Novel RRM2B Mutation and Severe Mitochondrial DNA Depletion: Report of 2 Cases and Review of the Literature

Abstract

Purpose To describe the clinical presentation and implications of mitochondrial DNA depletion disorder of two siblings with early fatal encephalomyopathy and a novel mutation in the RRM2B gene. The relevant literature is reviewed.

Methods We describe two brothers aged 2.5 months and 1 month, respectively, who were hospitalized in a tertiary pediatric medical center for evaluation of focal seizures, hypotonia, poor feeding, failure to thrive, lactic acidosis, and developmental delay. The older brother also had seizures, and the younger had severe bilateral neurosensory deafness.

Results Genetic sequencing of the RRM2B gene revealed the same novel mutation in both the siblings. Both children died due to respiratory failure at ages 3 and 2.5 months, respectively.

Conclusion The combination of neonatal hypotonia, developmental delay, and lactic acidosis should raise a clinician's suspicion of a mitochondrial depletion disorder and prompt further genetic studies.

Keywords

RRM2B gene mutation - hypotonia - elevated lactate - deafness - seizures - tubulopathy

^* The authors Nesia Kropach, Vered Shkalim-Zemer, and Naama Orenstein have contributed equally to the work.

• References

• 1 El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 2013; 10 (2): 186-198
• 2 Copeland WC. Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol 2012; 47 (01) 64-74
• 3 Finsterer J, Ahting U. Mitochondrial depletion syndromes in children and adults. Can J Neurol Sci 2013; 40 (05) 635-644
• 4 Wong LJ. Diagnostic challenges of Mitochondrial DNA disorders. Mitochondrion 2007; Feb-Apr; 7 (1–2): 45-52
• 5 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
• 6 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
• 7 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
• 8 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
• 9 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
• 10 Stojanovic V, Mayr JA, Sperl W. , et al. 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
• 11 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
• 12 Nogueira C, Almeida LS, Nesti C. , et al. Syndromes associated with mitochondrial DNA depletion. Ital J Pediatr 2014; 40: 34
• 13 Shaibani A, Shchelochkov OA, Zhang S. , et al. Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol 2009; 66 (08) 1028-1032
• 14 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
• 15 Pitceathly RD, Smith C, Fratter C. , et al. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain 2012; 135 (11): 3392-3403