GM1-ганглиозидоз: современный взгляд на этиопатогенез, гетерогенность фенотипа и инновационные терапевтические стратегии

GM1-ганглиозидоз – это редкое наследственное заболевание с аутосомно-рецессивным типом наследования, связанное с мутацией в гене GLB1. Недостаточная активность фермента β-галактозидазы ведет к избыточному накоплению GM1-ганглиозида преимущественно в клетках центральной нервной системы, а также внутренних органов, обуславливая прогрессирующую нейродегенерацию и висцеральные симптомы. Клиническая картина может значительно варьировать и включает неврологические нарушения, эпилепсию, скелетные аномалии, дисморфию лица, патологию внутренних органов и офтальмологические симптомы. Полиморфизм клинической картины, различный возраст манифестации и степень вовлеченности нервной системы и систем органов в патологический процесс обусловлены разной степенью остаточной активности фермента. В связи с этим выделяют три типа GM1-ганглиозидоза: инфантильный, ювенильный и поздний. В статье обсуждаются современные данные об этиологии, биохимических нарушениях и патогенезе, клинических проявлениях, диагностике GM1-ганглиозидоза, а также новые возможные подходы к терапии пациентов с этим заболеванием с использованием животных моделей. Эффективного лечения GM1-ганглиозидоза на сегодняшний день не существует. Однако такие подходы, как фермент-заместительная терапия, субстрат-редуцирующая терапия, терапия шаперонами, трансплантация гепомоэтических стволовых клеток и генная терапия с использованием аденоассоциированных вирусных векторов, рассматриваются как наиболее перспективные методы лечения, некоторые из которых в настоящее время уже находятся на стадии клинических исследований.

1. Lang FM, Korner P, Harnett M, Karunakara A, Tifft C J. The natural history of Type 1 infantile GM1 gangliosidosis: A literature-based meta-analysis. Mol Genet Metab. 2020;129(3):228–235. https://doi.org/10.1016/j.ymgme.2019.12.012.

2. Brunetti-Pierri N, Scaglia F. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab. 2008;94(4):391–396. https://doi.org/10.1016/j.ymgme.2008.04.012.

3. Sinigerska I, Chandler D, Vaghjiani V, Hassanova I, Gooding R, Morrone A et al. Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population. Mol Genet Metab. 2006;88(1):93–95. https://doi.org/10.1016/j.ymgme.2005.12.009.

4. Oshima A, Tsuji A, Nagao Y, Sakuraba H, Suzuki Y. Cloning, sequencing, and expression of cDNA for human β-galactosidase. Biochem Biophys Res Commun. 1988;157(1):238–244. https://doi.org/10.1016/s0006-291x(88)80038-x.

5. Morreau H, Galjart NJ, Gillemans N, Willemsen R, van der Horst GT, d’Azzo A. Alternative splicing of β-galactosidase mRNA generates the classic lysosomal enzyme and a β-galactosidase-related protein. J Biol Chem. 1989;264(34):20655–20663. https://doi.org/10.1016/S0021-9258(19)47114-7.

6. Privitera S, Prody CA, Callahan JW, Hinek A. The 67-kDa enzymatically inactive alternatively spliced variant of beta-galactosidase is identical to the elastin/laminin-binding protein. J Biol Chem. 1998;273(11):6319–6326. https://doi.org/10.1074/jbc.273.11.6319.

7. Hinek A, Zhang S, Smith AC, Callahan JW. Impaired elastic-fiber assembly by fibroblasts from patients with either Morquio B disease or infantile GM1-gangliosidosis is linked to deficiency in the 67-kD spliced variant of β-galactosidase. Am J Hum Genet. 2000;67(1):23–36. https://doi.org/10.1086/302968.

8. Baiotto C, Sperb F, Matte U, da Silva CD, Sano R, Coelho JC, Giugliani R. Population analysis of the GLB1 gene in South Brazil. Genet Mol Biol. 2011;34(1):45–48. https://doi.org/10.1590/S1415-47572011000100009.

9. Santamaria R, Blanco M, Chabás A, Grinberg D, Vilageliu L. Identification of 14 novel GLB1 mutations, including five deletions, in 19 patients with GM1 gangliosidosis from South America. Clin Genet. 2007;71(3):273–279. https://doi.org/10.1111/j.1399-0004.2007.00767.x.

10. Santamaria R, Chabás A, Coll MJ, Miranda CS, Vilageliu L, Grinberg D. Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies. Hum Mutat. 2006;27(10):1060. https://doi.org/10.1002/humu.9451.

11. Caciotti A, Bardelli T, Cunningham J, D’Azzo A, Zammarchi E, Morrone A. Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient. Hum Genet. 2003;113(1):44–50. https://doi.org/10.1007/s00439-003-0930-8.

12. Chakraborty S, Rafi MA, Wenger DA. Mutations in the lysosomal β-galactosidase gene that cause the adult form of GM1 gangliosidosis. Am J Hum Genet. 1994;54(6):1004–1013. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC1918177/.

13. Ferreira CR, Gahl WA. Lysosomal storage diseases. Transl Sci Rare Dis. 2017;2(1-2):1–71. https://doi.org/10.3233/TRD-160005.

14. Mayer FQ, Pereira Fdos S, Fensom AH, Slade C, Matte U, Giugliani R. New GLB1 mutation in siblings with Morquio type B disease presenting with mental regression. Mol Genet Metab. 2009;96(3):148. https://doi.org/10.1016/j.ymgme.2008.11.159.

15. Regier DS, Kwon HJ, Johnston J, Golas G, Yang S, Wiggs E et al. MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis. Am J Med Genet A. 2016;170(3):634–644. https://doi.org/10.1002/ajmg.a.37468.

16. Patterson MC. Gangliosidoses. Handb Clin Neurology. 2013;113:1707–1708. https://doi.org/10.1016/B978-0-444-59565-2.00039-3.

17. Rösner H, al-Aqtum M, Rahmann H. Gangliosides and neuronal differentiation. Neurochem Int. 1992;20(3):339–351. https://doi.org/10.1016/0197-0186(92)90048-V.

18. Arboleda G, Morales LC, Benítez B, Arboleda H. Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration. Brain Res Rev. 2009;59(2):333–346. https://doi.org/10.1016/j.brainresrev.2008.10.001.

19. Palmano K, Rowan A, Guillermo R, Guan J, McJarrow P. The Role of Gangliosides in Neurodevelopment. Nutrients. 2015;7(5):3891–3913. https://doi.org/10.3390/nu7053891.

20. Lawrence R, Van Vleet JL, Mangini L, Harris A, Martin N, Clark W et al. Characterization of glycan substrates accumulating in GM1 Gangliosidosis. Mol Genet Metab Rep. 2019;21:100524. https://doi.org/10.1016/j.ymgmr.2019.100524.

21. Tessitore A, Martin MdP, Sano R, Ma Y, Mann L, Ingrassia A et al. GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell. 2004;15(5):753–766. https://doi.org/10.1016/j.molcel.2004.08.029.

22. d’Azzo A, Tessitore A, Sano R. Gangliosides as apoptotic signals in ER stress response. Cell Death Differ. 2006;13(3):404–414. https://doi.org/10.1038/sj.cdd.4401834.

23. van der Voorn JP, Kamphorst W, van der Knaap MS, Powers JM. The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss and axonal dysfunction. Acta Neuropathol. 2004;107(6):539–545. https://doi.org/10.1007/s00401-004-0848-9.

24. Folkerth RD. Abnormalities of developing white matter in lysosomal storage diseases. J Neuropathol Exp Neurol. 1999;58(9):887–902. https://doi.org/10.1097/00005072-199909000-00001.

25. Jeyakumar M, Thomas R, Elliot-Smith E, Smith DA, van der Spoel AC, d’Azzo A et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain. 2003;126(Pt 4): 974–987. https://doi.org/10.1093/brain/awg089.

26. Yang CF, Wu JY, Tsai FJ. Three novel beta-galactosidase gene mutations in Han Chinese patients with GM1 gangliosidosis are correlated with disease severity. J Biomed Sci. 2010;17(1):79. https://doi.org/10.1186/1423-0127-17-79.

27. Caciotti A, Garman SC, Rivera-Colón Y, Procopio E, Catarzi S, Ferri L et al. GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta. 2011;1812(7):782–790. https://doi.org/10.1016/j.bbadis.2011.03.018.

28. Jarnes Utz JR, Kim S, King K, Ziegler R, Schema L, Redtree ES, Whitley CB. Infantile gangliosidoses: Mapping a timeline of clinical changes. Mol Genet Metab. 2017;121(2):170–179. https://doi.org/10.1016/j.ymgme.2017.04.011.

29. Erol I, Alehan F, Pourbagher MA, Canan O, Yildirim SV. Neuroimaging findings in infantile GM1 gangliosidosis. Eur J Paediatr Neurol. 2006;10(5-6):245–248. https://doi.org/10.1016/j.ejpn.2006.08.005.

30. De Grandis E, Di M, Pessagno RA, Veneselli E, Rossi A. MR Imaging Findings in 2 Cases of Late Infantile GM1 Gangliosidosis. AJNR Am J Neuroradiol. 2009;30(7):1325–1327. https://doi.org/10.3174/ajnr.A1508.

31. Suzuki Y, Nakamura N, Fukuoka K. GM1-gangliosidosis: accumulation of ganglioside GM1 in cultured skin fibroblasts and correlation with clinical types. Hum Genet. 1978;43(2):127–131. https://doi.org/10.1007/BF00293589.

32. Arash-Kaps L, Komlosi K, Seegräber M, Diederich S, Paschke E, Amraoui Y et al. The Clinical and Molecular Spectrum of GM1 Gangliosidosis. J Pediatr. 2019;215:152–157.e3. https://doi.org/10.1016/j.jpeds.2019.08.016.

33. Karimzadeh P, Naderi S, Modarresi F, Dastsooz H, Nemati H, Farokhashtiani T et al. Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene. BMC Med Genet. 2017;18(1):73. https://doi.org/10.1186/s12881-017-0417-4.

34. Sperb F, Vairo F, Burin M, Mayer FQ, Matte U, Giugliani R. Genotypic and phenotypic characterization of Brazilian patients with GM1 gangliosidosis. Gene. 2013;512(1):113–116. https://doi.org/10.1016/j.gene.2012.09.106.

35. Cerulli Irelli E, Cocchi E, Ramantani G, Morano A, Riva A, Caraballo RH et al. Sex-based electroclinical differences and prognostic factors in epilepsy with eyelid myoclonia. Epilepsia. 2023;64:e105–e111. https://doi.org/10.1111/epi.17609.

36. Gamirova R, Shagimardanova E, Sato T, Kannon T, Gamirova G, Tajima A. Identification of potential disease-associated variants in idiopathic generalized epilepsy using targeted sequencing. J Hum Genet. 2024;69(2):59–67. https://doi.org/10.1038/s10038-023-01208-3.

37. Laur D, Pichard S, Bekri S, Caillaud C, Froissart R, Levade T et al. Natural history of GM1 gangliosidosis – Retrospective cohort study of 61 French patients from 1998 to 2019. J Inherit Metab Dis. 2023;46(5):972–981. https://doi.org/10.1002/jimd.12646.

38. Lee JS, Choi JM, Lee M, Kim SY, Lee S, Lim BC et al. Diagnostic challenge for the rare lysosomal storage disease: Late infantile GM1 gangliosidosis. Brain Dev. 2018;40(5):383–390. https://doi.org/10.1016/j.braindev.2018.01.009.

39. Karimzadeh P, Ebrahimi M, Etemad K, Abadi FA, Nezhad ZH. GM1 and GM2-Gangliosidosis: Clinical Features, Neuroimaging Findings and Electroencephalography. Iran J Child Neurol. 2024;18(2):127–140. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11015724/.

40. Pampiglione G, Harden A. Neurophysiological Investigations in GM 1 and GM 2 Gangliosidoses. Neuropediatrics. 1984;15:74–84. https://doi.org/10.1055/s-2008-1052386.

41. Feng Y, Huang Y, Zhao X, Sheng H, Feng Y, Zhang W, Liu L. Clinical and molecular characteristics of 11 Chinese probands with GM1 gangliosidosis. Metab Brain Dis. 2018;33(6):2051–2057. https://doi.org/10.1007/s11011-018-0315-2.

42. Concolino D, Deodato F, Parini R. Enzyme replacement therapy: efficacy and limitations. Ital J Pediatr. 2018;44(Suppl. 2):120. https://doi.org/10.1186/s13052-018-0562-1.

43. Movahedpour A, Ahmadi N, Ghalamfarsa F, Ghesmati Z, Khalifeh M, Maleksabet A et al. β-Galactosidase: From its source and applications to its recombinant form. Biotechnol Appl Biochem. 2022;69(2):612–628. https://doi.org/10.1002/bab.2137.

44. Suzuki Y, Ogawa S, Sakakibara Y. Chaperone therapy for Neuronopathic lysosomal diseases: Competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities. Perspect Medicin Chem. 2009;3:7–19. https://doi.org/10.4137/PMC.S2332.

45. Chen JC, Luu AR, Wise N, De Angelis R, Agrawal V, Mangini L et al. Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice. J Biol Chem. 2020;295(39):13532–13555. https://doi.org/10.1074/jbc.RA119.009811.

46. Kelly JM, Gross AL, Martin DR, Byrne ME. Polyethylene glycol-b-poly (lactic acid) polymersomes as vehicles for enzyme replacement therapy. Nanomedicine. 2017;12(23):2591–2606. https://doi.org/10.2217/nnm-2017-0221.

47. Kida S, Koshimura Y, Yoden E, Yoshioka A, Morimoto H, Imakiire A et al. Enzyme replacement with transferrin receptor-targeted α-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice. Mol Ther Methods Clin Dev. 2023;29:439–449. https://doi.org/10.1016/j.omtm.2023.05.010.

48. Platt FM, Jeyakumar M, Andersson U, Heare T, Dwek RA, Butters TD. Substrate reduction therapy in mouse models of the glycosphingolipidoses. Philos Trans R Soc Lond B Biol Sci. 2003;358(1443):947–954. https://doi.org/10.1098/rstb.2003.1279.

49. Tifft C, Adams DR, Morgan CP. 55 Miglustat improves function in patients with juvenile GM1 gangliosidosis. Mol Genet Metab 2007;92(4):24. https://doi.org/10.1016/j.ymgme.2007.08.060.

50. Deodato F, Procopio E, Rampazzo A, Taurisano R, Donati MA, Dionisi-Vici C et al. The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression. Metab Brain Dis. 2017;32(5):1529–1536. https://doi.org/10.1007/s11011-017-0044-y.

51. Fischetto R, Palladino V, Mancardi MM, Giacomini T, Palladino S, Gaeta A et al. Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience. Mol Genet Genomic Med. 2020;8(10):e1371. https://doi.org/10.1002/mgg3.1371.

52. Kasperzyk JL, El‐Abbadi MM, Hauser EC, d’Azzo A, Platt FM, Seyfried TN. N‐ butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis. J Neurochem. 2004;89(3):645–653. https://doi.org/10.1046/j.1471-4159.2004.02381.x.

53. Sano R, Tessitore A, Ingrassia A, d’Azzo A. Gene therapy of murine GM1 Gangliosidosis by genetically modified bone marrow hematopoietic progenitor cells. Mol Ther 2004;9(S1):S265. https://doi.org/10.1016/j.ymthe.2004.06.650.

54. Sano R, Tessitore A, Ingrassia A, d’Azzo A. Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology. Blood. 2005;106(7):2259–2268. https://doi.org/10.1182/blood-2005-03-1189.

55. Shield JPH, Stone J, Steward CG. Bone marrow transplantation correcting β-galactosidase activity does not influence neurological outcome in juvenile GM1-gangliosidosis. J Inherit Metab Dis. 2005;28(5):797–798. https://doi.org/10.1007/s10545-005-0089-7.

56. Higaki K, Li L, Bahrudin U, Okuzawa S, Takamuram A, Yamamoto K et al. Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β‐galactosidase deficiency. Human Mutat. 2011;32(7):843–852. https://doi.org/10.1002/humu.21516.

57. Hosseini K, Fallahi J, Tabei SMB, Razban V. Gene therapy approaches for GM1 gangliosidosis: focus on animal and cellular studies. Cell Biochem Funct. 2023;41(8):1093–1105. https://doi.org/10.1002/cbf.3887.

58. Broekman MLD, Baek RC, Comer LA, Fernandez JL, Seyfried TN, Sena-Esteves M. Complete correction of enzymatic deficiency and neurochemistry in the GM1-gangliosidosis mouse brain by neonatal adeno-associated virus-mediated gene delivery. Mol Ther. 2007;15(1):30–37. https://doi.org/10.1038/sj.mt.6300004.

59. Baek RC, Boekman MLD, Leroy SG, Tierney LA, Sandberg MA, d’Azzo A et al. AAV-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in CNS and improves survival. PLoS ONE. 2010;5(10):e13468. https://doi.org/10.1371/journal.pone.0013468.

60. Weismann CM, Ferreira J, Keeler AM, Su Q, Qui L, Shaffer SA et al. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Hum Mol Genet. 2015;24(15):4353–4364. https://doi.org/10.1093/hmg/ddv168.

61. Hinderer C, Nosratbakhsh B, Katz N, Wilson JM. A Single Injection of an Optimized Adeno-Associated Viral Vector into Cerebrospinal Fluid Corrects Neurological Disease in a Murine Model of GM1 Gangliosidosis. Hum Gene Ther. 2020;31(21-22):1169–1177. https://doi.org/10.1089/hum.2018.206.

62. Baker Jr HJ, Lindsey JR, McKhann GM, Farrell DF. Neuronal GM1 gangliosidosis in a Siamese cat with β-galactosidase deficiency. Science. 1971;174(4011):838–839. https://doi.org/10.1126/science.174.4011.838.

63. Gray-Edwards HL, Regier DS, Shirley JL, Randle AN, Salibi N, Thomas SE et al. Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model. Mol Ther. 2017;25(4):892–903. https://doi.org/10.1016/j.ymthe.2017.01.009.

64. Gray-Edwards HL, Maguire AS, Salibi N, Ellis LE, Voss TL, Diffie EB et al. 7T MRI Predicts Amelioration of Neurodegeneration in the Brain after AAV Gene Therapy. Mol. Ther Methods Clin Dev. 2020;17:258–270. https://doi.org/10.1016/j.omtm.2019.11.023.