Neuromuscular DiseasesNeuromuscular DiseasesНервно-мышечные болезни2222-87212413-0443Publishing House ABV Press50910.17650/2222-8721-2022-12-4-56-72ORIGINAL REPORTSОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯA new mutation in the TYMP-gene: clinical and morphological characteristics of a patient with MNGIE syndromeНовая мутация в гене TYMP: клинико-морфологическая характеристика пациента с синдромом MNGIEhttps://orcid.org/0000-0002-3804-6245BardakovS. N.БардаковС. Н.
Russian Federation

Sergey Nikolaevich Bardakov  

6 Akademika Lebedeva St., Saint Petersburg 194044

Сергей Николаевич Бардаков  

194044 Санкт-Петербург, ул. Академика Лебедева, 6

epistaxis@mail.ruLimaevI. S.ЛимаевИ. С.
Russian Federation

41 Kirochnaya St., Saint Petersburg 191123

191123 Санкт-Петербург, ул. Кирочная, 41

https://orcid.org/0000-0003-4109-0105EmelinA. M.ЕмелинА. М.
Russian Federation

41 Kirochnaya St., Saint Petersburg 191123

191123 Санкт-Петербург, ул. Кирочная, 41

NikitinsV.НикитинсВ.
Russian Federation

41 Kirochnaya St., Saint Petersburg 191123

191123 Санкт-Петербург, ул. Кирочная, 41

PresnyakovE. V.ПресняковЕ. В.
Russian Federation

41 Kirochnaya St., Saint Petersburg 191123

191123 Санкт-Петербург, ул. Кирочная, 41

https://orcid.org/0000-0002-8886-5222KurbatovS. A.КурбатовС. А.
Russian Federation

10 Studencheskaya St., Voronezh 394622

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TsygankovaP. G.ЦыганковаП. Г.
Russian Federation

1 Moskvorechye St., Moscow 115478

115478 Москва, ул. Москворечье, 1

https://orcid.org/0000-0002-5459-986XTsargushV. A.ЦаргушВ. А.
Russian Federation

Build. 1, 24 Petrovka St., Moscow 127051

127051 Москва, ул. Петровка, 24, стр. 1

https://orcid.org/0000-0003-0126-4473ChekmarevaI. A.ЧекмареваИ. А.
Russian Federation

27 Bolshaya Serpukhovskaya St., Moscow 115093

115093 Москва, ул. Большая Серпуховская, 27

https://orcid.org/0000-0002-1745-6982KolmakovaE. V.КолмаковаЕ. В.
Russian Federation

41 Kirochnaya St., Saint Petersburg 191123

191123 Санкт-Петербург, ул. Кирочная, 41

BakulinaN. V.БакулинаН. В.
Russian Federation

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191123 Санкт-Петербург, ул. Кирочная, 41

https://orcid.org/0000-0001-8389-3841DeevR. V.ДеевР. В.
Russian Federation

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3 Gubkina St., Moscow 119333

191123 Санкт-Петербург, ул. Кирочная, 41

119333 Москва, ул. Губкина, 3

S.M. Kirov Military Medical Academy, Ministry of Defense of RussiaФГБОУ ВО «Военно-медицинская академия им. С.М. Кирова» Минобороны РоссииNorth-Western State Medical University named after I.I. Mechnikov, Ministry of Health of RussiaФГБОУ ВО «Северо-Западный государственный медицинский университет им. И.И. Мечникова» Минздрава РоссииScientific Research Institute of Experimental Biology and Medicine, Voronezh State Medical University named after N.N. BurdenkoНаучно-исследовательский институт экспериментальной биологии и медицины ФГБОУ ВО «Воронежский государственный медицинский университет им. Н.Н. Бурденко»Laboratory of Hereditary Metabolic Diseases of the Medical Genetic Research Center named after acad. N.P. BochkovЛаборатория наследственных болезней обмена веществ ФБГНУ «Медико-генетический научный центр им. акад. Н.П. Бочкова»Scientific and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Department of HealthГБУЗ г. Москвы «Научно-практический клинический центр диагностики и телемедицинских технологий Департамента здравоохранения г. Москвы»National Medical Research Center for Surgery named after A.V. Vishnevsky, Ministry of Health of RussiaФГБОУ «Национальный медицинский исследовательский центр хирургии им. А.В. Вишневского» Минздрава РоссииHuman Stem Cell InstituteИнститут стволовых клеток человека1312202212456721312202213122022Copyright ©; 2022, Bardakov S.N., Limaev I.S., Emelin A.M., Nikitins V., Presnyakov E.V., Kurbatov S.A., Tsygankova P.G., Tsargush V.A., Chekmareva I.A., Kolmakova E.V., Bakulina N.V., Deev R.V.Copyright ©; 2022, Бардаков С.Н., Лимаев И.С., Емелин А.М., Никитинс В., Пресняков Е.В., Курбатов С.А., Цыганкова П.Г., Царгуш В.А., Чекмарева И.А., Колмакова Е.В., Бакулина Н.В., Деев Р.В.2022Bardakov S.N., Limaev I.S., Emelin A.M., Nikitins V., Presnyakov E.V., Kurbatov S.A., Tsygankova P.G., Tsargush V.A., Chekmareva I.A., Kolmakova E.V., Bakulina N.V., Deev R.V.Бардаков С.Н., Лимаев И.С., Емелин А.М., Никитинс В., Пресняков Е.В., Курбатов С.А., Цыганкова П.Г., Царгуш В.А., Чекмарева И.А., Колмакова Е.В., Бакулина Н.В., Деев Р.В.https://creativecommons.org/licenses/by/4.0https://nmb.abvpress.ru/jour/article/view/509

Mitochondrial neurogastrointestinal encephalomyopathy is an extremely rare (1–9:1 000 000, Orphanet, 2021) multisystem genetic disease caused by mutations in the TYMP gene encoding the enzyme thymidine phosphorylase.The article presents the data of a thirteen‑year survey on 40‑year‑old patient D. with clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy syndrome associated with the previously undescribed missense mutation c.1301G>T (p.Gly434Val) of the TYMP gene. Detailed clinical picture (gastrointestinal dysfunction, cachexia, blepharoptosis, ophthalmoparesis, peripheral polyneuropathy and leukoaraiosis), electroneuromyography data (demyelination with secondary axonopathy), high blood serum level of dihydrothymine together with normal levels of thymidine and deoxyuridine made it possible to verify the diagnosis. Histopathological examination revealed atrophy of the longitudinal (outer) muscle layer of the small and large intestines and a significant decrease in the number of CD117+ cells (telocytes), signs of damage to the striated skeletal muscles of a mixed nature with a predominance of the myogenic pattern, as well the destruction of the myelin sheaths of peripheral nerves. Histochemical examination did not reveal “ragged red fibers” characteristic of mitochondrial pathology. Transmission electron microscopy demonstrated the presence of megalomitochondria in the myocardium.

Синдром митохондриальной нейрогастроинтестинальной энцефаломиопатии – редкое (1–9:1000000, Orphanet, 2021) генетическое мультисистемное заболевание, обусловленное мутациями в ядерном гене TYMP, кодирующем фермент тимидинфосфорилазу.Представлены данные 13‑летнего наблюдения пациентки Д., 40 лет, с синдромом митохондриальной нейрогастроинтестинальной энцефаломиопатии, связанным с ранее не описанной миссенс‑заменой c.1301G>T (p.Gly434Val) в гене TYMP. Диагноз синдрома митохондриальной нейрогастроинтестинальной энцефаломиопатии был поставлен на основании клинических проявлений (дисфункция желудочно‑кишечного тракта, кахексия, блефароптоз, офтальмопарез, периферическая полинейропатия и лейкоэнцефалопатия), результатов электронейромиографии (демиелинизация с вторичной аксонопатией), а также повышения уровня дигидротимина в сыворотке крови при нормальных уровнях тимидина и дезоксиуридина. Патогистологическое исследование выявило атрофию продольного (наружного) мышечного слоя тонкой и толстой кишок и значимое уменьшение количества CD117+‑клеток (телоцитов), поражение скелетных мышц смешанного характера с преобладанием миогенного паттерна, а также деструкцию миелиновых оболочек периферических нервов. Исследование S100‑положительных вегетативных образований кишечной стенки не выявило патологических изменений. При гистохимическом исследовании не были обнаружены «рваные красные волокна», характерные для митохондриопатий. Трансмиссионная электронная микроскопия продемонстрировала наличие полиморфизма митохондрий кардиомиоцитов и мегаломитохондрий лейомиоцитов кишечника.

mitochondrial neurogastrointestinal encephalomyopathyMNGIETYMPtelocytesCD117S100митохондриальная нейрогастроинтестинальная энцефаломиопатияMNGIETYMPтелоцитыCD117S100The funding for this study was provided by the Ministry of Science and Higher Education of Russia (agreement No. 075-15-2021-1346).Исследование выполнено при финансовой поддержке Минобрнауки России (cоглашение № 075-15-2021-1346).1. Prevalence and Incidence of Rare Diseases: Bibliographic Data. Orphanet Report Series, 2021. Available at: https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf.Prevalence and Incidence of Rare Diseases: Bibliographic Data. Orphanet Report Series, 2021. Available at: https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf.2. Pacitti D., Levene M., Garone C. et al. Mitochondrial neurogastrointestinal encephalomyopathy: into the fourth decade, what we have learned so far. Front Genet 2018;21(9):669. 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