SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency

Brain. 2018 Mar 1;141(3):662-672. doi: 10.1093/brain/awx369.


Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adult
  • Animals
  • Axons / pathology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Charcot-Marie-Tooth Disease / complications*
  • Charcot-Marie-Tooth Disease / diagnostic imaging
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • Child
  • Copper / deficiency*
  • DNA Mutational Analysis
  • Electron Transport Complex IV / metabolism
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / ultrastructure
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Models, Molecular
  • Mutation / genetics*
  • Oxygen Consumption / genetics
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Sciatic Nerve / ultrastructure


  • Carrier Proteins
  • Mitochondrial Proteins
  • SCO2 protein, human
  • Copper
  • Adenosine Triphosphate
  • Electron Transport Complex IV