Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease

Mov Disord. 2022 Oct;37(10):2147-2153. doi: 10.1002/mds.29167. Epub 2022 Sep 1.


Background: COQ4 codes for a mitochondrial protein required for coenzyme Q10 (CoQ10 ) biosynthesis. Autosomal recessive COQ4-associated CoQ10 deficiency leads to an early-onset mitochondrial multi-organ disorder.

Methods: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines.

Results: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.

Conclusion: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: cerebellar ataxia; coenzyme Q10 deficiency; hereditary spastic paraplegia; mitochondriopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia / genetics
  • Cerebellar Ataxia* / genetics
  • Humans
  • Mitochondrial Diseases
  • Mitochondrial Proteins* / genetics
  • Muscle Spasticity
  • Muscle Weakness
  • Mutation / genetics
  • Ubiquinone* / deficiency
  • Ubiquinone* / genetics
  • Ubiquinone* / metabolism


  • COQ4 protein, human
  • Mitochondrial Proteins
  • Ubiquinone

Supplementary concepts

  • Coenzyme Q10 Deficiency