Mitochondrial Neurogastrointestinal Encephalopathy Due to Mutations in RRM2B

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Abstract
Background Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a progressive neurodegenerative disorder associated with thymidine phosphorylase deficiency resulting in high levels of plasma thymidine and a characteristic clinical phenotype. Objective To investigate the molecular basis of MNGIE in a patient with a normal plasma thymidine level. Design Clinical, neurophysiological, and histopathological examinations as well as molecular and genetic analyses. Setting Nerve and muscle center and genetic clinic. Patient A 42-year-old woman with clinical findings strongly suggestive for MNGIE. Main Outcome Measures Clinical description of the disease and its novel genetic cause. Results Identification of mitochondrial DNA depletion in muscle samples (approximately 12% of the control mean content) prompted us to look for other causes of our patient's condition. Sequencing of genes associated with mitochondrial DNA depletion—POLG,PEO1,ANT1,SUCLG1, andSUCLA2—did not reveal deleterious mutations. Results of sequencing and array comparative genomic hybridization of the mitochondrial DNA for point mutations and deletions in blood and muscle were negative. Sequencing ofRRM2B,a gene encoding cytosolic p53-inducible ribonucleoside reductase small subunit (RIR2B), revealed 2 pathogenic mutations, c.329G>A (p.R110H) and c.362G>A (p.R121H). These mutations are predicted to affect the docking interface of the RIR2B homodimer and likely result in impaired enzyme activity. Conclusions This study expands the clinical spectrum of impaired RIR2B function, challenges the notion of locus homogeneity of MNGIE, and sheds light on the pathogenesis of conditions involved in the homeostasis of the mitochondrial nucleotide pool. Our findings suggest that patients with MNGIE who have normal thymidine levels should be tested forRRM2Bmutations.