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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive, progressive neurodegenerative disorder classically linked to thymidine phosphorylase deficiency but can arise from defects in mitochondrial dNTP maintenance. In a 42-year-old woman with clinical features of MNGIE and normal plasma thymidine, muscle biopsy revealed mitochondrial DNA depletion (~12% of control mean content) [PMID:19667227]. Sequencing identified compound heterozygous RRM2B variants, c.329G>A (p.Arg110His) and c.362G>A (p.Arg121His), predicted to impair RIR2B homodimer docking and enzyme activity [PMID:19667227]. No additional affected relatives or families have been reported, limiting segregation data. While broader functional studies of p53R2 support a loss-of-function mechanism, direct experimental rescue in patient-derived tissues is lacking.
Key take-home: RRM2B should be considered in MNGIE patients with normal thymidine levels as a recessive cause of mitochondrial DNA depletion.
Gene–Disease AssociationLimitedSingle proband with recessive RRM2B variants and concordant mtDNA depletion Genetic EvidenceLimitedOne case-level observation of biallelic variants without segregation Functional EvidenceLimitedPredicted impact on homodimer interface and enzyme activity from modeling |