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

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.