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Aziz Shaibani, MD; Oleg A. Shchelochkov, MD; Shulin Zhang, MD, PhD; Panagiotis Katsonis, PhD; Olivier Lichtarge, MD, PhD; Lee-Jun Wong, PhD; Marwan Shinawi, MD

Arch Neurol. 2009;66(8):1028-1032.

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, and SUCLA2—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 of RRM2B, 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 for RRM2B mutations.

Author Affiliations: Nerve and Muscle Center of Texas, Houston (Dr Shaibani); Departments of Medicine (Dr Shaibani), Molecular and Human Genetics (Drs Shchelochkov, Zhang, Katsonis, Lichtarge, Wong, and Shinawi), Biochemistry and Molecular Biology (Dr Lichtarge), and Pharmacology (Dr Lichtarge) and Medical Genetics Laboratories (Drs Zhang and Wong), Baylor College of Medicine, Houston; and Texas Children's Hospital, Houston (Drs Shchelochkov and Shinawi).

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RELATED LETTERS

Mitochondrial Neurogastrointestinal Encephalopathy Without Elevated Thymidine Levels
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Arch Neurol. 2010;67(5):644-645.
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