.70150

PMID: 42493470

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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.

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Title: Subtitle: Biallelic SCO2 Variants Presenting as Motor‐Predominant Axonal Neuropathy With Complex IV Deficiency
Creators: Adriana P. Rebelo - University of Miami
Katie Lutz - University of Iowa
Tiffany Grider - University of Iowa
Craig M. Zaidman - Washington University in St. Louis
Michael E. Shy - University of Iowa
Stephan Zuchner - University of Miami
Resource Type: Journal article
Publication Details: Journal of the peripheral nervous system, Vol.31(3), e70150
DOI: 10.1111/jns.70150
PMID: 42493470
NLM abbreviation: J Peripher Nerv Syst
ISSN: 1085-9489
eISSN: 1529-8027
Publisher: Wiley
Grant note: Charcot-Marie-Tooth Association: GR026322
This work was supported by the Charcot-Marie-Tooth Association (CMTA) (GR026322).
Language: English
Electronic publication date: 07/23/2026
Date published: 09/2026
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9985183559902771

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