The Ndufs4−/− mouse model is characterized by reduced cI activity in all tissues, although a prevalent neurological component has been reported.13 Accordingly, systemic administration of viral particles in both adults and newborn mutant animals was unable to correct the clinical phenotype, although a marked correction of cI deficiency was observed in muscle and heart, the most affected tissues outside the CNS in early-onset cI encephalomyopathies. This evidence concerns the gene NDUFS4 and mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria.