Gaucher Disease: Clinical phenotypes and GBA1 variants spectrum in Kazakhstani patients

Aliya Amangeldiyeva; Riza  Boranbayeva; Gulnara  Abdilova; Indira  Jaxybayeva; Dilorom  Akhmedova

doi:10.23750/abm.2026.17731

Gaucher Disease: Clinical phenotypes and GBA1 variants spectrum in Kazakhstani patients

Authors

Aliya Amangeldiyeva Scientific Center of Pediatrics and Pediatric Surgery, Almaty, Kazakhstan
Riza Boranbayeva MedInvestGroup Kazakhstan, Almaty, Kazakhstan
Gulnara Abdilova Scientific Center of Pediatrics and Pediatric Surgery, Almaty, Kazakhstan
Indira Jaxybayeva S.D. Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
Dilorom Akhmedova Tashkent State Medical University, Tashkent, Uzbekistan

Keywords:

Gaucher disease, mutations, β-D-glucocerebrosidase, GBA gene

Abstract

Background and Aim: Gaucher disease (GD) is a rare lysosomal storage disorder caused by mutations in the β-glucosidase (GBA1) gene, with more than 500 variants described. This study aimed to investigate the clinical features and spectrum of GBA1 variants in Kazakhstani patients with GD. Methods: Medical records from the national referral center for GD in Kazakhstan were reviewed. Forty-five patients with confirmed GD were included. Diagnosis was confirmed by reduced β-glucosidase, glucocerebrosidase enzyme activity, and supported by elevated plasma chitotriosidase activity. The entire coding region of GBA1 was analyzed using bidirectional Sanger sequencing. Results: Among 45 patients from 38 unrelated families, 15 variants were identified in 20 combinations, including 12 missense variants, 2 nonsense variants, 1 frameshift variant, 1 splice-site variant, and 1 recombinant variant. Of the missense variants, 10 were pathogenic, while 2 novel variants (A316L and F477R) were classified as likely pathogenic. The most frequent variants were L444P (28) and N370S (19). The N370S variant was predominant in GD type 1 (19), whereas L444P occurred in both type 1 (15) and type 3 (11) disease. Conclusions: This study demonstrated that 28 of 45 patients with GD in the Republic of Kazakhstan have type 1 disease, with the N370S mutation being the predominant genetic variant (28). Among the 17 patients with type 2 and 3 GD who had central nervous system involvement, the most frequent finding was the L444P mutation.

References

1. Beutler E, Demina A, Gelbart T. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994;1:82–92. doi:10.1007/BF03403534.

2. Rodriguez-Porcel F, Espay AJ, Carecchio M. Parkinson disease in Gaucher disease. J Clin Mov Disord. 2017;4:7. doi:10.1186/s40734-017-0054-2.

3. Choy FY, Zhang W, Shi HP, et al. Gaucher disease among Chinese patients: review on genotype/phenotype correlation from 29 patients and identification of novel and rare alleles. Blood Cells Mol Dis. 2007;38(3):287–93. doi:10.1016/j.bcmd.2006.11.003.

4. Koto Y, Narita A, Noto S, et al. Qualitative analysis of patient interviews on the burden of neuronopathic Gaucher disease in Japan. Orphanet J Rare Dis. 2022;17:280. doi:10.1186/s13023-022-02429-z.

5. Jeong SY, Park SJ, Kim HJ. Clinical and genetic characteristics of Korean patients with Gaucher disease. Blood Cells Mol Dis. 2011;46(1):11–4. doi:10.1016/j.bcmd.2010.07.010.

6. Mehta A, Belmatoug N, Bembi B, et al. Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians. Mol Genet Metab. 2017;122(3):122–9. doi:10.1016/j.ymgme.2017.08.002.

7. Tylki-Szymańska A, Szymańska-Rożek P, Hasiński P, Lugowska A. Chitotriosidase activity in plasma compared with plasma glucosylsphingosine in a wide range of Gaucher disease phenotypes: a statistical analysis. Mol Genet Metab. 2018;123(4):495–500. doi:10.1016/j.ymgme.2018.02.004.

8. Wang L, Xu CM, Tsai CH, Lee KK, Hu WL, Tsai FJ. Mutation analysis in patients with Gaucher disease in Taiwan: high prevalence of RecNciI and L444P mutations. Blood Cells Mol Dis. 2006;36(3):422–5. doi:10.1016/j.bcmd.2006.02.001.

9. Beutler E, Grabowski GA. Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 3635–68.

10. Horowitz M, Zimran A. Mutations causing Gaucher disease. Hum Mutat. 1994;3(1):1–11. doi:10.1002/humu.1380030102.

11. Grabowski GA. Gaucher disease. In: Harris H, Hirschhorn K, eds. Advances in human genetics. Vol 21. Boston: Springer; 1993. p. 165–242. doi:10.1007/978-1-4615-3010-7_5.

12. Nalishnik L, Rotella P, Simeone JK, Hamed A, Weinreb N. Epidemiology and natural course of Gaucher disease: a comprehensive review of the literature. Hematology. 2017;22(2):65–73. doi:10.1080/10245332.2016.1240391.

13. Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat. 2008;29(5):567–83. doi:10.1002/humu.20676.

14. Koprivica V, Stone DL, Park JK, et al. Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. Am J Hum Genet. 2000;66(6):1777–86. doi:10.1086/302925.

15. Ida H, Rennert OM, Kawame H, Maekawa K, Eto Y. Mutation prevalence among 47 unrelated Japanese patients with Gaucher disease: identification of four novel mutations. J Inherit Metab Dis. 1997;20(1):67–73. doi:10.1023/a:1005313724361.

16. Phetthong T, Tim-Aroon T, Khongkraparn A, et al. Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients. Orphanet J Rare Dis. 2021;16(1):519. doi:10.1186/s13023-021-02151-2.

17. Gumus E, Karhan AN, Hizarcioglu-Gulsen H, et al. Clinical-genetic characteristics and treatment outcomes of Turkish children with Gaucher disease type 1 and type 3: a sixteen year single-center experience. Eur J Med Genet. 2021;64(11):104339. doi:10.1016/j.ejmg.2021.104339.

18. Diaz GA, Gelb BD, Risch N, et al. Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations. Am J Hum Genet. 2000;66(6):1821–32. doi:10.1086/302946.

19. Giraldo P, Alfonso P, Irun P, Gort L, et al. Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula. Orphanet J Rare Dis. 2012;7:17. doi:10.1186/1750-1172-7-17.

20. Lukina KA, Fevraleva IS, Sysoeva EP, Mamonov BE, Sudarikov AB, Lukina EA. Characterization of the genotypes of patients with Gaucher disease type 1 in the Russian Federation. Ter Arkh. 2013;85(7):72–5. [Russian]. [INCOMPLETE]

21. Sheth J, Bhavsar R, Mistri M, et al. Gaucher disease: molecular characterisation of a single gene in a hundred Indian patients reveals novel variants and the most common mutation. BMC Med Genet. 2019;20(1):31. doi:10.1186/s12881-019-0759-1.

22. Rice M, Schaefer E, Luhrs T, et al. Critical evaluation of the chitotriosidase assay in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease types A/B and C. J Inherit Metab Dis. 2006;29(5):647–52. doi:10.1007/s10545-006-0363-3.

23. Giuffrida G, Markovic U, Condorelli A, et al. Glucosylsphingosine (Lyso-Gb1) as a reliable biomarker in Gaucher disease: a narrative review. Orphanet J Rare Dis. 2023;18(1):27. doi:10.1186/s13023-023-02623-7.

24. Lee YS, Poh LK, Ida H, Loke KY. Type II Gaucher disease: compound heterozygote with RecNciI and L444P mutations. J Trop Pediatr. 2001;47(2):115–17. doi:10.1093/tropej/47.2.110-a.

25. Gawad Tantawy AA, Moneam Adly AA, Madkour SS, Salah El-Din NY. Pulmonary manifestations in young Gaucher disease patients: phenotype-genotype correlation and radiological findings. Pediatr Pulmonol. 2020;55(2):441–8. doi:10.1002/ppul.24544.

26. Zhong W, Li D, Fei Y, Pan H, Zhang L, Cheng N. A review of type 3 Gaucher disease: unique neurological manifestations and advances in treatment. Acta Neurol Belg. 2024;124(4):1213–23. doi:10.1007/s13760-024-02493-1.