Синдром на Leigh – обзор

Резюме

Синдромът на Leigh е рядко, прогресиращо митохондриално заболяване с дебют още през кърмаческия период, характеризиращо се с тежка невродегенерация и висока смъртност. Етиологията му е генетично хетерогенна и включва патогенни варианти както в митохондриалната, така и в ядрената ДНК, водещи до нарушена функция на дихателната верига и окислителното фосфорилиране. Клиничната картина обхваща широк спектър от неврологични и системни прояви, като характерните билатерални лезии в базалните ганглии и мозъчния ствол, установими чрез ядрено-магнитен резонанс, са ключови за поставянето на диагнозата.

Настоящият обзор обобщава съвременните данни за патогенезата, генотип – фенотип корелациите, клиничните характеристики и диагностичния подход при синдрома на Leigh, с акцент върху ролята на молекулярно-генетичните изследвания. Разгледани са възможностите и ограниченията на медико-генетичната консултация и пренаталната диагностика, както и актуалните терапевтични стратегии.

Ключови думи: митохондриални заболявания, синдром на Leigh, хетероплазмия, невродегенерация

Библиография

1. 1. Russell OM, Gorman GS, Lightowlers RN, et al. Hope for the Future. Cell. 2020 Apr 2; 168-188.

2. Wen H, Deng H, Li B, et al. Mitochondrial diseases: from molecular mechanisms to therapeutic advances. Sig Transduct Target Ther 10, 9 (2025).

3. Pizzamiglio С, Hanna M, Pitceathly R, Chapter 4 – Primary mitochondrial diseases, Handbook of Clinical Neurology, Volume 204,

2024, 53-76.

4. Kistol D, Tsygankova P, Krylova, et al. Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia. Int. J. Mol. Sci. 2023, 24, 1597.

5. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: Clinical features and biochemical and DNA abnormalities. Ann. Neurol. 1996, 39, 343–351.

6. Thorburn D, Rahman S. Mitochondrial DNA-Associated Leigh Syndrome Spectrum. 2003 Oct 30 [Updated 2024 May 9]. GeneReviews, Seattle (WA); 1993-2025.

7. Ogawa E, Fushimi T, Ogawa-Tominaga M, et al. Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis. J Inherit Metab Dis. 2020 Jul;43(4):819-826.

8. Gorman G, Chinnery P, DiMauro S, et al. Mitochondrial diseases. Nat Rev Dis Primers 2, 16080 (2016).

9. Chinnery F, Primary Mitochondrial Disorders Overview. 2000 Jun 8 [Updated 2021 Jul 29]. GeneReviews. Seattle (WA): University of Washington.

10. Mei J, Ding P, Gao C, еt al. Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances. MedComm (2020). 2025 Sep 12:6(9).

11. Gupta R, Kanai M, Durham TJ, et al. Nuclear Genetic Control of

mtDNA Copy Number and Heteroplasmy in Humans,” Nature 620, no.

7975(2023): 839–848.

12. Bakare B, Lesnefsky J, Iyer S. Leigh Syndrome: A Tale of Two Genomes. Front. Physiol. 2021.

13. Rahman S, Horvath, R, Hirano M. Chapter 4 – Leigh syndrome. In Handbook of Clinical Neurology; Eds.; Elsevier, 2023.

14. Sofou K, de Coo I, Ostergaard E, et al. Phenotype-genotype correlations in Leigh syndrome: New insights from a multicentre study of 96 patients. J. Med.

15. Alves C, Teixeira S, Martin-Saavedra J, et al. Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations. 2020.

16. Lake N, Compton A, Rahman et al. Leigh syndrome: one     disorder, more than 75 monogenic causes. Ann. Neurol. 79, 2015: 190–203.

17. Rahman S, Thorburn DR, Ball M. Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview. 2015 Oct 1 GeneReviews, 1993-2025. 18. Magro G, Laterza V, Tosto F. Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments. Biomedicines 2025, 13, 733.

19. Wedatilake Y, Brown RM, McFarland R, et al. SURF1 deficiency: a multi-centre natural history study. Orphanet J Rare Dis. 2013 Jul 5: 8:96.

20. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951 Aug;14(3):216-21.

21. Laterza V, Tosto F. Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments. Biomedicines 2025, 13, 733.

22. Piao Y, Tang G, Yang H, et al. Clinico-neuropathological study of a Chinese case of familial adult Leigh syndrome. Neuropathology 2006, 26, 218–221.

23. Ng YS, Martikainen MH, Gorman GS, et al Pathogenic variants in MT-ATP6: a United Kingdom-based mitochondrial disease cohort study. Ann Neurol. 2019;86:310-5.

24. Alston C, Morak M, Reid C, et al. A novel mitochondrial MT-ND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy. Neuromuscul. Disord. 2010, 20:131–135.

25. Hong CM, Na JH, Park S, et al. Clinical characteristics of early-onset and late-onset Leigh syndrome. Front Neurol. 2020;11:267.

26. Lim AZ, Ng YS, Blain A, et al. Natural history of Leigh syndrome: a study of disease burden and progression. Ann Neurol. 2022:117-30.

27. Stenton SL, Zou Y, Cheng H, et al. Leigh syndrome: a study of 209 patients at the Beijing Children’s Hospital. Ann Neurol. 2022:466-82.

28. Qstergaard E, Bradinova I, Simeonov E, et al. Hypertrichosis in

patients with SURF1 mutations. Am. J. Med. Genet. Part A 2005: 384–388.

29. McCormick EM, Keller K, Taylor JP, et al. Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum. Ann Neurol. 2023 Oct;94(4):696-712.

30. Bonfante E, Koenig M, Adejumo R, et al. The neuroimaging of Leigh syndrome: Case series and review of the literature. Pediatr. Radiol. 2016, 46:443–451.

31. Horváth R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J. Neurol. Neurosurg. Psychiatry 2006;77:74–76.

32. Schubert M, Vilarinho L. Molecular basis of Leigh syndrome: a current look. Orphanet J Rare Dis. 2020 Jan 29;15(1):31.

33. Davis RL, Kumar KR, Puttick C, et al. Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis. Neurology. 2022 Aug 16;99(7)

34. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015.

35. Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry. 2014 Mar;85(3):257-65.

36. Mavraki E, Labrum R, Sergeant K, et al. Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines. Eur J Hum Genet. 2023;31:148-63.

37. Sallevelt SC, de Die-Smulders CE, Hendrickx AT, et al. De novo mtDNA point mutations are common and have a low recurrence risk. J Med Genet. 2017;54:73-83.

38. De Vries MC, Brown DA, Allen ME, et al. Safety of drug use in patients with a primary mitochondrial disease: An international Delphi-based consensus. J Inherit Metab Dis. 2020;43:800-18.

Адрес за кореспонденция:

Д. Атова

Клиника за лечение на деца с генетични заболявания, СБАЛДБ „Проф. Иван Митев“

Медицински университет – София

България, София

бул. „Акад. Иван Гешов“ 11

e-mail: dinaatova@yahoo.com