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

Abstract

Background: COQ4 codes for a mitochondrial protein required for coenzyme Q 10 (CoQ 10 ) biosynthesis. Autosomal recessive COQ4associated CoQ 10 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 CoQ 10 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.

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

“…Adult-onset cases of COQ4 deficiency were reported only recently [ 31 ]. Three individuals presented with spastic paraparesis, whereas three other patients showed cerebellar ataxia.…”

Biallelic COQ4 Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization

“…Among these variants, c.370G > A, 434G > A, and c.550T > C were previously identified as pathogenic variants leading to neonatal-onset encephalo-cardiomyopathy and adult-onset ataxia-spasticity spectrum. 9,17 The pathogenicity of the other two missense variants (c.719G > A and c.745C > T) was supported by their absence in multiple public human genome or exome databases, their predicted changes at highly conserved amino acid sites (Fig. 1B,C), and in silico prediction of pathogenesis (Table S4).…”

“…Investigation of the functional impacts of the p.-Arg240His and p.Arg249Trp through COQ4 complementation assays in COQ4-KO HEK293T cells (Fig. S3A-F), with the previously reported p.Gly124Ser (hereafter COQ4 G124S ) and p.Arg145His (hereafter COQ4 R145H ) mutants as positive controls, 9,17 showed dramatically lower growth rates in the COQ4 G124S and COQ4 R145H complementation lines compared to COQ4 WT cells, which were positively correlated with ubiquinone levels (Fig. S3G-M).…”

“…The COQ4 c.376G > A and c.402 + 1G > C variants were previously detected separately in individuals with adult-onset ataxia-spasticity spectrum and neonatal-onset encephalo-cardiomyopathy. 9,17 Collectively, these analyses identified eight COQ4 variants (six missense and two splicing) in six families from three different populations. These variants segregated with HSP, in agreement with an autosomal recessive inheritance pattern.…”

“…8 A very recent study reported compound heterozygous variants in the COQ4 (coenzyme Q4) gene (encoding a known CoQ10 biosynthesis protein) in 3 patients within a German cohort of adultonset ataxia-spasticity spectrum disease. 9 Fibroblast lines derived from these 3 patients displayed decreased COQ4 protein levels and CoQ10 concentrations.…”