RRM2B encodes a regulatory subunit of ribonucleotide reductase that plays a crucial role in mitochondrial DNA maintenance and repair. The protein functions as part of the ribonucleotide reductase complex with RRM1 to synthesize deoxyribonucleotides (dNTPs) required for DNA repair and mitochondrial DNA replication in non-dividing cells 1. RRM2B deficiency specifically depletes dATP and dGTP pools while leaving dCTP and dTTP levels stable, which impairs mitochondrial DNA synthesis 2. Mutations in RRM2B cause mitochondrial DNA depletion syndromes, presenting with marked phenotypic heterogeneity including skeletal muscle weakness, neurological decline, renal dysfunction, and progressive external ophthalmoplegia 34. The encephalomyopathic form typically presents during infancy with hypotonia and pronounced neurological features 3. RRM2B mutations are also associated with a distinct retinopathy phenotype characterized by substantial photoreceptor atrophy and lack of foveal sparing 5. These disorders represent severe mitochondrial DNA maintenance defects with poor prognosis and limited therapeutic options, requiring comprehensive symptomatic management 34.