Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder associated with mitochondrial alterations. MNGIE is characterized by severe gastrointestinal dysmotility, cachexia, ophthalmoplegia, ptosis, peripheral neuropathy, and leukoencephalopathy. The condition is caused by mutation of the TYMP gene. We studied the clinical and biochemical characteristics of a family with MNGIE. The proband was a 48-year-old male presenting with diarrhea and progressive weight loss. He also had ptosis and exhibited eyeball fixation. His blood and cerebrospinal fluid lactate levels were elevated. Magnetic resonance imaging of the brain revealed diffuse leukoencephalopathy. Ragged red fibers and cytochrome c oxidase-deficient fibers were apparent on muscle biopsy. His vision and ptosis deteriorated significantly during follow-up. Our clinical diagnosis of MNGIE was confirmed by TYMP gene analysis. We discovered a homozygous TYMP c.1193-1216 dup-GGGCGCTGCCGCTGGCGCTGGTGC mutation (a duplication). Some of the family members were heterozygous for the mutation but had no clinical features. We predicted the function of this mutation using PredictProtein and found that the secondary structure had changed in the region of the helix and strand, the transmembrane region, and the protein–protein binding sites. The family described herein exhibited biochemically, genetically, and functionally confirmed MNGIE syndrome.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Cardaioli E, Da Pozzo P, Malfatti E, Battisti C, Gallus GN, Gaudiano C, Macucci M, Malandrini A, Margollicci M, Rubegni A, Dotti MT, Federico A (2010) A second MNGIE patient without typical mitochondrial skeletal muscle involvement. Neurol Sci 31:491–494
Okamura K, Santa T, Nagae K, Omae T (1976) Congenital oculoskeletal myopathy with abnormal muscle and liver mitochondria. J Neurol Sci 27:79–91
Libernini L, Lupis C, Mastrangelo M, Carrozzo R, Santorelli FM, Inghilleri M, Leuzzi V (2012) Mitochondrial neurogastrointestinal encephalomyopathy: novel pathogenic mutations in thymidine phosphorylase gene in two Italian brothers. Neuropediatrics 43:201–208
Garone C, Tadesse S, Hirano M (2011) Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain 134:3326–3332
Nalini A, Gayathri N (2011) Mitochondrial neurogastrointestinal encephalopathy in an Indian family with possible manifesting carriers of heterozygous TYMP mutation. J Neurol Sci 309:131–135
Nishino I, Spinazzola A, Hirano M (1999) Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283:689–692
Hirano M, Garcia-de-Yebenes J, Jones AC, Nishino I, DiMauro S, Carlo JR, Bender AN, Hahn AF, Salberg LM, Weeks DE, Nygaard TG (1998) Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter. Am J Hum Genet 63:526–533
Hirano M, Nishigaki Y, Marti R (2004) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes. Neurologist 10:8–17
Nishigaki Y, Marti R, Copeland WC, Hirano M (2003) Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J Clin Investig 111:1913–1921
Hirano M (1993) Mitochondrial neurogastrointestinal encephalopathy disease. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH et al (eds) GeneReviews®. University of Washington, Seattle
Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ (2011) Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet 48:669–681
Marti R, Verschuuren JJGM, Buchman A, Hirano I, Tadesse S, van Kuilenburg ABP, van Gennip AH, Poorthuis BJHM, Hirano M (2005) Late-onset MNGIE due to partial loss of thymidine phosphorylase activity. Ann Neurol 58:649–652
Massa R, Tessa A, Margollicci M, Micheli V, Romigi A, Tozzi G, Terracciano C, Piemonte F, Bernardi G, Santorelli FM (2009) Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity. Neuromuscul Disord 19:837–840
Nakhro K, Chung KW, Kim SM, Sunwoo IN, Cho EM, Park SW, Hwang JH, Choi BO (2011) Compound mutations of PEO1 and TYMP in a progressive external ophthalmoplegia patient with incomplete mitochondrial neurogastrointestinal encephalomyopathy phenotype. Genes Genom 33:431–437
Shaibani A, Shchelochkov OA, Zhang S, Katsonis P, Lichtarge O, Wong LJ, Shinawi M (2009) Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol 66:1028–1032
Tang S, Dimberg EL, Milone M, Wong LJ (2012) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations. J Neurol 259:862–868
Farrar GJ, Chadderton N, Kenna PF, Millington-Ward S (2013) Mitochondrial disorders: aetiologies, models systems, and candidate therapies. Trends Genet TIG 29:488–497
Hirano M, Garone C, Quinzii CM (2012) CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders. Biochim Biophys Acta 1820:625–631
Kanabus M, Heales SJ, Rahman S (2014) Development of pharmacological strategies for mitochondrial disorders. Br J Pharmacol 171:1798–1817
Poole OV, Hanna MG, Pitceathly RD (2015) Mitochondrial disorders: disease mechanisms and therapeutic approaches. Discov Med 20:325–331
Enns GM (2014) Treatment of mitochondrial disorders: antioxidants and beyond. J Child Neurol 29:1235–1240
Marti R, Spinazzola A, Tadesse S, Nishino I, Nishigaki Y, Hirano M (2004) Definitive diagnosis of mitochondrial neurogastrointestinal encephalomyopathy by biochemical assays. Clin Chem 50:120–124
Lim SE, Copeland WC (2001) Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem 276:23616–23623
Szigeti K, Sule N, Adesina AM, Armstrong DL, Saifi GM, Bonilla E, Hirano M, Lupski JR (2004) Increased blood-brain barrier permeability with thymidine phosphorylase deficiency. Ann Neurol 56:881–886
Schüpbach WM, Vadday KM, Schaller A, Brekenfeld C, Kappeler L, Benoist JF, Xuan-Huong CN, Burgunder JM, Seibold F, Gallati S, Mattle HP (2007) Mitochondrial neurogastrointestinal encephalomyopathy in three siblings: clinical, genetic and neuroradiological features. J Neurol 254:146–153
Acknowledgments
The editorial assistance of Jie Zhou is acknowledged. We are grateful to Dr. Cuimei Wu for performing the muscle biopsies.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Funding information
Chinese Health Department of Shanxi Province scientific research project funds (2011025).
Conflict of interest
The authors declare no conflicts of interest.
Ethical approval
Ethical approval was obtained from the first hospital of ShanXi Medical University Reasearch Ethics Committee.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Wang, HF., Wang, J., Wang, YL. et al. A novel thymidine phosphorylase mutation in a Chinese MNGIE patient. Acta Neurol Belg 117, 259–267 (2017). https://doi.org/10.1007/s13760-016-0701-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13760-016-0701-7