Journal article
Biallelic SCO2 Variants Presenting as Motor‐Predominant Axonal Neuropathy With Complex IV Deficiency
Journal of the peripheral nervous system, Vol.31(3), e70150
09/2026
DOI: 10.1111/jns.70150
PMCID: PMC13395627
PMID: 42493470
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.
Details
- Title: Subtitle
- Biallelic SCO2 Variants Presenting as Motor‐Predominant Axonal Neuropathy With Complex IV Deficiency
- Creators
- Adriana P. Rebelo - University of MiamiKatie Lutz - University of IowaTiffany Grider - University of IowaCraig M. Zaidman - Washington University in St. LouisMichael E. Shy - University of IowaStephan 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
- PMCID
- PMC13395627
- 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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