Abstract

POLG-related disorders are a spectrum of mitochondrial diseases resulting from mutations in the POLG gene, critical for mitochondrial DNA replication. These disorders are a rare group of neurodegenerative mitochondrial diseases affecting the genes encoding the alpha subunit of DNA polymerase gamma (Pol γ). Pol γ is the only DNA polymerase capable of replicating mitochondrial DNA (mtDNA), which is critical for mitochondrial function. Individuals with pathogenic POLG variants present with a spectrum of symptoms, including seizures, early-onset photophobia, myopathy, neuropathy, developmental impairment, and liver problems, which can lead to multiple organ failure. This is a progressive and degenerative disease with a prognosis ranging from 3 months to 12 years after diagnosis. In this mini-review, we explore the disorder, as well as emerging evidence surrounding the use of nucleoside supplementation as a novel therapeutic option. Preclinical and clinical trials suggest promising outcomes, including improved mitochondrial function and reduced disease severity, with nucleoside therapy, particularly in pediatric patients with mtDNA depletion syndromes. While findings are encouraging, further research using larger multicenter trials is necessary to validate these results across larger cohorts and broader phenotypes.

Keywords

POLG, mitochondrial DNA, mtDNA depletion syndrome, mitochondrial gene therapy, deoxythymidine, deoxycytidine, nucleoside therapy, mitochondrial disease