Phenotypic and Genotypic Heterogeneity of RRM2B Variants

Abstract

Objectives 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.

Method 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.

Results 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.

Conclusions 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.

Keywords

mitochondrial - mtDNA - phenotype - genotype - myopathy - muscle biopsy - RRM2B

• References

• 1 Kropach N, Shkalim-Zemer V, Orenstein N, Scheuerman O, Straussberg R. Novel RRM2B mutation and severe mitochondrial DNA depletion: report of 2 cases and review of the literature. Neuropediatrics 2017; 48 (06) 456-462
• 2 Bourdon A, Minai L, Serre V. , et al. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet 2007; 39 (06) 776-780
• 3 Paquis-Flucklinger V, Pellissier JF, Camboulives J. , et al. Early-onset fatal encephalomyopathy associated with severe mtDNA depletion. Eur J Pediatr 1995; 154 (07) 557-562
• 4 Bornstein B, Area E, Flanigan KM. , et al. Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. Neuromuscul Disord 2008; 18 (06) 453-459
• 5 Spinazzola A, Invernizzi F, Carrara F. , et al. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis 2009; 32 (02) 143-158
• 6 Kollberg G, Darin N, Benan K. , et al. A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromuscul Disord 2009; 19 (02) 147-150
• 7 Acham-Roschitz B, Plecko B, Lindbichler F. , et al. A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy. Mol Genet Metab 2009; 98 (03) 300-304
• 8 Stojanovic V, Mayr JA, Sperl W, Barišić N, Doronjski A, Milak G. Infantile peripheral neuropathy, deafness, and proximal tubulopathy associated with a novel mutation of the RRM2B gene: case study. Croat Med J 2013; 54 (06) 579-584
• 9 Hernández-Laín A, Guerrero AM, Domínguez-González C. , et al. A novel RRM2B gene variant associated with Telbivudine-induced mitochondrial myopathy. J Neurol Sci 2015; 358 (1-2): 481-483
• 10 Pitceathly RD, Smith C, Fratter C. , et al. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain 2012; 135 (Pt 11): 3392-3403
• 11 Shaibani A, Shchelochkov OA, Zhang S. , et al. Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol 2009; 66 (08) 1028-1032
• 12 Valencia CA, Wang X, Wang J. , et al. Deep sequencing reveals novel genetic variants in children with acute liver failure and tissue evidence of impaired energy metabolism. PLoS One 2016; 11 (08) e0156738
• 13 Pitceathly RD, Fassone E, Taanman JW. , et al. Kearns-Sayre syndrome caused by defective R1/p53R2 assembly. J Med Genet 2011; 48 (09) 610-617
• 14 Tyynismaa H, Ylikallio E, Patel M, Molnar MJ, Haller RG, Suomalainen A. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet 2009; 85 (02) 290-295
• 15 Takata A, Kato M, Nakamura M. , et al. Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome Biol 2011; 12 (09) R92
• 16 Wilichowski EKG, Abicht A, Mayr H, Horvath R, Sperl W, Gärtner J. Autosomal recessive Kearns-Sayre syndrome in a girl with altered mitochondrial DNA transcription caused by RRM2B gene defect. Neuromuscul Disord 2014; 24: 866 (abstract)
• 17 Fratter C, Raman P, Alston CL. , et al. RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions. Neurology 2011; 76 (23) 2032-2034
• 18 Horga A, Pitceathly RD, Blake JC. , et al. Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia. Brain 2014; 137 (Pt 12): 3200-3212
• 19 Gorman GS, Taylor RW. RRM2B-Related Mitochondrial Disease. 2014 Apr 17. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K. , editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. –2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK195854/ . Accessed September, 2017