Homozygous COQ9 mutation: a new cause of potentially treatable hereditary spastic paraplegia

Abstract

Primary Coenzyme Q10 (CoQ10) deficiencies are a group of clinically heterogenous mitochondrial disorders that result from defects in CoQ10 biosynthesis. Their diagnosis is complicated by the absence of pathognomonic signs and poor genotype-phenotype correlations. Pathogenic variants in the COQ9 gene are a rare cause of CoQ10 deficiency: few cases have been reported, and the clinical presentation was described as a very severe multisystemic disorder with neonatal onset, ultimately leading to premature death. Through exome sequencing, we identified a novel homozygous splicing variant c.73 G > A in the COQ9 gene (NG_027696.1, NM_020312.4) in two adult siblings who presented with pure spastic paraplegia with onset in childhood. mRNA analysis from different tissues of one of the siblings revealed that this variant alters COQ9 splicing, resulting in undetectable levels of COQ9 and COQ7 proteins and reduced concentrations of CoQ10 in muscle and fibroblasts. Additionally, the accumulation of 6-demethoxycoenzyme Q10, the substrate of COQ7, was observed in both plasma and fibroblasts. Furthermore, fibroblast proliferation rate was reduced when enhancing the mitochondrial metabolism by replacing glucose with galactose in the culture medium, and was rescued by the addition of exogenous CoQ10, suggesting a therapeutic avenue for these patients. Altogether, we report here the first example of hereditary spastic paraplegia related to a mutation of the COQ9 gene that expands the spectrum of clinical manifestations and opens new therapeutic opportunities.