PEO is a common mitochondrial disease phenotype and associated either with primary mtDNA mutations or mutations of nuclear genes involved in mtDNA homeostasis, such as polymerase gamma (POLG1 & POLG2) [48], [49], C10orf2[50], ANT1[51], TK2[52] and RRM2B[53] that cause secondary mtDNA changes including multiple deletions and/or depletion. Here, RRM2B is linked to inborn mitochondrial metabolism disorder.