GEMIN5 exerts key biological functions regulating pre-mRNAs intron removal to generate mature mRNAs. A series of patients were reported harboring mutations in GEMIN5. No treatments are currently available for this disease. We treated two of these patients with oral Coenzyme Q (CoQ ), which resulted in neurological improvements, although MRI abnormalities remained. Whole Exome Sequencing demonstrated compound heterozygosity at the GEMIN5 gene in both cases: Case one: p.Lys742* and p.Arg1016Cys; Case two: p.Arg1016Cys and p.Ser411Hisfs*6. Functional studies in fibroblasts revealed a decrease in CoQ biosynthesis compared to controls. Supplementation with exogenous CoQ restored it to control intracellular CoQ levels. Mitochondrial function was compromised, as indicated by the decrease in oxygen consumption, restored by CoQ supplementation. Transcriptomic analysis of GEMIN5 patients compared with controls showed general repression of genes involved in CoQ biosynthesis. In the rigor mortis defective flies, CoQ levels were decreased, and CoQ supplementation led to an improvement in the adult climbing assay performance, a reduction in the number of motionless flies, and partial restoration of survival. Overall, we report the association between GEMIN5 dysfunction and CoQ deficiency for the first time. This association opens the possibility of oral CoQ therapy, which is safe and has no observed side effects after long-term therapy.