Клинический полиморфизм болезней накопления: дифференциально-диагностический алгоритм

В статье представлен обзор современного состояния вопроса о лизосомных болезнях накопления (ЛБН), группе редких генетических заболеваний, характеризующихся аномальным накоплением продуктов деградации макромолекул в клеточных органеллах. Клинические проявления ЛБН сильно варьируются в зависимости от типа заболевания и могут включать поражение печени, нервной системы и других органов. Для наилучшей демонстрации особенностей клинического течения и механизмов поражения печени при различных ЛБН в работе рассмотрены отдельные нозологии, такие как болезнь Гоше, болезнь Ниманна – Пика, дефицит лизосомной кислой липазы, ганглиозидозы и мукополисахаридозы, имеющие существенные различия в патогенезе и клиническом течении. Описаны диагностические критерии, такие как измерение активности ферментов и обнаружение патологических генотипов, а также специализированные биомаркеры, используемые для подтверждения диагноза. Диагностика ЛБН основывается на измерении активности ферментов или концентрации метаболитов в биологических образцах. Для подтверждения диагноза «ЛБН» используется молекулярно-генетическое тестирование. В данном обзоре авторами рассматриваются терапевтические стратегии, включая ферментозаместительную терапию (ФЗТ), субстратредукционную терапию и трансплантацию печени при наличии тяжелых форм поражения органа. Подчеркнута важность раннего выявления и назначения терапии для предотвращения необратимых изменений в печени и других органах. Также отмечены перспективы применения генотерапии, продемонстрировавшие положительный опыт в экспериментальных условиях, открывающие путь к новым методам лечения, способствующие восстановлению нормальной функции ферментов и профилактике прогрессирования заболевания. Представленные материалы обеспечивают комплексное понимание вопросов диагностики и лечения ЛБН, что важно для практикующих врачей и исследователей, занимающихся вопросами орфанных заболеваний.

1. Строкова ТВ, Журкова НВ, Павловская ЕВ, Каганов БС. Наследственные метаболические болезни печени: 1. Нарушения метаболизма углеводов; 2. Лизосомные болезни накопления. Вопросы практической педиатрии. 2009;4(5):28–37. Режим доступа: https://raspm.ru/files/articles/2009/5/4_5_3.pdf.

2. vom Dahl S, Mengel E. Lysosomal storage diseases as differential diagnosis of hepatosplenomegaly. Best Pract Res Clin Gastroenterol. 2010;24(5):619–628. https://doi.org/10.1016/j.bpg.2010.09.001.

3. Ferreira CR, Cassiman D, Blau N. Clinical and biochemical footprints of inherited metabolic diseases. II. Metabolic liver diseases. Mol Genet Metab. 2019;127(2):117–121. https://doi.org/10.1016/j.ymgme.2019.04.002.

4. Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol. 2022;14(10):1844–1861. https://doi.org/10.4254/wjh.v14.i10.1844.

5. Szymańska-Rożek P, Czartoryska B, Kleinotiene G, Lipiński P, Tylki-Szymańska A, Ługowska A. A 20-Year Longitudinal Study of Plasma Chitotriosidase Activity in Treated Gaucher Disease Type 1 and 3 Patients-A Qualitative and Quantitative Approach. Biomolecules. 2023;13(3):436. https://doi.org/10.3390/biom13030436.

6. Jezela-Stanek A, Kleinotiene G, Chwialkowska K, Tylki-Szymańska A. Do Not Miss the (Genetic) Diagnosis of Gaucher Syndrome: A Narrative Review on Diagnostic Clues and Management in Severe Prenatal and Perinatal-Lethal Sporadic Cases. J Clin Med. 2021;10(21):4890. https://doi.org/10.3390/jcm10214890.

7. Maurya SK, Gupta S, Mishra R. Transcriptional and epigenetic regulation of microglia in maintenance of brain homeostasis and neurodegeneration. Front Mol Neurosci. 2023;15:1072046. https://doi.org/10.3389/fnmol.2022.1072046.

8. Szymańska E, Lipiński P, Rokicki D, Książyk J, Tylki-Szymańska A. Over 20-Year Follow-up of Patients with Hepatic Glycogen Storage Diseases: Single-Center Experience. Diagnostics. 2020;10(5):297. https://doi.org/10.3390/diagnostics10050297.

9. Gardin A, Remih K, Gonzales E, Andersson ER, Strnad P. Modern therapeutic approaches to liver-related disorders. J Hepatol. 2022;76(6):1392–1409. https://doi.org/10.1016/j.jhep.2021.12.015.

10. Platt FM, d’Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Lysosomal storage diseases. Nat Rev Dis Primers. 2018;4(1):27. https://doi.org/10.1038/s41572-018-0025-4.

11. Yoldas Celik M, Yazici H, Erdem F, Yuksel Yanbolu A, Canda E, Sezer E et al. Splenomegaly and progressive neurologic involvement: Think about Niemann-Pick type C disease. Pediatr Int. 2024;66(1):e15832. https://doi.org/10.1111/ped.15832.

12. Schlotawa L, Adang LA, Radhakrishnan K, Ahrens-Nicklas RC. Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification. Int J Mol Sci. 2020;21(10):3448. https://doi.org/10.3390/ijms21103448.

13. McGovern MM, Avetisyan R, Sanson BJ, Lidove O. Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis. 2017;12(1):41. https://doi.org/10.1186/s13023-017-0572-x.

14. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670–679. https://doi.org/10.1016/S2468-1253(17)30052-3.

15. Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol. 2022;14(10):1844–1861. https://doi.org/10.4254/wjh.v14.i10.1844.

16. Wang NL, Lin J, Chen L, Lu Y, Xie XB, Abuduxikuer K, Wang JS. Neonatal cholestasis is an early liver manifestation of children with acid sphingomyelinase deficiency. BMC Gastroenterol. 2022;22(1):227. https://doi.org/10.1186/s12876-022-02310-0.

17. Daykin EC, Ryan E, Sidransky E. Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes. Mol Genet Metab. 2021;132(2):49–58. https://doi.org/10.1016/j.ymgme.2021.01.002.

18. Tylki-Szymańska A, Vellodi A, El-Beshlawy A, Cole JA, Kolodny E. Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. J Inherit Metab Dis. 2010;33(4):339–346. https://doi.org/10.1007/s10545-009-9009-66.

19. Lipiński P, Szymańska-Rożek P, Socha P, Tylki-Szymańska A. Controlled attenuation parameter and liver stiffness measurements using transient elastography by FibroScan in Gaucher disease. Mol Genet Metab. 2020;129(2):125–131. https://doi.org/10.1016/j.ymgme.2019.10.0133.

20. Nascimbeni F, Cassinerio E, Dalla Salda A, Motta I, Bursi S, Donatiello S et al. Prevalence and predictors of liver fibrosis evaluated by vibration controlled transient elastography in type 1 Gaucher disease. Mol Genet Metab. 2018;125(1-2):64–72. https://doi.org/10.1016/j.ymgme.2018.08.004.

21. McGovern MM, Avetisyan R, Sanson BJ, Lidove O. Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis. 2017;12(1):41. https://doi.org/10.1186/s13023-017-0572-x.

22. Geberhiwot T, Wasserstein M, Wanninayake S, Bolton SC, Dardis A, Lehman A et al. Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B). Orphanet J Rare Dis. 2023;18(1):85. https://doi.org/10.1186/s13023-023-02686-6.

23. Wasserstein M, Dionisi-Vici C, Giugliani R, Hwu WL, Lidove O, Lukacs Z et al. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Mol Genet Metab. 2019;126(2):98–105. https://doi.org/10.1016/j.ymgme.2018.11.014.

24. Lipiński P, Kuchar L, Zakharova EY, Baydakova GV, Ługowska A, Tylki-Szymańska A. Chronic visceral acid sphingomyelinase deficiency (Niemann-Pick disease type B) in 16 Polish patients: long-term follow-up. Orphanet J Rare Dis. 2019;14(1):55. https://doi.org/10.1186/s13023-019-1029-1.

25. Seker Yilmaz B, Baruteau J, Rahim AA, Gissen P. Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease. Int J Mol Sci. 2020;21(14):5059. https://doi.org/10.3390/ijms21145059.

26. López de Frutos L, Cebolla JJ, de Castro-Orós I, Irún P, Giraldo P. Neonatal cholestasis and Niemann-pick type C disease: A literature review. Clin Res Hepatol Gastroenterol. 2021;45(6):101757. https://doi.org/10.1016/j.clinre.2021.101757.

27. Berry-Kravis E. Niemann-Pick Disease, Type C: Diagnosis, Management and Disease-Targeted Therapies in Development. Semin Pediatr Neurol. 2021;37:100879. https://doi.org/10.1016/j.spen.2021.100879.

28. Tylki-Szymańska A, Jurecka A. Lysosomal acid lipase deficiency: wolman disease and cholesteryl ester storage disease. Pril. 2014;35(1):99–106. Available at: https://pubmed.ncbi.nlm.nih.gov/24798600.

29. Santos Silva E, Klaudel-Dreszler M, Bakuła A, Oliva T, Sousa T, Fernandes PC et al. Early onset lysosomal acid lipase deficiency presenting as secondary hemophagocytic lymphohistiocytosis: Two infants treated with sebelipase alfa. Clin Res Hepatol Gastroenterol. 2018;42(5):e77–e82. https://doi.org/10.1016/j.clinre.2018.03.012.

30. Jones SA, Rojas-Caro S, Quinn AG, Friedman M, Marulkar S, Ezgu F et al. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017;12(1):25. https://doi.org/10.1186/s13023-017-0587-3.

31. Lipiński P, Ługowska A, Zakharova EY, Socha P, Tylki-Szymańska A. Diagnostic Algorithm for Cholesteryl Ester Storage Disease: Clinical Presentation in 19 Polish Patients. J Pediatr Gastroenterol Nutr. 2018;67(4):452–457. https://doi.org/10.1097/MPG.0000000000002084.

32. Lipiński P, Cielecka-Kuszyk J, Bożkiewicz-Kasperczyk A, Perkowska B, Jurkiewicz E, Tylki-Szymańska A. Progressive macrophage accumulation in lysosomal acid lipase deficiency. Mol Genet Metab Rep. 2020;23:100594. https://doi.org/10.1016/j.ymgmr.2020.100594.

33. Balwani M, Balistreri W, D’Antiga L, Evans J, Ros E, Abel F, Wilson DP. Lysosomal acid lipase deficiency manifestations in children and adults: Baseline data from an international registry. Liver Int. 2023;43(7):1537–1547. https://doi.org/10.1111/liv.15620.

34. Foster D, Williams L, Arnold N, Larsen J. Therapeutic developments for neurodegenerative GM1 gangliosidosis. Front Neurosci. 2024;18:1392683. https://doi.org/10.3389/fnins.2024.1392683.

35. Guo Z. Ganglioside GM1 and the Central Nervous System. Int J Mol Sci. 2023;24(11):9558. https://doi.org/10.3390/ijms24119558.

36. Vasques JF, de Jesus Gonçalves RG, da Silva-Junior AJ, Martins RS, Gubert F, Mendez-Otero R. Gangliosides in nervous system development, regeneration, and pathologies. Neural Regen Res. 2023;18(1):81–86. https://doi.org/10.4103/1673-5374.343890.

37. Godbole NP, Haxton E, Rowe OE, Locascio JJ, Schmahmann JD, Eichler FS et al. Clinical and imaging predictors of late-onset GM2 gangliosidosis: A scoping review. Ann Clin Transl Neurol. 2024;11(1):207–224. https://doi.org/10.1002/acn3.51947.

38. Соловьева ВВ, Шаймарданова АА, Чулпанова ДС, Китаева КВ, Ризванов АА. Болезнь Тея-Сакса: диагностика, моделирование и подходы к терапии. Гены и клетки. 2020;15(1):17–22. https://doi.org/10.23868/202003002.

39. Howie AH, Tingley K, Inbar-Feigenberg M, Mitchell JJ, Angel K, Gentle J et al. Review of clinical trials and guidelines for children and youth with mucopolysaccharidosis: outcome selection and measurement. Orphanet J Rare Dis. 2024;19(1):393. https://doi.org/10.1186/s13023-024-03364-x.

40. Гаджикеримов ГЭ, Аль-зрер К, Гуменюк ОИ, Черненков ЮВ. Оценка эффективности скрининга на мукополисахаридозы у детей. Российский вестник перинатологии и педиатрии. 2021;66(4):240–241. https://doi.org/10.21508/1027-4065-congress-2021.

41. Costi S, Caporali RF, Marino A. Mucopolysaccharidosis: What Pediatric Rheumatologists and Orthopedics Need to Know. Diagnostics. 2022;13(1):75. https://doi.org/10.3390/diagnostics13010075.

42. Rintz E, Banacki M, Ziemian M, Kobus B, Wegrzyn G. Causes of death in mucopolysaccharidoses. Mol Genet Metab. 2024;142(3):108507. https://doi.org/10.1016/j.ymgme.2024.108507.

43. Herbst ZM, Hong X, Sadilek M, Fuller M, Gelb MH. Newborn screening for the full set of mucopolysaccharidoses in dried blood spots based on first-tier enzymatic assay followed by second-tier analysis of glycosaminoglycans. Mol Genet Metab. 2023;140(3):107698. https://doi.org/10.1016/j.ymgme.2023.107698.

44. Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E et al. Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1. Orphanet J Rare Dis. 2022;17(1):442. https://doi.org/10.1186/s13023-022-02573-6.

45. Platt FM, d’Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Lysosomal storage diseases. Nat Rev Dis Primers. 2018;4(1):27. https://doi.org/10.1038/s41572-018-0025-4.

46. Fernández-Pereira C, San Millán-Tejado B, Gallardo-Gómez M, Pérez-Márquez T, Alves-Villar M, Melcón-Crespo C et al. Therapeutic Approaches in Lysosomal Storage Diseases. Biomolecules. 2021;11(12):1775. https://doi.org/10.3390/biom11121775.

47. Kishnani PS, Al-Hertani W, Balwani M, Göker-Alpan Ö, Lau HA, Wasserstein M et al. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab. 2022;135(2):154–162. https://doi.org/10.1016/j.ymgme.2021.12.009.

48. Diaz GA, Giugliani R, Guffon N, Jones SA, Mengel E, Scarpa M et al. Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results. Orphanet J Rare Dis. 2022;17(1):437. https://doi.org/10.1186/s13023-022-02587-0.

49. Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010;25(3):300–305. https://doi.org/10.1177/0883073809344222.

50. Cox TM, Charrow J, Lukina E, Mistry PK, Foster MC, Peterschmitt MJ. Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1. Genet Med. 2023;25(2):100329. https://doi.org/10.1016/j.gim.2022.10.011.

51. Valayannopoulos V, Malinova V, Honzík T, Balwani M, Breen C, Deegan PB et al. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014;61(5):1135–1142. https://doi.org/10.1016/j.jhep.2014.06.022.

52. Liu Y, Luo Y, Xia L, Qiu B, Zhou T, Feng M et al. The Effects of Liver Transplantation in Children With Niemann-Pick Disease Type B. Liver Transpl. 2019;25(8):1233–1240. https://doi.org/10.1002/lt.25457.

53. Sitarska D, Tylki-Szymańska A, Ługowska A. Treatment trials in Niemann-Pick type C disease. Metab Brain Dis. 2021;36(8):2215–2221. https://doi.org/10.1007/s11011-021-00842-0.

54. Modin L, Ng V, Gissen P, Raiman J, Pfister ED, Das A et al. A Case Series on Genotype and Outcome of Liver Transplantation in Children with Niemann-Pick Disease Type C. Children. 2021;8(9):819. https://doi.org/10.3390/children8090819.

55. Lam P, Ashbrook A, Zygmunt DA, Yan C, Du H, Martin PT. Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency. Mol Ther Methods Clin Dev. 2022;26:413–426. https://doi.org/10.1016/j.omtm.2022.08.001.

56. Laurent M, Harb R, Jenny C, Oustelandt J, Jimenez S, Cosette J et al. Rescue of Lysosomal Acid Lipase Deficiency in Mice by rAAV8 Liver Gene Transfer. Commun Med. 2025;5(1):110. https://doi.org/10.1038/s43856-025-00816-8.

57. Kulkarni A, Chen T, Sidransky E, Han TU. Advancements in Viral Gene Therapy for Gaucher Disease. Genes. 2024;15(3):364. https://doi.org/10.3390/genes15030364.

58. Miranda CJ, McIntosh J, Kia A, Canavese M, Foley J, Leeb D et al. Liver Directed AAV Gene Therapy to Treat Gaucher Disease. Blood. 2019;134:3354. https://doi.org/10.1182/blood-2019-124280.