Infectious stress triggers a POLG-related mitochondrial disease

• Published in: Neurogenetics 2020, Vol.21 (1), p.19-27
• Main Authors: Gaudó, Paula, Emperador, Sonia, Garrido-Pérez, Nuria, Ruiz-Pesini, Eduardo, Yubero, Delia, García-Cazorla, Angels, Artuch, Rafael, Montoya, Julio, Bayona-Bafaluy, María Pilar
• Format: Article
• Language: English
• Subjects: Antibiotics; Antiretroviral drugs; Biomedical and Life Sciences; Biomedicine; Ceftriaxone; Drug therapy; Electron transport; Environmental factors; Epilepsy; Fibroblasts; Genetic screening; Human Genetics; Lidocaine; Mitochondria; Mitochondrial DNA; Molecular Medicine; Mutation; Neurological complications; Neurosciences; Original Article; Patients; Toxicity
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-019-00593-2

A 3-year-old girl presented with severe epilepsy in the context of Borrelia infection. After ceftriaxone/lidocaine administration, she showed secondarily generalized focal crises that led to neurological and motor sequelae. Genetic studies identified in the patient two heterozygous POLG mutations (c.2591A>G; p.Asn864Ser and c.3649G>C; p.Ala1217Pro). Through analysis of POLG activity in cultured fibroblasts, we confirmed that the mutations altered the mtDNA turnover. Moreover, patient fibroblasts were more sensitive than controls in the presence of a mitochondrial replication-affecting drug, the antiretroviral azidothymidine. To test if ceftriaxone treatment could worsen the deleterious effect of the patient mutations, toxicity assays were performed. Cell toxicity, without direct effect on mitochondrial respiratory function, was detected at different antibiotic concentrations. The clinical outcome, together with the different in vitro sensitivity to ceftriaxone among patient and control cells, suggested that the mitochondrial disease symptoms were hastened by the infection and were possibly worsened by the pharmacological treatment. This study underscores the benefit of early genetic diagnosis of the patients with mitochondrial diseases, since they may be a target group of patients especially vulnerable to environmental factors.