Phenotypic and Genotypic Heterogeneity of RRM2B Variants

Genotype and phenotype of RRM2B mutation have become increasingly heterogeneous. This review aims at summarizing recent advances concerning the genotypic and phenotypic variability of RRM2B mutations.

The review evaluated clinical and instrumental data of 82 patients carrying a mutation in the RRM2B gene reported in 18 publications with regard to onset, frequency, and type of clinical manifestations and genetic findings.

The review showed marked variety of clinical manifestations and marked variety of age at onset. Organs predominantly affected in RRM2B mutation carriers are the skeletal muscle, the brain, and the kidneys. Additionally affected may be the eyes, ears, endocrine organs, heart, gastro-intestinal tract, bone marrow, or the peripheral nerves. So far 43 mutations in 81 patients have been reported. Diagnosing RRM2B-associated disease requires demonstration of an appropriate phenotype and a RRM2B mutation. Various clinical manifestations are accessible to various invasive or noninvasive therapeutic measures. The outcome of RRM2B-associated mitochondrial disorders is highly variable ranging from early death to survival into adulthood.

Phenotype and genotype in RRM2B mutation carriers are more widespread than anticipated. Particularly in patients with chronic progressive external ophthalmoplegia, ptosis, limb muscle weakness, muscle hypotonia, renal tubulopathy, ataxia, deafness, and lactic acidosis, a RRM2B mutation should be considered.