With the exception of SSBP1, a key component of the mitochondrial replication fork (19), to date, all nuclear genes directly involved in mtDNA replication (POLG, POLG2, TWINKLE, RNASEH1, DNA2, MGME1) have been associated with mitochondrial disease, mtDNA depletion, and/or mtDNA deletion (2). This evidence concerns the gene POLG2 and inborn mitochondrial metabolism disorder.