Leigh syndrome: clinical and molecular genetic features, modern approaches to diagnosis and therapy

D. V. Kistol; P. G. Tsygankova; E. Yu. Zakharova

doi:10.25557/2073-7998.2022.04.3-15

Leigh syndrome: clinical and molecular genetic features, modern approaches to diagnosis and therapy

D. V. Kistol, P. G. Tsygankova, E. Yu. Zakharova

https://doi.org/10.25557/2073-7998.2022.04.3-15

Full Text:

PDF (Rus)

Generate QR code

Abstract

Mitochondrial diseases are clinically and genetically heterogeneous group of inherited diseases resulting from impaired oxidative phosphorylation in mitochondria. One of the most common representatives of this group among children is Leigh syndrome, or subacute necrotizing encephalomyelopathy, a severe neurodegenerative disease with manifestation in childhood. The characteristic neuroradiological features are bilateral symmetrical hypointensities in the basal ganglia on CT or bilateral symmetrical hyperintense lesions in the brainstem and/or basal ganglia on T2-weighted MRI. Currently, 80 genes are known that are responsible for the development of LS, which significantly complicates the diagnosis. In the review we provide clinical and molecular genetic features, current approaches in diagnostic and treatment for LS. Finally, an algorithm for the complex diagnosis of LS including regional aspects of mutational spectrum is described.

Keywords

mitochondrial diseases, Leigh syndrome, subacute necrotizing encephalomyelopathy, mitochondrial respiratory chain, gene therapy

About the Authors

D. V. Kistol

Research Centre for Medical Genetics
Russian Federation

P. G. Tsygankova

Research Centre for Medical Genetics
Russian Federation

E. Yu. Zakharova

Research Centre for Medical Genetics
Russian Federation

References

1. Ng Y.S., Turnbull D.M. Mitochondrial disease: genetics and management. J Neurol. 2016; 263(1): 179-191. doi: 10.1007/s00415-015-7884-3

2. Rahman S. Mitochondrial disease in children. J Intern Med. 2020; 287(6): 609-633. doi: 10.1111/joim.13054

3. Ogawa E., Fushimi T., Ogawa-Tominaga M. et al. Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis. Jrnl of Inher Metab Disea. 2020; 43(4): 819-826. doi: 10.1002/jimd.12218

4. Saneto R., Ruhoy I. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet. 2014; 7: 221-234. doi: 10.2147/TACG.S46176

5. Oláhová M., Hardy S.A., Hall J. et al. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. Brain. 2015; 138(12): 3503-3519. doi: 10.1093/brain/awv291

6. Ostergaard E., Hansen F.J., Sorensen N. et al. Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain. 2007; 130(3): 853-861. doi: 10.1093/brain/awl383

7. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. Journal of Neurology, Neurosurgery & Psychiatry. 1951; 14(3): 216-221. doi: 10.1136/jnnp.14.3.216

8. Cooper J.R., Itokawa Y., Pincus J.H. Thiamine Triphosphate Deficiency in Subacute Necrotizing Encephalomyelopathy. Science. 1969; 164(3875): 74-75. doi: 10.1126/science.164.3875.74

9. Hommes F.A., Polman H.A., Reerink J.D. Leigh’s encephalomyelopathy: an inborn error of gluconeogenesis. Archives of Disease in Childhood. 1968; 43(230): 423-426. doi: 10.1136/adc.43.230.423

10. Gordon N., Marsden H.B., Lewis D.M. Subacute Necrotising Encephalomyelopathy in Three Siblings. Developmental Medicine & Child Neurology. 2008; 16(1): 64-72. doi: 10.1111/j.1469-8749.1974.tb02713.x

11. Willems J.L., Monnens L.A., Trijbels J.M. et al. Leigh’s Encephalomyelopathy in a Patient With Cytochrome c Oxidase Deficiency in Muscle Tissue. Pediatrics. 1977; 60(6): 850-857.

12. Fernandez-Vizarra E., Zeviani M. Mitochondrial disorders of the OXPHOS system. FEBS Lett. 2021; 595(8): 1062-1106. doi: 10.1002/1873-3468.13995

13. Benard G., Bellance N., Jose C., Rossignol R. Relationships Between Mitochondrial Dynamics and Bioenergetics. Mitochondrial Dynamics and Neurodegeneration. Springer Netherlands, 2011; 47-68. doi: 10.1007/978-94-007-1291-1_2

14. Lake N.J., Compton A.G., Rahman S., Thorburn D.R. Leigh syndrome: One disorder, more than 75 monogenic causes: Leigh Syndrome. Ann Neurol. 2016; 79(2): 190-203. doi: 10.1002/ana.24551

15. Bakare A.B., Lesnefsky E.J., Iyer S. Leigh Syndrome: A Tale of Two Genomes. Front. Physiol. 2021; 12: 693734. doi: 10.3389/fphys.2021.693734

16. Gerards M., Sallevelt S.C.E.H., Smeets H.J.M. Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options. Molecular Genetics and Metabolism. 2016; 117(3): 300-312. doi: 10.1016/j.ymgme.2015.12.004

17. Baertling F., Rodenburg R.J., Schaper J. et al. A guide to diagnosis and treatment of Leigh syndrome. Journal of Neurology, Neurosurgery & Psychiatry. 2014; 85(3): 257-265. doi: 10.1136/jnnp-2012-304426

18. Finsterer J. Leigh and Leigh-Like Syndrome in Children and Adults. Pediatric Neurology. 2008; 39(4): 223-235. doi: 10.1016/j.pediatrneurol.2008.07.013

19. Hong C.-M., Na J.-H., Park S., Lee Y.-M. Clinical Characteristics of Early-Onset and Late-Onset Leigh Syndrome. Front. Neurol. 2020; 11: 267. doi: 10.3389/fneur.2020.00267

20. Alves C.A.P.F., Teixeira S.R., Martin-Saavedra J.S. et al. Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations. Ann Neurol. 2020; 88(2): 218-232. doi: 10.1002/ana.25789

21. Rahman J., Noronha A., Thiele I., Rahman S. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Ann Neurol. 2017; 81(1): 9-16. doi: 10.1002/ana.24835

22. Fassone E., Rahman S.Complex I deficiency: clinical features, biochemistry and molecular genetics. J Med Genet. 2012; 49(9): 578-590. doi: 10.1136/jmedgenet-2012-101159

23. Assouline Z., Jambou M., Rio M. et al. A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2012; 1822(6): 1062-1069. doi: 10.1016/j.bbadis.2012.01.013

24. Kose M., Canda E., Kagnici M. et al. SURF1 related Leigh syndrome: Clinical and molecular findings of 16 patients from Turkey. Molecular Genetics and Metabolism Reports. 2020; 25: 100657. doi: 10.1016/j.ymgmr.2020.100657

25. Danis D., Brennerova K., Skopkova M. et al. Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients. Endocrine Regulations. 2018; 52(2): 110-118. doi: 10.2478/enr-2018-0013

26. Цыганкова П.Г., Михайлова С.В., Захарова Е.Ю. и др. Синдром Ли, обусловленный мутациями в гене SURF1: клинические и молекулярно-генетические особенности. Журнал неврологии и психиатрии им. С.С. Корсакова. 2010; 110(1): 25-32.

27. Lee I.-C., Chiang K.-L. Clinical Diagnosis and Treatment of Leigh Syndrome Based on SURF1: Genotype and Phenotype. Antioxidants. 2021; 10(12): 1950. doi: 10.3390/antiox10121950

28. Patel K.P., O’Brien T.W., Subramony S.H. et al. The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients. Molecular Genetics and Metabolism. 2012; 105(1): 34-43. doi: 10.1016/j.ymgme.2011.09.032

29. DeBrosse S.D., Okajima K., Zhang S. et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: Lack of correlation with genotype. Molecular Genetics and Metabolism. 2012; 107(3): 394-402. doi: 10.1016/j.ymgme.2012.09.001

30. Melegh B., Trombitás K. Valproate Treatment Induces Lipid Globule Accumulation with Ultrastructural Abnormalities of Mitochondria in Skeletal Muscle. Neuropediatrics. 1997; 28(05): 257-261. doi: 10.1055/s-2007-973710

31. Stacpoole P.W., Kurtz T.L., Han Z., Langaee T. Role of dichloroacetate in the treatment of genetic mitochondrial diseases. Advanced Drug Delivery Reviews. 2008; 60(13-14): 1478-1487. doi: 10.1016/j.addr.2008.02.014

32. Felici R., Lapucci A., Cavone L. et al. Pharmacological NAD-Boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-Mutant Fibroblasts. Mol Pharmacol. 2015; 87(6): 965-971. doi: 10.1124/mol.114.097204

33. Kanabus M., Heales S.J., Rahman S. Development of pharmacological strategies for mitochondrial disorders: Mitochondrial disease pharmacological strategies. Br J Pharmacol. 2014; 171(8): 1798-1817. doi: 10.1111/bph.12456

34. Tiet M.Y., Lin Z., Gao F. et al. Targeted Therapies for Leigh Syndrome: Systematic Review and Steps Towards a “Treatabolome”. J Neuromuscul Dis. 2021; 8(6): 885-897. doi: 10.3233/JND-210715

35. Viscomi C., Burlina A.B., Dweikat I. et al.Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat Med. 2010; 16(8): 869-871. doi: 10.1038/nm.2188

36. Manfredi G., Fu J., Ojaimi J. et al. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat Genet. 2002; 30(4): 394-399. doi: 10.1038/ng851

37. Alexeyev M.F., Venediktova N., Pastukh V. et al. Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther. 2008; 15(7): 516-23. doi: 10.1038/gt.2008.11

38. Ling Q., Rioux M., Hu Y. et al. Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome. Molecular Therapy - Methods & Clinical Development. 2021; 23: 158-168. doi: 10.1016/j.omtm.2021.09.001

39. Uchino S., Iida A., Sato A. et al. A novel compound heterozygous variant of ECHS1 identified in a Japanese patient with Leigh syndrome. Hum Genome Var. 2019; 6(1): 19. doi: 10.1038/s41439-019-0050-1

40. Perrone E., Cavole T.R., Oliveira M.G. et al. Leigh syndrome in a patient with a novel C12orf65 pathogenic variant: case report and literature review. Genet. Mol. Biol. 2020; 43(2): e20180271. doi: 10.1590/1678-4685-gmb-2018-0271

41. Mani S., Chandak G.R., Singh K.K. et al. Novel p.P298L SURF1 mutation in thiamine deficient Leigh syndrome patients compromises cytochrome c oxidase activity. Mitochondrion. 2020; 53: 91-98. doi: 10.1016/j.mito.2020.04.009

42. Stenton S.L., Kremer L.S., Kopajtich R. et al. The diagnosis of inborn errors of metabolism by an integrative “multi-omics” approach: A perspective encompassing genomics, transcriptomics, and proteomics. Jrnl of Inher Metab Disea. 2020; 43(1): 25-35. doi: 10.1002/jimd.12130

43. Stenton S.L., Shimura M., Piekutowska-Abramczuk D. et al. Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes. Genetic and Genomic Medicine, 2021. doi: 10.1101/2021.06.21.21259171

44. Craven L., Alston C.L., Taylor R.W., Turnbull D.M. Recent Advances in Mitochondrial Disease. Annu. Rev. Genom. Hum. Genet. 2017; 18(1): 257-275. doi: 10.1146/annurev-genom-091416-035426

Review

For citations:

Kistol D.V., Tsygankova P.G., Zakharova E.Yu. Leigh syndrome: clinical and molecular genetic features, modern approaches to diagnosis and therapy. Medical Genetics. 2022;21(4):3-15. (In Russ.) https://doi.org/10.25557/2073-7998.2022.04.3-15

ISSN 2073-7998 (Print)

Username
Password
	Remember me
Not a user? Register with this site Forgot your password?

User

Medical Genetics

Leigh syndrome: clinical and molecular genetic features, modern approaches to diagnosis and therapy

Full Text:

Abstract

Keywords

About the Authors

References

Review

For citations:

Cookies policy