Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Dario Pacitti, Michelle Levene, Caterina Garone, Niranjanan Nirmalananthan, Bridget E Bax, Dario Pacitti, Michelle Levene, Caterina Garone, Niranjanan Nirmalananthan, Bridget E Bax

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

Keywords: MNGIE; TYMP; deoxyribonucleoside; mitochondrial DNA; mitochondrial disease; mitochondrial neurogastrointestinal encephalomyopathy; rare disease; thymidine phosphorylase.

Figures

Figure 1
Figure 1
Reactions catalysed by thymidine phosphorylase.
Figure 2
Figure 2
Deoxynucleotide salvage and de-novo synthesis pathways. Abbreviations are as follows: deoxythymidine (dThd), deoxyuridine (dUrd), deoxythymidine monophosphate (dTMP), deoxythymidine diphosphate (dTDP), deoxynucleotidase 1 (dNT1), thymidine phosphorylase (TP), thymidine kinase 1 (TK1), deoxynucleotidase 2 (dNT2), nucleotide monophosphate kinase (NMPK), nucleotide diphosphate kinase (NDPK), deoxythymidine triphosphate (dTTP), thymidine kinase 2 (TK2), DNA polymerase Y (DNA pol Y), nucleotide diphosphate (NDP), ribonucleotide reductase (RNR), deoxyribonucleotide diphosphate (dNDP), and deoxynucleotide triphosphate (dNTP).
Figure 3
Figure 3
Metabolic defect in MNGIE.
Figure 4
Figure 4
Pathogenic TYMP gene mutations (NM_001113755.2; NP_001107227) in exonic and intronic regions. Protein changes, where known are indicated in red font.
Figure 5
Figure 5
Major clinical features of MNGIE. Copyright permission was obtained for the reproduction of images taken from Bariş et al. (2010), Filosto et al. (2011), Scarpelli et al. (2012).
Figure 6
Figure 6
Mechanism of EE-TP action. Plasma thymidine and deoxyuridine enter the erythrocyte via nucleoside transports located in the cell membrane, where the encapsulated thymidine phosphorylase catalyses their metabolism to thymine and uracil. The products are then free to diffuse out of the cell into the blood plasma where they can enter the normal metabolic pathways.
Figure 7
Figure 7
Timeline of pre-clinical and clinical investigational therapeutic approaches for MNGIE.

References

    1. Aksoy F., Demirel G., Bilgiç T., Güngör I. G., Ozçelik A. (2005). A previously diagnosed mitochondrial neurogastrointestinal encephalomyopathy patient presenting with perforated ileal diverticulitis. Turk. J. Gastroenterol. 16, 228–231.
    1. Anuras S., Mitros F. A., Nowak T. V., Ionasescu V. V., Gurll N. J., Christensen J., et al. . (1983). A familial visceral myopathy with external ophthalmoplegia and autosomal recessive transmission. Gastroenterology 84, 346–353.
    1. Asai K., Hirano T., Kaneko S., Moriyama A., Nakanishi K., Isobe I., et al. . (1992a). A novel glial growth inhibitory factor, gliostatin, derived from neurofibroma. J. Neurochem. 59, 307–317. 10.1111/j.1471-4159.1992.tb08905.x
    1. Asai K., Nakanishi K., Isobe I., Eksioglu Y. Z., Hirano A., Hama K., et al. . (1992b). Neurotrophic action of gliostatin on cortical neurons. Identity of gliostatin and platelet-derived endothelial cell growth factor J. Biol. Chem. 267, 20311–20316.
    1. Baker M. K., Schutte C. M., Ranchhod N., Brittain D., van Rensburg J. E. (2017). Transient clinical improvement of a mitochondrial neurogastrointestinal encephalomyopathy-like syndrome after allogeneic haematopoietic stem cell transplantation. BMJ Case Rep. 2017:bcr-2016-218276. 10.1136/bcr-2016-218276
    1. Balasubramaniam S., Duley J. A., Christodoulou J. (2014). Inborn errors of pyrimidine metabolism: clinical update and therapy. J. Inherit. Metab. Dis. 37, 687–698. 10.1007/s10545-014-9742-3
    1. Barboni P., Savini G., Plazzi G., Bellan M., Valentino M. L., Zanini M., et al. . (2004). Ocular findings in mitochondrial neurogastrointestinal encephalomyopathy: a case report. Graefe's Arch. Clin. Exp. Ophthalmol. 242, 878–880. 10.1007/s00417-004-0914-y
    1. Bardosi A., Creutzfeldt W., DiMauro S., Felgenhauer K., Friede R. L., Goebel H. H., et al. . (1987). Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase. A new mitochondrial multisystem disorder. Acta Neuropathol. 74, 248–258. 10.1007/BF00688189
    1. Bariş Z., Eminoglu T., Dalgiç B., Tümer L., Hasanoglu A. (2010). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): case report with a new mutation. Eur. J. Pediatr. 169, 1375–1378. 10.1007/s00431-010-1237-0
    1. Barragán-Campos H. M., Vallée J. N., Lô D., Barrera-Ramírez C. F., Argote-Greene M., Sánchez-Guerrero J., et al. . (2005). Brain magnetic resonance imaging findings in patients with mitochondrial cytopathies. Arch. Neurol. 62, 737–742. 10.1001/archneur.62.5.737
    1. Bax B. E., Bain M. D., Scarpelli M., Filosto M., Tonin P., Moran N. (2013). Clinical and biochemical improvements in a patient with MNGIE following enzyme replacement. Neurology 81, 1269–1271. 10.1212/WNL.0b013e3182a6cb4b
    1. Bedlack R. S., Vu T., Hammans S., Sparr S. A., Myers B., Morgenlander J., et al. . (2004). MNGIE neuropathy: five cases mimicking chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 29, 364–368. 10.1002/mus.10546
    1. Benureau A., Meyer P., Maillet O., Leboucq N., Legras S., Jeziorski E., et al. (2014). L'encéphalomyopathie neuro-gastro-intestinale mitochondriale: un tableau d'anorexie mentale atypique. Archives de Pédiatrie 21, 1370–1374. 10.1016/j.arcped.2014.08.006
    1. Blazquez A., Martín M. A., Lara M. C., Martí R., Campos Y., Cabello A., et al. . (2005). Increased muscle nucleoside levels associated with a novel frameshift mutation in the thymidine phosphorylase gene in a Spanish patient with MNGIE. Neuromuscul. Disord. 15, 775–778. 10.1016/j.nmd.2005.07.008
    1. Bogenhagen D. F. (1999). Repair of mtDNA in vertebrates. Am. J. Human Gene. 64, 1276–1281. 10.1086/302392
    1. Borhani Haghighi A., Nabavizadeh A., Sass J. O., Safari A., Lankarani K. B. (2009). Mitochondrial neurogastrointestinal encephalomyopathy. Arch. Iran Med. 12, 588–590.
    1. Boschetti E., D'Alessandro R., Bianco F., Carelli V., Cenacchi G., Pinna A. D., et al. . (2014). Liver as a source for thymidine phosphorylase replacement in mitochondrial neurogastrointestinal encephalomyopathy. PLoS ONE 9:e96692. 10.1371/journal.pone.0096692
    1. Calvo S. E., Compton A. G., Hershman S. G., Lim S. C., Lieber D. S., Tucker E. J., et al. . (2012). Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4:118ra110. 10.1126/scitranslmed.3003310
    1. Cardaioli E., Da Pozzo P., Malfatti E., Battisti C., Gallus G. N., Gaudiano C., et al. . (2010). A second MNGIE patient without typical mitochondrial skeletal muscle involvement. Neurol. Sci. 31, 491–494. 10.1007/s10072-010-0225-5
    1. Carod-Artal F. J., Herrero M. D., Lara M. C., López-Gallardo E., Ruiz-Pesini E., Martí R., et al. . (2007). Cognitive dysfunction and hypogonadotrophic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation. Eur. J. Neurol. 14, 581–585. 10.1111/j.1468-1331.2007.01720.x
    1. Carroll C. J., Brilhante V., Suomalainen A. (2014). Next-generation sequencing for mitochondrial disorders. Br. J. Pharmacol. 171, 1837–1853. 10.1111/bph.12469
    1. Celebi N., Sahin A., Canbay O., Uzümcügil F., Aypar U. (2006). Abdominal pain related to mitochondrial neurogastrointestinal encephalomyopathy syndrome may benefit from splanchnic nerve blockade. Paediatr. Anaesth. 16, 1073–1076. 10.1111/j.1460-9592.2006.01918.x
    1. Chandra V. S., Lakshmi B. S., Padmavathi Devi S. V. V., Praveen N., Sameera N. S., Reddy A. S., et al. . (2018). Mitochondrial neurogastrointestinal encephalomyopathy: a nonrenal indication for peritoneal dialysis. Indian J. Nephrol. 28, 310–313. 10.4103/ijn.IJN_404_17
    1. Çoban G., Göktürk S., Yildirim E., Çalişkan Z., Horasanli B., Akca H. A. (2013). Mitochondrial neurogastrointestinal encephalomyopathy: imaging and clinical findings in three patients. Diagn. Interv. Radiol. 19, 191–194. 10.5152/dir.2013.008
    1. Craven L., Alston C. L., Taylor R. W., Turnbull D. M. (2017). Recent advances in mitochondrial disease. Annu. Rev. Genomics Hum. Genet. 18, 257–275. 10.1146/annurev-genom-091416-035426
    1. D'Angelo R., Rinaldi R., Carelli V., Boschetti E., Caporali L., Capristo M., et al. . (2016). ITA-MNGIE: an Italian regional and national survey for mitochondrial neuro-gastro-intestinal encephalomyopathy. Neurol. Sci. 37, 1149–1151. 10.1007/s10072-016-2552-7
    1. D'Angelo R., Rinaldi R., Pironi L., Dotti M. T., Pinna A. D., Boschetti E., et al. . (2017). Liver transplant reverses biochemical imbalance in mitochondrial neurogastrointestinal encephalomyopathy. Mitochondrion 34, 101–102. 10.1016/j.mito.2017.02.006
    1. De Giorgio R., Pironi L., Rinaldi R., Boschetti E., Caporali L., Capristo M., et al. . (2016). Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Ann. Neurol. 80, 448–455. 10.1002/ana.24724
    1. Debouverie M., Wagner M., Ducrocq X., Grignon Y., Mousson B., Weber M. (1997). MNGIE syndrome in 2 siblings. Rev. Neurol. 153, 547–553.
    1. Demaria F., De Crescenzo F., Caramadre A. M., D'Amico A., Diamanti A., Fattori F., et al. . (2016). Mitochondrial neurogastrointestinal encephalomyopathy presenting as anorexia nervosa. J. Adolescent Health 59, 729–731. 10.1016/j.jadohealth.2016.08.012
    1. Dreznik Y., Gutman M., Weiss B., Nevler A. (2014). Mitochondrial neuro-gastrointestinal encephalomyopathy presenting with recurrent bowel perforations and intra-abdominal abscesses. J. Gastrointest. Surg. 18, 2054–2056. 10.1007/s11605-014-2589-y
    1. el Kouni M. H., el Kouni M. M., Naguib F. N. (1993). Differences in activities and substrate specificity of human and murine pyrimidine nucleoside phosphorylases: implications for chemotherapy with 5-fluoropyrimidines. Cancer Res. 53, 3687–3693.
    1. El-Hattab A. W., Scaglia F. (2016). Mitochondrial Cardiomyopathies. Front. Cardiovas. Med. 3:25. 10.3389/fcvm.2016.00025
    1. Faber J., Fich A., Steinberg A., Steiner I., Granot E., Alon I., et al. . (1987). Familial intestinal pseudoobstruction dominated by a progressive neurologic disease at a young age. Gastroenterology 92, 786–790. 10.1016/0016-5085(87)90033-3
    1. Felhi R., Sfaihi L., Charif M., Desquiret-Dumas V., Bris C., Goudenège D., et al. . (2018). Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion. Clin. Chim. Acta 488, 104–110. 10.1016/j.cca.2018.11.003
    1. Ferraro P., Pontarin G., Crocco L., Fabris S., Reichard P., Bianchi V. (2005). Mitochondrial deoxynucleotide pools in quiescent fibroblasts: a possible model for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). J. Biol. Chem. 280, 24472–24480. 10.1074/jbc.M502869200
    1. Filosto M., Cotti Piccinelli S., Caria F., Gallo Cassarino S., Baldelli E., Galvagni A., et al. . (2018). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1). J. Clin. Med. 7:E389. 10.3390/jcm7110389
    1. Filosto M., Scarpelli M., Tonin P., Lucchini G., Pavan F., Santus F., et al. . (2012). Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy. J. Neurol. 259, 2699–2706. 10.1007/s00415-012-6572-9
    1. Filosto M., Scarpelli M., Tonin P., Testi S., Cotelli M. S., Rossi M., et al. . (2011). Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy. J. Inherit. Metab. Dis. 34, 1199–1203. 10.1007/s10545-011-9332-6
    1. Finkenstedt A., Schranz M., Bösch S., Karall D., Bürgi S. S., Ensinger C., et al. . (2013). MNGIE syndrome: liver cirrhosis should be ruled out prior to bone marrow transplantation. JIMD Rep. 10, 41–44. 10.1007/8904_2012_199
    1. Finsterer J., Frank M. (2017). Gastrointestinal manifestations of mitochondrial disorders: a systematic review. Therapeut. Adv. Gastroenterol. 10, 142–154. 10.1177/1756283X16666806
    1. Fox S. B., Moghaddam A., Westwood M., Turley H., Bicknell R., Gatter K. C., et al. . (1995). Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: an immunohistochemical study. J. Pathol. 176, 183–190. 10.1002/path.1711760212
    1. Gamez J., Ferreiro C., Accarino M. L., Guarner L., Tadesse S., Martí R. A., et al. . (2002). Phenotypic variability in a spanish family with MNGIE. Neurology 59, 455–457. 10.1212/WNL.59.3.455
    1. Garcia-Diaz B., Garone C., Barca E., Mojahed H., Gutierrez P., Pizzorno G., et al. . (2014). Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy. Brain 137, 1337–1349. 10.1093/brain/awu068
    1. Garone C., Tadesse S., Hirano M. (2011). Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain 134, 3326–3332. 10.1093/brain/awr245
    1. Giordano C., Sebastiani M., De Giorgio R., Travaglini C., Tancredi A., Valentino M. L., et al. . (2008). Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am. J. Pathol. 173, 1120–1128. 10.2353/ajpath.2008.080252
    1. Giordano C., Sebastiani M., Plazzi G., Travaglini C., Sale P., Pinti M., et al. . (2006). Mitochondrial neurogastrointestinal encephalomyopathy: evidence of mitochondrial DNA depletion in the small intestine. Gastroenterology 130, 893–901. 10.1053/j.gastro.2006.01.004
    1. Godfrin Y., Bax B. E. (2012). Enzymes bioreactors as drugs. Drugs Fut. 37, 263–272. 10.1358/dof.2012.037.04.1779020
    1. Godfrin Y., Horand F., Franco R., Dufour E., Kosenko E., Bax B. E., et al. . (2012). International seminar on the red blood cells as vehicles for drugs. Exp. Opin. Biol. Ther. 12, 127–133. 10.1517/14712598.2012.631909
    1. González-Vioque E., Torres-Torronteras J., Andreu A. L., Martí R. (2011). Limited dCTP availability accounts for mitochondrial DNA depletion in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). PLoS Genetics 7:e1002035. 10.1371/journal.pgen.1002035
    1. Gramegna L. L., Pisano A., Testa C., Manners D. N., D'Angelo R., Boschetti E., et al. (2018). Cerebral mitochondrial microangiopathy leads to leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Am. J. Neuroradiol. 39, 427–434. 10.3174/ajnr.A5507
    1. Granero Castro P., Fernández Arias S., Moreno Gijón M., Álvarez Martínez P., Granero Trancón J., Álvarez Pérez J. A., et al. . (2010). Emergency surgery in chronic intestinal pseudo-obstruction due to mitochondrial neurogastrointestinal encephalomyopathy: case reports. Int. Arch. Med. 3, 35–35. 10.1186/1755-7682-3-35
    1. Hafez H., Cordie A., Abdallah M., Hasaballah M., Elakel W., Darweesh S., et al. (2014). Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) Disease: A Case Report of a Rare Autosomal Recessive Inheretance with a poor Prognosis. World J. Pharm. Sci. 2:1647–1651. Available online at:
    1. Halter J., Schüpbach W. M., Casali C., Elhasid R., Fay K., Hammans S., et al. . (2010). Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach. Bone Marrow Transl. 46, 330–337. 10.1038/bmt.2010.100
    1. Halter J. P., Michael W., Schüpbach M., Mandel H., Casali C., Orchard K., et al. . (2015). Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Brain 138, 2847–2858. 10.1093/brain/awv226
    1. Haraguchi M., Tsujimoto H., Fukushima M., Higuchi I., Kuribayashi H., Utsumi H., et al. . (2002). Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice. Mol. Cell Biol. 22, 5212–5221. 10.1128/MCB.22.14.5212-5221.2002
    1. Hirano M., Garcia-de-Yebenes J., Jones A. C., Nishino I., DiMauro S., Carlo J. R., et al. . (1998). Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter. Am. J. Hum. Genet. 63, 526–533. 10.1086/301979
    1. Hirano M., Martí R., Casali C., Tadesse S., Uldrick T., Fine B., et al. . (2006). Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology 67, 1458–1460. 10.1212/01.wnl.0000240853.97716.24
    1. Hirano M., Martí R., Spinazzola A., Nishino I., Nishigaki Y. (2004a). Thymidine phosphorylase deficiency causes MNGIE: an autosomal recessive mitochondrial disorder. Nucleosides Nucleotides Nucleic Acids 23, 1217–1225. 10.1081/NCN-200027485
    1. Hirano M., Nishigaki Y., Martí R. (2004b). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes. Neurologist 10, 8–17. 10.1097/01.nrl.0000106919.06469.04
    1. Hirano M., Silvestri G., Blake D. M., Lombes A., Minetti C., Bonilla E., et al. . (1994). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44, 721–727. 10.1212/WNL.44.4.721
    1. Holt I. J., Harding A. E., Petty R. K., Morgan-Hughes J. A. (1990). A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 46, 428–433.
    1. Imperatore N., Tortora R., Gerbino N., Caporaso N., Rispo A. (2017). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) mimicking refractory celiac disease. Dig. Liver Dis. 49, 1061–1062. 10.1016/j.dld.2017.04.017
    1. Ionasescu V. (1983). Oculogastrointestinal muscular dystrophy. Am. J. Med. Genet. 15, 103–112. 10.1002/ajmg.1320150114
    1. Ionasescu V., Thompson S. H., Ionasescu R., Searby C., Anuras S., Christensen J., et al. . (1983). Inherited ophthalmoplegia with intestinal pseudo-obstruction. J. Neurol. Sci. 59, 215–228. 10.1016/0022-510X(83)90039-4
    1. Ionasescu V. V., Thompson H. S., Aschenbrener C., Anuras S., Risk W. S. (1984). Late-onset oculogastrointestinal muscular dystrophy. Am. J. Med. Genet. 18, 781–788. 10.1002/ajmg.1320180426
    1. Kalkan I. H., Köksal A. S., Evcimen S., Sapmaz F., Öztaş E., Önder F. O., et al. . (2015). Spontaneous abdominal esophageal perforation in a patient with mitochondrial neurogastrointestinal encephalomyopathy. Acta Clin. Belg. 70, 44–45. 10.1179/2295333714Y.0000000053
    1. Kalkan I. H., Tayfur O., Oztaş E., Beyazit Y., Yildiz H., Tunç B. (2012). A novel finding in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy): hypergonadotropic hypogonadism. Hormones 11, 377–379. 10.14310/horm.2002.1368
    1. Karyampudi A., Srivastava P., Mandal K., Yadav P., Ghoshal U. C., Verma A., et al. . (2016). Novel sequence variations in the thymidine phosphorylase gene causing mitochondrial neurogastrointestinal encephalopathy. Clin. Dysmorphol. 25, 156–162. 10.1097/MCD.0000000000000137
    1. Katsanis S. H., Katsanis N. (2013). Molecular genetic testing and the future of clinical genomics. Nat. Rev. Genet. 14, 415–426. 10.1038/nrg3493
    1. Kintarak J., Liewluck T., Sangruchi T., Hirano M., Kulkantrakorn K., Muengtaweepongsa S. (2007). A novel ECGF1 mutation in a Thai patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Clin. Neurol. Neurosurg. 109, 613–616. 10.1016/j.clineuro.2007.04.008
    1. Kocaefe Y. C., Erdem S., Ozgüç M., Tan E. (2003). Four novel thymidine phosphorylase gene mutations in mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) patients. Eur. J. Hum. Genet. 11, 102–104. 10.1038/sj.ejhg.5200908
    1. Kremer L. S., Bader D. M., Mertes C., Kopajtich R., Pichler G., Iuso A., et al. . (2017). Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat. Commun. 8:15824. 10.1038/ncomms15824
    1. Kucerová L., Dolina J., Dastych M., Bartušek D., Honzík T., Mazanec J., et al. . (2018). Mitochondrial neurogastrointestinal encephalomyopathy imitating Crohn's disease: a rare cause of malnutrition. J. Gastrointestin Liver Dis. 27, 321–325. 10.15403/jgld.2014.1121.273.kuc
    1. la Marca G., Malvagia S., Casetta B., Pasquini E., Pela I., Hirano M., et al. . (2006). Pre- and post-dialysis quantitative dosage of thymidine in urine and plasma of a MNGIE patient by using HPLC-ESI-MS/MS. J. Mass Spectrom 41, 586–592. 10.1002/jms.1013
    1. Laforce R., Jr., Valdmanis P. N., Dupré N., Rouleau G. A., Turgeon A. F., Savard M. (2009). A novel TYMP mutation in a French Canadian patient with mitochondrial neurogastrointestinal encephalomyopathy. Clin. Neurol. Neurosurg. 111, 691–694. 10.1016/j.clineuro.2009.05.005
    1. Lara M. C., Valentino M. L., Torres-Torronteras J., Hirano M., Martí R. (2007). Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): biochemical features and therapeutic approaches. Biosci. Rep. 27, 151–163. 10.1007/s10540-007-9043-2
    1. Lara M. C., Weiss B., Illa I., Madoz P., Massuet L., Andreu A. L., et al. . (2006). Infusion of platelets transiently reduces nucleoside overload in MNGIE. Neurology 67, 1461–1463. 10.1212/01.wnl.0000239824.95411.52
    1. Levene M., Coleman D. G., Kilpatrick H. C., Fairbanks L. D., Gangadharan B., Gasson C., et al. . (2013). Preclinical toxicity evaluation of erythrocyte-encapsulated thymidine phosphorylase in BALB/c mice and beagle dogs: an enzyme-replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy. Toxicol Sci. 131, 311–324. 10.1093/toxsci/kfs278
    1. Levene M., Enguita F., Bax B. (in press). Discovery profiling bioinformatics analysis of serum microRNA in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Nucleosides Nucleotides Nucl. Acids. 10.1080/15257770.2018.1492138
    1. Li W., Yue H. (2017). Thymidine phosphorylase: a potential new target for treating cardiovascular disease. Trends Cardiovasc. Med. 28, 157–171. 10.1016/j.tcm.2017.10.003
    1. Libernini L., Lupis C., Mastrangelo M., Carrozzo R., Santorelli F. M., Inghilleri M., et al. . (2012). Mitochondrial neurogastrointestinal encephalomyopathy: novel pathogenic mutations in thymidine phosphorylase gene in two Italian brothers. Neuropediatrics 43, 201–208. 10.1055/s-0032-1315431
    1. López L. C., Akman H. O., García-Cazorla A., Dorado B., Martí R., Nishino I., et al. . (2009). Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice. Hum. Mol. Genet. 18, 714–722. 10.1093/hmg/ddn401
    1. Martí R., Nishigaki Y., Hirano M. (2003). Elevated plasma deoxyuridine in patients with thymidine phosphorylase deficiency. Biochem. Biophys. Res. Commun. 303, 14–18. 10.1016/S0006-291X(03)00294-8
    1. Martí 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. 10.1373/clinchem.2003.026179
    1. Marti R., Verschuuren J. J., Buchman A., Hirano I., Tadesse S., van Kuilenburg A. B., et al. . (2005). Late-onset MNGIE due to partial loss of thymidine phosphorylase activity. Ann. Neurol. 58, 649–652. 10.1002/ana.20615
    1. Martín M. A., Blázquez A., Martí R., Bautista J., Lara M. C., Cabello A., et al. . (2004). Lack of gastrointestinal symptoms in a 60-year-old patient with MNGIE. Neurology 63, 1536–1537. 10.1212/01.WNL.0000141857.37073.97
    1. Martinez-Garcia F. A., Jimenez-Gomez M. R., Morsi-Hassan O., Fortuna-Alcaraz M. L., Sicilia-Guillen J., Fernandez-Barreiro A. (2001). Acute peritonitis and small bowel diverticula in a patient with mitochondrial neurogastrointestinal encephalomyopathy. Rev. Neurol. 33, 328–333.
    1. Massa R., Tessa A., Margollicci M., Micheli V., Romigi A., Tozzi G., et al. . (2009). Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity. Neuromuscul. Disord. 19, 837–840. 10.1016/j.nmd.2009.08.013
    1. Mazat J. P., Rossignol R., Malgat M., Rocher C., Faustin B., Letellier T. (2001). What do mitochondrial diseases teach us about normal mitochondrial functions…that we already knew: threshold expression of mitochondrial defects. Biochim Biophys. Acta 1504, 20–30. 10.1016/S0005-2728(00)00236-X
    1. Mihaylova V., Guergueltcheva V., Cherninkova S., Penev L., Georgieva G., Stoyanova K., et al. . (2013). Possible toxicity of tuberculostatic agents in a patient with a novel TYMP mutation leading to mitochondrial neurogastrointestinal encephalomyopathy. J. Neurogenet. 27, 19–22. 10.3109/01677063.2013.778256
    1. Millar W. S., Lignelli A., Hirano M. (2004). MRI of five patients with mitochondrial neurogastrointestinal encephalomyopathy. Am. J. Roentgenol. 182, 1537–1541. 10.2214/ajr.182.6.1821537
    1. Miyazono K., Okabe T., Urabe A., Takaku F., Heldin C. H. (1987). Purification and properties of an endothelial cell growth factor from human platelets. J. Biol. Chem. 262, 4098–4103.
    1. Mohamed S., Caporali L., De Giorgio R., Carelli V., Contin M. (2014). HPLC-UV analysis of thymidine and deoxyuridine in plasma of patients with thymidine phosphorylase deficiency. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 949–950:58–62. 10.1016/j.jchromb.2014.01.003
    1. Monroy N., Macias Kauffer L. R., Mutchinick O. M. (2008). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in two Mexican brothers harboring a novel mutation in the ECGF1 gene. Eur. J. Med. Genet. 51, 245–250. 10.1016/j.ejmg.2007.12.007
    1. Moran N. F., Bain M. D., Muqit M. M., Bax B. E. (2008). Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE. Neurology 71, 686–688. 10.1212/01.wnl.0000324602.97205.ab
    1. Morgan-Hughes J. A., Hanna M. G. (1999). Mitochondrial encephalomyopathies: the enigma of genotype versus phenotype. Biochim. Biophys. Acta Bioenerge. 1410, 125–145. 10.1016/S0005-2728(98)00162-5
    1. Mueller L. A., Camilleri M., Emslie-Smith A. M. (1999). Mitochondrial neurogastrointestinal encephalomyopathy: manometric and diagnostic features. Gastroenterology 116, 959–963. 10.1016/S0016-5085(99)70080-6
    1. Nagata J. M., Buckelew S. M. (2017). Mitochondrial neurogastrointestinal encephalomyopathy in the differential diagnosis of eating disorders. J. Adolescent Health 61:661. 10.1016/j.jadohealth.2017.06.023
    1. 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. 10.1016/j.jns.2011.06.052
    1. Needham M., Duley J., Hammond S., Herkes G. K., Hirano M., Sue C. M. (2007). Mitochondrial disease mimicking Charcot–Marie Tooth disease. J. Neurol. Neurosurg. Amp 78, 99–100. 10.1136/jnnp.2005.078857
    1. Nishigaki Y., Mart,í R., Copeland W. C., Hirano M. (2003). Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J. Clin. Invest. 111, 1913–1921. 10.1172/JCI17828
    1. Nishigaki Y., Marti R., Hirano M. (2004). ND5 is a hot-spot for multiple atypical mitochondrial DNA deletions in mitochondrial neurogastrointestinal encephalomyopathy. Hum. Mol. Genet. 13, 91–101. 10.1093/hmg/ddh010
    1. Nishino I., Spinazzola A., Hirano M. (1999). Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283, 689–692. 10.1126/science.283.5402.689
    1. Nishino I., Spinazzola A., Hirano M. (2001). MNGIE: from nuclear DNA to mitochondrial DNA. Neuromuscul. Disord. 11, 7–10. 10.1016/S0960-8966(00)00159-0
    1. Nishino I., Spinazzola A., Papadimitriou A., Hammans S., Steiner I., Hahn C. D., et al. . (2000). Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann. Neurol. 47, 792–800. 10.1002/1531-8249(200006)47:6<792::AID-ANA12>;2-Y
    1. Norman R. A., Barry S. T., Bate M., Breed J., Colls J. G., Ernill R. J., et al. . (2004). Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor. Structure 12, 75–84. 10.1016/j.str.2003.11.018
    1. O'Brien T. S., Fox S. B., Dickinson A. J., Turley H., Westwood M., Moghaddam A., et al. . (1996). Expression of the angiogenic factor thymidine phosphorylase/platelet-derived endothelial cell growth factor in primary bladder cancers. Cancer Res. 56, 4799–4804.
    1. Okamura K., Santa T., Nagae K., Omae T. (1976). Congenital oculoskeletal myopathy with abnormal muscle and liver mitochondria. J. Neurol. Sci. 27, 79–91. 10.1016/0022-510X(76)90236-7
    1. Orphanet (2018). Prevalence and Incidence of Rare Diseases: Bibliographic Data. Orphanet Report Series; Number 1, June 2018. Available online at: (Accessed November 12, 2018).
    1. Oztas E., Ozin Y., Onder F., Onal I. K., Oguz D., Kocaefe C. (2010). Chronic intestinal pseudo-obstruction and neurological manifestations in early adulthood: considering MNGIE syndrome in differential diagnosis. J. Gastrointestin. Liver Dis. 19, 195–197.
    1. Pacitti D. (2018). The Development of an in Vitro Cerebral Organoid Model for Investigating the Pathomolecular Mechanisms Associated With the Central Nervous System of Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): A Proof of Concept Study. Doctoral Ph.D. thesis, St. George's, University of London.
    1. Pacitti D., Bax B. (in press). The development of an in vitro cerebral organoid model for investigating the pathomolecular mechanisms associated with the Central nervous system involvement in mitochondrial neurogastrointestinal encephalomyopathy. Nucleosides Nucleotides Nucl. Acids. 10.1080/15257770.2018.1492139
    1. Papadimitriou A., Comi G. P., Hadjigeorgiou G. M., Bordoni A., Sciacco M., Napoli L., et al. . (1998). Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome. Neurology 51, 1086–1092. 10.1212/WNL.51.4.1086
    1. Peedikayil M. C., Kagevi E. I., Abufarhaneh E., Alsayed M. D., Alzahrani H. A. (2015). Mitochondrial neurogastrointestinal encephalomyopathy treated with stem cell transplantation: a case report and review of literature. Hematol. Oncol. Stem Cell Ther. 8, 85–90. 10.1016/j.hemonc.2014.12.001
    1. Peker S., Necmettin Pamir M. (2005). Trigeminal neuralgia in a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). J. Clin. Neurosci. 12, 172–174. 10.1016/j.jocn.2004.02.009
    1. Perez-Atayde A. R., Fox V., Teitelbaum J. E., Anthony D. A., Fadic R., Kalsner L., et al. . (1998). Mitochondrial neurogastrointestinal encephalomyopathy: diagnosis by rectal biopsy. Am. J. Surg. Pathol. 22, 1141–1147. 10.1097/00000478-199809000-00014
    1. Petcharunpaisan S., Castillo M. (2010). Multiple cranial nerve enhancement in mitochondrial neurogastrointestinal encephalomyopathy. J. Comput. Assist Tomogr. 34, 247–248. 10.1097/RCT.0b013e3181c71d48
    1. Pontarin G., Ferraro P., Valentino M. L., Hirano M., Reichard P., Bianchi V. (2006). Mitochondrial DNA depletion and thymidine phosphate pool dynamics in a cellular model of mitochondrial neurogastrointestinal encephalomyopathy. J. Biol. Chem. 281, 22720–22728. 10.1074/jbc.M604498200
    1. Pontarin G., Gallinaro L., Ferraro P., Reichard P., Bianchi V. (2003). Origins of mitochondrial thymidine triphosphate: Dynamic relations to cytosolic pools. Proc. Natl. Acad. Sci. U.S.A. 100, 12159–12164. 10.1073/pnas.1635259100
    1. Poulton J., Hirano M., Spinazzola A., Arenas Hernandez M., Jardel C., Lombès A., et al. . (2009). Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1). Biochim. Biophys. Acta Mol. Basis Dis. 1792, 1109–1112. 10.1016/j.bbadis.2009.08.016
    1. Prasun P., Koeberl D. D. (2014). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype in a patient with a novel heterozygous POLG mutation. J. Neurol. 261, 1818–1819. 10.1007/s00415-014-7428-2
    1. Rampazzo C., Ferraro P., Pontarin G., Fabris S., Reichard P., Bianchi V. (2004). Mitochondrial deoxyribonucleotides, pool sizes, synthesis, and regulation. J. Biol. Chem. 279, 17019–17026. 10.1074/jbc.M313957200
    1. Rampazzo C., Gallinaro L., Milanesi E., Frigimelica E., Reichard P., Bianchi V. (2000). A deoxyribonucleotidase in mitochondria: Involvement in regulation of dNTP pools and possible link to genetic disease. Proc. Natl. Acad. Sci. U.S.A. 97, 8239–8244. 10.1073/pnas.97.15.8239
    1. Röeben B., Marquetand J., Bender B., Billing H., Haack T. B., Sanchez-Albisua I., et al. (2017). Hemodialysis in MNGIE transiently reduces serum and urine levels of thymidine and deoxyuridine, but not CSF levels and neurological function. Orphanet J. Rare Dis. 12:135 10.1186/s13023-017-0687-0
    1. Rötig A., Poulton J. (2009). Genetic causes of mitochondrial DNA depletion in humans. Biochim. Biophys. Acta Mol. Basis Dis. 1792, 1103–1108. 10.1016/j.bbadis.2009.06.009
    1. Round J. L., Mazmanian S. K. (2009). The gut microbiome shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323. 10.1038/nri2515
    1. Rylova S. N., Mirzaee S., Albertioni F., Eriksson S. (2007). Expression of deoxynucleoside kinases and 5'-nucleotidases in mouse tissues: implications for mitochondrial toxicity. Biochem. Pharmacol. 74, 169–175. 10.1016/j.bcp.2007.03.029
    1. Said G., Lacroix C., Plante-Bordeneuve V., Messing B., Slama A., Crenn P., et al. . (2005). Clinicopathological aspects of the neuropathy of neurogastrointestinal encephalomyopathy (MNGIE) in four patients including two with a Charcot-Marie-Tooth presentation. J. Neurol. 252, 655–662. 10.1007/s00415-005-0712-4
    1. Samsonoff W. A., Reston J., McKee M., O'Connor B., Galivan J., Maley G., et al. . (1997). Intracellular location of thymidylate synthase and its state of phosphorylation. J. Biol. Chem. 272, 13281–13285. 10.1074/jbc.272.20.13281
    1. Scaglia F., Wong L. J., Vladutiu G. D., Hunter J. V. (2005). Predominant cerebellar volume loss as a neuroradiologic feature of pediatric respiratory chain defects. AJNR Am. J. Neuroradiol. 26, 1675–1680.
    1. Scarpelli M., Ricciardi G. K., Beltramello A., Zocca I., Calabria F., Russignan A., et al. . (2013). The role of brain MRI in mitochondrial neurogastrointestinal encephalomyopathy. Neuroradiol. J. 26, 520–530. 10.1177/197140091302600505
    1. Scarpelli M., Russignan A., Zombor M., Bereczki C., Zappini F., Buono R., et al. . (2012). Poor outcome in a mitochondrial neurogastrointestinal encephalomyopathy patient with a novel TYMP mutation: the need for early diagnosis. Case Rep. Neurol. 4, 248–253. 10.1159/000346260
    1. Schupbach W. M., Vadday K. M., Schaller A., Brekenfeld C., Kappeler L., Benoist J. F., et al. . (2007). Mitochondrial neurogastrointestinal encephalomyopathy in three siblings: clinical, genetic and neuroradiological features. J. Neurol. 254, 146–153. 10.1007/s00415-006-0255-3
    1. Shaibani A., Shchelochkov O. A., Zhang S., Katsonis P., Lichtarge O., Wong L.-J., et al. . (2009). Mitochondrial Neurogastrointestinal Encephalopathy Due to Mutations in RRM2B. Arch. Neurol. 66, 1028–1032. 10.1001/archneurol.2009.139
    1. Simon L. T., Horoupian D. S., Dorfman L. J., Marks M., Herrick M. K., Wasserstein P., et al. . (1990). Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction: POLIP syndrome. Ann. Neurol. 28, 349–360. 10.1002/ana.410280308
    1. Sivadasan A., Muthusamy K., Patil A. K., Mathew V., Alexander M. (2016). Pearls & Oy-sters: Mitochondrial neurogastrointestinal encephalomyopathy: diagnosis and response to peritoneal dialysis. Neurology 86, e147–e150. 10.1212/WNL.0000000000002536
    1. Slama A., Lacroix C., Plante-Bordeneuve V., Lombes A., Conti M., Reimund J. M., et al. . (2005). Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome. Mol. Genet. Metab. 84, 326–331. 10.1016/j.ymgme.2004.12.004
    1. Song S., Wheeler L. J., Mathews C. K. (2003). Deoxyribonucleotide pool imbalance stimulates deletions in HeLa cell mitochondrial DNA. J. Biol. Chem. 278, 43893–43896. 10.1074/jbc.C300401200
    1. Spinazzola A., Marti R., Nishino I., Andreu A. L., Naini A., Tadesse S., et al. . (2002). Altered thymidine metabolism due to defects of thymidine phosphorylase. J. Biol. Chem. 277, 4128–4133. 10.1074/jbc.M111028200
    1. Stenson P. D., Mort M., Ball E. V., Shaw K., Phillips A. D., Cooper D. N. (2014). The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum. Genet. 133, 1–9. 10.1007/s00439-013-1358-4
    1. Suh B. C., Jeong H. N., Yoon B. S., Park J. H., Kim H. J., Park S. W., et al. . (2013). Compound heterozygous mutations of TYMP as underlying causes of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Mol. Med. Rep. 8, 17–22. 10.3892/mmr.2013.1479
    1. Sun Q. (2016). Urine pyrimidine metabolite determination by HPLC tandem mass spectrometry. Methods Mol. Biol. 1378, 237–242. 10.1007/978-1-4939-3182-8_25
    1. Szigeti K., Sule N., Adesina A. M., Armstrong D. L., Saifi G. M., Bonilla E., et al. . (2004a). Increased blood–brain barrier permeability with thymidine phosphorylase deficiency. Ann. Neurol. 56, 881–886. 10.1002/ana.20302
    1. Szigeti K., Wong L. J., Perng C. L., Saifi G. M., Eldin K., Adesina A. M., et al. . (2004b). MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation. J. Med. Genet. 41, 125–129. 10.1136/jmg.2003.013789
    1. Taanman J.-W., Daras M., Albrecht J., Davie C. A., Mallam E. A., Muddle J. R., et al. . (2009). Characterization of a novel TYMP splice site mutation associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Neuromuscu. Disord. 19, 151–154. 10.1016/j.nmd.2008.11.002
    1. Teitelbaum J. E., Berde C. B., Nurko S., Buonomo C., Perez-Atayde A. R., Fox V. L. (2002). Diagnosis and management of MNGIE syndrome in children: case report and review of the literature. J. Pediatr. Gastroenterol. Nutr. 35, 377–383. 10.1097/00005176-200209000-00029
    1. Torres-Torronteras J., Cabrera-Perez R., Barba I., Costa C., de Luna N., Andreu A. L., et al. . (2016). Long-term restoration of thymidine phosphorylase function and nucleoside homeostasis using hematopoietic gene therapy in a murine model of mitochondrial neurogastrointestinal encephalomyopathy. Hum. Gene. Ther. 27, 656–667. 10.1089/hum.2015.160
    1. Torres-Torronteras J., Rodriguez-Palmero A., Pinós T., Accarino A., Andreu A. L., Pintos-Morell G., et al. (2011). A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy. Hum. Mutation 32, E2061–E2068. 10.1002/humu.21447
    1. Torres-Torronteras J., Viscomi C., Cabrera-Pérez R., Cámara Y., Di Meo I., Barquinero J., et al. . (2014). Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE. Mol. Ther. 22, 901–907. 10.1038/mt.2014.6
    1. Ueki T., Nakanishi K., Asai K., Okouchi Y., Isobe I., Eksioglu Y. Z., et al. . (1993). Neurotrophic action of gliostatin on cocultured neurons with glial cells. Brain Res. 622, 299–302. 10.1016/0006-8993(93)90833-9
    1. Valentino M. L., Mart,í R., Tadesse S., Lopez L. C., Manes J. L., Lyzak J., et al. . (2007). Thymidine and deoxyuridine accumulate in tissues of patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). FEBS Lett. 581, 3410–3414. 10.1016/j.febslet.2007.06.042
    1. van den Elsen L. W. J., Poyntz H. C., Weyrich L. S., Young W., Forbes-Blom E. E. (2017). Embracing the gut microbiota: the new frontier for inflammatory and infectious diseases. Clin. Transl. Immunol. 6:e125. 10.1038/cti.2016.91
    1. Verma A., Piccoli D. A., Bonilla E., Berry G. T., Dimauro S., Moraes C. T. (1997). A Novel Mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy. Pediatr. Res. 42, 448–454. 10.1203/00006450-199710000-00005
    1. Vollono C., Primiano G., Della Marca G., Losurdo A., Servidei S. (2018). Migraine in mitochondrial disorders: prevalence and characteristics. Cephalalgia 38, 1093–1106. 10.1177/0333102417723568
    1. Vondrácková A., Veselá K., Kratochvílová H., Kucerová Vidrová V., Vinšová K., tránecký V., et al. . (2014). Large copy number variations in combination with point mutations in the TYMP and SCO2 genes found in two patients with mitochondrial disorders. Eur. J. Hum. Genet. 22, 431–434. 10.1038/ejhg.2013.148
    1. Walia A., Thapa B. R., Kim V. (2006). Mitochondrial neuro-gastrointestinal encephalopathy syndrome. Indian J. Pediatr. 73, 1112–1114. 10.1007/BF02763058
    1. Wang H. F., Wang J., Wang Y. L., Fan J. J., Mo G. L., Gong F. Y., et al. . (2017). A novel thymidine phosphorylase mutation in a Chinese MNGIE patient. Acta Neurol. Belg. 117, 259–267. 10.1007/s13760-016-0701-7
    1. Wang J., Chen W., Wang F., Wu D., Qian J., Kang J., et al. . (2015). Nutrition Therapy for Mitochondrial Neurogastrointestinal encephalopathy with homozygous mutation of the TYMP Gene. Clin. Nutrit. Res. 4, 132–136. 10.7762/cnr.2015.4.2.132
    1. Yadak R., Boot M. V., van Til N. P., Cazals-Hatem D., Finkenstedt A., Bogaerts E., et al. . (2018a). Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice. BMC Gastroenterol. 18:149. 10.1186/s12876-018-0881-0
    1. Yadak R., Cabrera-Pérez R., Torres-Torronteras J., Bugiani M., Haeck J. C., Huston M. W., et al. . (2018b). Preclinical efficacy and safety evaluation of hematopoietic stem cell gene therapy in a mouse model of MNGIE. Mol. Ther. Methods Clin. Dev. 8, 152–165. 10.1016/j.omtm.2018.01.001
    1. Yasuda K., Murase N., Yoshinaga K., Ohtani R., Goto Y. I., Takahashi R., et al. . (2018). Leukoencephalopathy with a case of heterozygous POLG mutation mimicking mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). J. Clin. Neurosci. [Epub ahead of print]. 10.1016/j.jocn.2018.10.054
    1. Yavuz H., Ozel A., Christensen M., Christensen E., Schwartz M., Elmaci M., et al. . (2007). Treatment of mitochondrial neurogastrointestinal encephalomyopathy with dialysis. Arch. Neurol. 64, 435–438. 10.1001/archneur.64.3.435
    1. Yolcu M., Yolcu C., Kaya Z., Cakmak E. O., Sezen Y. (2014). Endocarditis in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome: the first in the literature. J. Clin. Diag. Res. 8, SD01–SD02. 10.7860/JCDR/2014/9528.5016
    1. Yoshimura A., Kuwazuru Y., Furukawa T., Yoshida H., Yamada K., Akiyama S.-,i. (1990). Purification and tissue distribution of human thymidine phosphorylase; high expression in lymphocytes, reticulocytes and tumors. Biochim. Biophys. Acta Gene. Subjects 1034, 107–113. 10.1016/0304-4165(90)90160-X
    1. Zhou X., Solaroli N., Bjerke M., Stewart J. B., Rozell B., Johansson M., et al. . (2008). Progressive loss of mitochondrial DNA in thymidine kinase 2-deficient mice. Hum. Mol. Genet. 17, 2329–2335. 10.1093/hmg/ddn133
    1. Zimmer V., Feiden W., Becker G., Zimmer A., Reith W., Raedle J., et al. . (2009). Absence of the interstitial cell of Cajal network in mitochondrial neurogastrointestinal encephalomyopathy. Neurogastroenterol. Motil. 21, 627–631. 10.1111/j.1365-2982.2009.01264.x
    1. Zimmer V., Hirano M., Zimmer A., Lammert F. (2014). Diagnosis of mitochondrial neurogastrointestinal encephalomyopathy: proposal of a clinical algorithm. Digest. Liver Dis. 46, 664–665. 10.1016/j.dld.2014.03.006

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する