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Mitochondrial Neurogastrointestinal Encephalopathy Due to Mutations in RRM2B

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Mitochondrial Neurogastrointestinal Encephalopathy Due to Mutations in RRM2B OBSERVATION Mitochondrial Neurogastrointestinal Encephalopathy Due to Mutations in RRM2B 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 Background: Mitochondrial neurogastrointestinal en- of our patient’s condition. Sequencing of genes associ- cephalopathy (MNGIE) is a progressive neurodegenera- ated with mitochondrial DNA depletion—POLG, PEO1, tive disorder associated with thymidine phosphorylase ANT1, SUCLG1, and SUCLA2—did not reveal deleteri- deficiency resulting in high levels of plasma thymidine ous mutations. Results of sequencing and array com- and a characteristic clinical phenotype. parative genomic hybridization of the mitochondrial DNA for point mutations and deletions in blood and muscle Objective: To investigate the molecular basis of MNGIE were negative. Sequencing of RRM2B, a gene encoding in a patient with a normal plasma thymidine level. cytosolic p53-inducible ribonucleoside reductase small subunit (RIR2B), revealed 2 pathogenic mutations, Design: Clinical, neurophysiological, and histopatho- c.329GϾA (p.R110H) and c.362GϾA (p.R121H). These logical examinations as well as molecular and genetic mutations are predicted to affect the docking interface analyses. of the RIR2B homodimer and likely result in impaired Setting: Nerve and muscle center and genetic clinic. enzyme activity. Patient: A 42-year-old woman with clinical findings Conclusions: This study expands the clinical spectrum strongly suggestive for MNGIE. of impaired RIR2B function, challenges the notion of lo- cus homogeneity of MNGIE, and sheds light on the patho- Main Outcome Measures: Clinical description of the genesis of conditions involved in the homeostasis of the disease and its novel genetic cause. mitochondrial nucleotide pool. Our findings suggest that patients with MNGIE who have normal thymidine lev- Results: Identification of mitochondrial DNA deple- els should be tested for RRM2B mutations. tion in muscle samples (approximately 12% of the con- trol mean content) prompted us to look for other causes Arch Neurol. 2009;66(8):1028-1032 ITOCHONDRIAL NEURO- notype associated with multiple mtDNA gastrointestinal en- deletions3 or mutations in POLG4 have cephalopathy(MNGIE) been reported. is an autosomal reces- Although mtDNA depletion is one of the sive disease character- characteristic molecular findings in MNGIE, Author Affiliations: Nerve and ized by gastrointestinal dysmotility, oph- mtDNA depletion is also associated with Muscle Center of Texas, M thalmoplegia, ptosis, cachexia, peripheral mutations in nuclear genes that affect mi- Houston (Dr Shaibani); 1 Departments of Medicine neuropathy, and leukoencephalopathy. It tochondrial nucleotide metabolism and (Dr Shaibani), Molecular and is caused by mutations in TYMP, a gene mtDNA replication. These genes exert their 2 Human Genetics encoding thymidine phosphorylase. De- action by either directly affecting the mtDNA (Drs Shchelochkov, Zhang, ficiency in thymidine phosphorylase leads replication fork (POLG, POLG2, and PEO1) Katsonis, Lichtarge, Wong, and to marked elevation of thymidine and de- or regulating the mitochondrial deoxy- Shinawi), Biochemistry and oxyuridine levels, resulting in imbalance nucleotide triphosphate pool (TYMP, TK2, Molecular Biology of the mitochondrial nucleotide pool. It has DGUOK, SUCLA2, SUCLG1, and ANT1).5 (Dr Lichtarge), and been hypothesized that alteration of de- Mutations in RRM2B (GenBank AB036532) Pharmacology (Dr Lichtarge) oxynucleotide triphosphate homeostasis were recently implicated in a novel mito- and Medical Genetics results in improper mitochondrial DNA chondrial depletion syndrome presenting Laboratories (Drs Zhang and Wong), Baylor College of (mtDNA) replication that in turn causes with early-onset seizures, hypotonia, diar- Medicine, Houston; and Texas mtDNA deletion, point mutations, and rhea, renal tubulopathy, lactic acidosis, and 2 6-9 Children’s Hospital, Houston depletion. Although TYMP is the only early lethality. (Drs Shchelochkov and gene known to be associated with typical Here we describe a 42-year-old woman Shinawi). MNGIE, a few cases of MNGIE-like phe- with clinical findings strongly suggestive (REPRINTED) ARCH NEUROL / VOL 66 (NO. 8), AUG 2009 WWW.ARCHNEUROL.COM 1028 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 A B Figure 1. Axial fluid-attenuated inversion recovery, T2-weighted magnetic resonance images of the brain showing symmetric, hyperintense, nonenhancing lesions in the basal ganglia (arrows) (A) and patchy signals throughout the white matter (arrows) (B). for MNGIE but whose plasma thymidine level was nor- showed mild elevation of the levels of total protein, IgG, mal. Further analysis showed severe mtDNA depletion myelin basic protein, and lactate. Funduscopic evaluation, in muscle tissue, and sequencing analysis revealed 2 patho- echocardiography, and needle electromyography results were genic mutations in the RRM2B gene. normal. Nerve conduction studies revealed normal sural potentials, generalized motor slowing (32-37 m/s), and pro- longed distal latencies consistent with demyelinating neu- METHODS ropathy. Brain magnetic resonance imaging showed increased T2-weighted signal in the basal ganglia and patchy CLINICAL PRESENTATION T2-weighted signals throughout the periventricular and sub- cortical white matter (Figure 1). The muscle biopsy revealed A 42-year-old woman of mixed African American and Latin Ameri- mild variation of fiber size (Figure 2A), increased endo- can descent was referred to us for evaluation of ophthalmople- mysial connective tissue, rare ragged red fibers on modified gia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neu- Gomori trichrome stain (Figure 2B), and numerous ragged ropathy, and brain magnetic resonance imaging changes blue fibers on succinate dehydrogenase reaction (Figure 2C). (Figure 1). She was in good health until age 30 years, when she The overall findings were consistent with mitochondrial developed recurrent and severe episodes of nausea and vomiting myopathy and mild neurogenic atrophy with reinnervation. due to gastrointestinal dysmotility. In the same year, she was hos- The activity of the respiratory chain complexes in muscle was pitalized with systemic bacterial infection and received intrave- within the normal range (data not shown). nous gentamicin sulfate, which was followed by the develop- ment of sensorineural hearing loss. Owing to her gastrointestinal problems, she lost significant weight; in fact, she weighed 30 kg ANALYSES (body mass index [calculated as weight in kilograms divided by height in meters squared], 12.5) a year before her presentation Spectrophotometric analysis of the respiratory chain com- to us. Since age 37 years, she had progressive restriction of eye plexes was performed according to previously described pro- movements, ptosis, micronystagmus, dysarthria, unsteady gait, tocols.10 The coding exons and the immediate flanking in- generalized muscle weakness, and loss of deep tendon reflexes. tronic sequences of RRM2B, POLG1, ANT1, PEO1, SUCLG1, Her sensorium was preserved. Her family history was negative and SUCLA2 were amplified by polymerase chain reaction and for similarly affected relatives. sequenced in the forward and reverse directions using auto- Her initial diagnostic evaluation revealed normal levels of mated fluorescence dideoxy-sequencing methods. The poten- plasma thymidine (100 mmol/L; reference range, Ͻ150 tial effects of mutants on the protein structure were estimated mmol/L), serum aminotransferases, creatine phosphokinase, by comparing the local environments of mutants11 among the and plasma amino acids as well as a normal acylcarnitine pro- homologs of the ribonucleoside reductase small subunit (RIR2B) file. Her plasma lactate level was mildly elevated (27.9 mg/dL protein family. Nuclear DNA and mtDNA copy numbers were [to convert to millimoles per liter, multiply by 0.111]; refer- determined by real-time quantitative polymerase chain reac- ence range, 1.8-18.0 mg/dL). Cerebrospinal fluid analysis tion according to a previously validated protocol.12 (REPRINTED) ARCH NEUROL / VOL 66 (NO. 8), AUG 2009 WWW.ARCHNEUROL.COM 1029 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 A B C Figure 2. Muscle biopsy suggestive of mitochondrial dysfunction. A, Decreased cytochrome-c oxidase staining (original magnification ϫ100). B, Modified Gomori trichrome staining showing a ragged red fiber (original magnification ϫ400). Mild variation in fiber size is seen. C, Succinate dehydrogenase staining showing multiple ragged blue fibers (original magnification ϫ40). These findings were suggestive of the mitochondrial dysfunction. Other findings included rare denervated fibers and several small fiber-type groups (data not shown). quencing and deletions by array comparative genomic S112 V115 Q113 hybridization. A homoplasmic unclassified missense vari- V117 Q116 E114 ant, m.15077GϾA (E111K, CytB), was detected and pre- P118 viously reported in the Polysite database (http://www F111 .genpat.uu.se/mtDB/) with a frequency of 2702:2 (A:G). A homoplasmic variant, m.16017TϾC, in transfer RNA E119 R186 located at the first base of the stem region of the amino A120 acid acceptor arm was detected. The clinical conse- R121 S181 quences of these nucleotide changes are unknown but C122 likely represent
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