CMT-SCO2

SCO2 | 2018

What Is CMT-SCO2?

CMT-SCO2 is a type of CMT caused by autosomal recessive mutations in the SCO2 gene. This gene provides instructions for making a protein required for the assembly of the mitochondrial enzyme complex that produces cellular energy. Mutations in the SCO2 gene disrupt this function, leading to impaired nerve signal transmission.

CMT-SCO2 is autosomal recessive, meaning that both copies of the gene must have a mutation to cause this subtype.

Clinical Features

The age of symptom onset in CMT-SCO2 is variable, ranging from childhood to adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.

CMT-SCO2 symptoms may include:

  • Weakness in the feet and lower legs
  • Muscle atrophy
  • Foot drop
  • Reduced or absent reflexes
  • Reduced sensation
  • A steppage-style walking pattern
  • Foot deformities, including high arches, and hammertoes (clawed toes)
  • Progressive involvement of the hands and forearms
  • Difficulty with fine motor skills and manual dexterity
  • Additional symptoms not listed here

Disease Course

CMT-SCO2 shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.

Clinical Basics

Subtype
CMT-SCO2

Classification
Unclassified Subtypes

Neuropathy Type
Axonal

Inheritance Pattern
autosomal recessive

Genetic Context

HGNC-Approved Gene Symbol
SCO2

Gene Full Name
Synthesis of Cytochrome C Oxidase 2

Chromosome
22q13.33

Zygosity of Responsible Variant
Compound Heterozygous

Mitochondrial Involvement
Yes

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Biallelic

Confidence:
Medium

Prediction:
The literature predicts a biallelic loss-of-function mechanism for CMT-SCO2: SCO2 encodes a copper metallochaperone required for cytochrome c oxidase (Complex IV) assembly, and the recessive missense and truncating alleles reduce COX assembly and mitochondrial respiratory function, with disease manifesting only when both copies are impaired. Restored wild-type SCO2 is predicted to rescue COX assembly, consistent with loss of function rather than a dominant-negative effect.

Rationale:
Recessive SCO2 missense and truncating alleles reduce copper-metallochaperone-dependent Complex IV assembly, and disease appears only when both copies are compromised. Because restored wild-type SCO2 is predicted to rescue assembly, the mechanism is biallelic loss of function, not dominant-negative interference.

ClinVar Pathogenic Variants

View CMT-SCO2 ClinVar Variants

ClinGen Curation

View SCO2 ClinGen Curation

SCO2 OMIM Entry

SCO2 OMIM

More Info

CMT-SCO2 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

SCO2 Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease Associated with Cellular Copper Deficiency

Authors

Rebelo, A. P., Saade, D., Pereira, C. V., Farooq, A., Huff, T. C., Abreu, L., Moraes, C. T., Mnatsakanova, D., Mathews, K., Yang, H., Schon, E. A., Züchner, S., & Shy, M. E.

Publication Date
January 16, 2018

DOI
10.1093/brain/awx369

Updated: July 18, 2026 | By: K. Raymond

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