Skip to main content

Advertisement

SpringerLink
Log in

Effect of GBA gene variants on clinical characteristics of dementia with Lewy bodies: a review and meta-analyses

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Objectives

Glucocerebrosidase (GBA) gene may be a risk factor for dementia with Lewy bodies (DLB). However, due to the small number of existing studies and the small sample size of previous investigations, it is necessary to conduct objective and quantitative analyses of the association between GBA variants and DLB. There is no consensus regarding the relationship between GBA and the clinical characteristics of DLB. Therefore, we conducted multiple systematic reviews and meta-analyses with a particular focus on the age of onset, sex, and cognitive impairment.

Methods

PubMed, Cochrane, and EMBASE databases were searched to retrieve related studies. The odds ratios and 95% confidence interval were calculated to determine the association between GBA and DLB and between GBA and the clinical characteristics of DLB.

Results

Our meta-analysis confirmed that the GBA variant rate was significantly higher in the DLB group than in the control group, as were the variant rates of L444P, N370S, and E326K, whereas the variant rate of T369M showed no significant difference between the groups. Furthermore, the relevant literature was summarised again for meta-analyses. The GBA variant group had a younger age of onset and lower Montreal Cognitive Assessment score than the GBA non-variant group in DLB patients. GBA variants do not differ between sexes in DLB patients.

Conclusions

GBA variants increased the risk of DLB, especially N370S, E326K, and L444P which are strongly associated with DLB, but T369M was not. Patients harbouring GBA variants have an earlier age of onset, more severe cognitive impairment, and rapid symptom progression; however, sex is irrelevant in DLB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Rongve A, Witoelar A, Ruiz A et al (2019) GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Sci Rep 9(1):7013. https://doi.org/10.1038/s41598-019-43458-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Guerreiro R, Ross OA, Kun-Rodrigues C et al (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17(1):64–74. https://doi.org/10.1016/s1474-4422(17)30400-3

    Article  PubMed  Google Scholar 

  3. Mueller C, Ballard C, Corbett A et al (2017) The prognosis of dementia with Lewy bodies. Lancet Neurol 16(5):390–398. https://doi.org/10.1016/s1474-4422(17)30074-1

    Article  PubMed  Google Scholar 

  4. McKeith IG, Boeve BF, Dickson DW et al (2017) Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89(1):88–100. https://doi.org/10.1212/wnl.0000000000004058

    Article  PubMed  PubMed Central  Google Scholar 

  5. Guerreiro R, Escott-Price V, Darwent L et al (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson’s and Alzheimer’s diseases. Neurobiol Aging 38214:e217-214.e210. https://doi.org/10.1016/j.neurobiolaging.2015.10.028

    Article  CAS  Google Scholar 

  6. Boot BP, Orr CF, Ahlskog JE et al (2013) Risk factors for dementia with Lewy bodies: a case-control study. Neurology 81(9):833–840. https://doi.org/10.1212/WNL.0b013e3182a2cbd1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wenning GK, Jellinger KA (2005) The role of alpha-synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathol 109(2):129–140. https://doi.org/10.1007/s00401-004-0935-y

    Article  CAS  PubMed  Google Scholar 

  8. Halliday GM, Holton JL, Revesz T et al (2011) Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122(2):187–204. https://doi.org/10.1007/s00401-011-0852-9

    Article  CAS  PubMed  Google Scholar 

  9. Horowitz M, Wilder S, Horowitz Z et al (1989) The human glucocerebrosidase gene and pseudogene: structure and evolution. Genomics 4(1):87–96. https://doi.org/10.1016/0888-7543(89)90319-4

    Article  CAS  PubMed  Google Scholar 

  10. Winfield SL, Tayebi N, Martin BM et al (1997) Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: implications for Gaucher disease. Genome Res 7(10):1020–1026. https://doi.org/10.1101/gr.7.10.1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gan-Or Z, Liong C, Alcalay RN (2018) GBA-associated Parkinson’s disease and other synucleinopathies. Curr Neurol Neurosci Rep 18(8):44. https://doi.org/10.1007/s11910-018-0860-4

    Article  CAS  PubMed  Google Scholar 

  12. DePaolo J, Goker-Alpan O, Samaddar T et al (2009) The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. Mov Disord 24(11):1571–1578. https://doi.org/10.1002/mds.22538

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lim Y, Kehm VM, Lee EB et al (2011) α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. J Neurosci 31(27):10076–10087. https://doi.org/10.1523/jneurosci.0618-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sidransky E, Lopez G (2012) The link between the GBA gene and parkinsonism. Lancet Neurol 11(11):986–998. https://doi.org/10.1016/s1474-4422(12)70190-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sidransky E (2004) Gaucher disease: complexity in a “simple” disorder. Mol Genet Metab 83(1–2):6–15. https://doi.org/10.1016/j.ymgme.2004.08.015

    Article  CAS  PubMed  Google Scholar 

  16. Goker-Alpan O, Schiffmann R, LaMarca ME et al (2004) Parkinsonism among Gaucher disease carriers. J Med Genet 41(12):937–940. https://doi.org/10.1136/jmg.2004.024455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mata IF, Leverenz JB, Weintraub D et al (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson’s disease. Mov Disord 31(1):95–102. https://doi.org/10.1002/mds.26359

    Article  CAS  PubMed  Google Scholar 

  18. Davis MY, Johnson CO, Leverenz JB et al (2016) Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol 73(10):1217–1224. https://doi.org/10.1001/jamaneurol.2016.2245

    Article  PubMed  PubMed Central  Google Scholar 

  19. Riboldi GM, Di Fonzo AB (2019) GBA, Gaucher disease, and Parkinson's disease: from genetic to clinic to new therapeutic approaches. Cells 8(4). https://doi.org/10.3390/cells8040364

  20. Walker L, Stefanis L, Attems J (2019) Clinical and neuropathological differences between Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies - current issues and future directions. J Neurochem 150(5):467–474. https://doi.org/10.1111/jnc.14698

    Article  CAS  PubMed  Google Scholar 

  21. Nalls MA, Duran R, Lopez G et al (2013) A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol 70(6):727–735. https://doi.org/10.1001/jamaneurol.2013.1925

    Article  PubMed  Google Scholar 

  22. Gámez-Valero A, Prada-Dacasa P, Santos C et al (2016) GBA mutations are associated with earlier onset and male sex in dementia with Lewy bodies. Mov Disord 31(7):1066–1070. https://doi.org/10.1002/mds.26593

    Article  CAS  PubMed  Google Scholar 

  23. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605. https://doi.org/10.1007/s10654-010-9491-z

    Article  PubMed  Google Scholar 

  24. Mata IF, Samii A, Schneer SH et al (2008) Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 65(3):379–382. https://doi.org/10.1001/archneurol.2007.68

    Article  PubMed  PubMed Central  Google Scholar 

  25. Farrer MJ, Williams LN, Algom AA et al (2009) Glucosidase-beta variations and Lewy body disorders. Parkinsonism Relat Disord 15(6):414–416. https://doi.org/10.1016/j.parkreldis.2008.08.004

    Article  PubMed  Google Scholar 

  26. Asselta R, Rimoldi V, Siri C et al (2014) Glucocerebrosidase mutations in primary parkinsonism. Parkinsonism Relat Disord 20(11):1215–1220. https://doi.org/10.1016/j.parkreldis.2014.09.003

    Article  PubMed  PubMed Central  Google Scholar 

  27. Keogh MJ, Kurzawa-Akanbi M, Griffin H et al (2016) Exome sequencing in dementia with Lewy bodies. Transl Psychiatry 6(2):e728. https://doi.org/10.1038/tp.2015.220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Keogh MJ, Wei W, Wilson I et al (2017) Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource. Genome Res 27(1):165–173. https://doi.org/10.1101/gr.210609.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Moors TE, Paciotti S, Ingrassia A et al (2019) Characterization of brain lysosomal activities in GBA-related and sporadic Parkinson’s disease and dementia with Lewy bodies. Mol Neurobiol 56(2):1344–1355. https://doi.org/10.1007/s12035-018-1090-0

    Article  CAS  PubMed  Google Scholar 

  30. Biswas A, Sadhukhan D, Biswas A et al (2021) Identification of GBA mutations among neurodegenerative disease patients from eastern India. Neurosci Lett 751135816. https://doi.org/10.1016/j.neulet.2021.135816

  31. van der Lee SJ, van Steenoven I, van de Beek M et al (2021) Genetics contributes to concomitant pathology and clinical presentation in dementia with Lewy bodies. J Alzheimers Dis 83(1):269–279. https://doi.org/10.3233/jad-210365

    Article  PubMed  PubMed Central  Google Scholar 

  32. Goker-Alpan O, Giasson BI, Eblan MJ et al (2006) Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67(5):908–910. https://doi.org/10.1212/01.wnl.0000230215.41296.18

    Article  CAS  PubMed  Google Scholar 

  33. Lerche S, Machetanz G, Wurster I et al (2019) Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha-synuclein profile. Mov Disord 34(7):1069–1073. https://doi.org/10.1002/mds.27731

    Article  CAS  PubMed  Google Scholar 

  34. Bregman N, Kavé G, Mirelman A et al (2019) Distinguishing dementia with Lewy bodies from Alzheimer disease: what is the influence of the GBA genotype in Ashkenazi Jews? Alzheimer Dis Assoc Disord 33(3):279–281. https://doi.org/10.1097/wad.0000000000000283

    Article  PubMed  Google Scholar 

  35. Shiner T, Mirelman A, Rosenblum Y et al (2021) The effect of GBA mutations and APOE polymorphisms on dementia with Lewy bodies in Ashkenazi Jews. J Alzheimers Dis 80(3):1221–1229. https://doi.org/10.3233/jad-201295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sidransky E, Lopez G (2012) The link between the GBA gene and parkinsonism. Lancet Neurol 11(11):986–998. https://doi.org/10.1016/S1474-4422(12)70190-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mazzulli JR, Xu YH, Sun Y et al (2011) Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146(1):37–52. https://doi.org/10.1016/j.cell.2011.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gomperts SN (2016) Lewy body dementias: dementia with Lewy bodies and Parkinson disease dementia. Continuum (Minneap Minn) 22(2 Dementia):435–463. https://doi.org/10.1212/con.0000000000000309

  39. Perez-Roca L, Adame-Castillo C, Campdelacreu J, et al. (2018) Glucocerebrosidase mRNA is diminished in brain of Lewy body diseases and changes with disease progression in blood. Aging Dis 9(2):208–219. https://doi.org/10.14336/ad.2017.0505

  40. Thaler A, Gurevich T, Bar Shira A et al (2017) A “dose” effect of mutations in the GBA gene on Parkinson’s disease phenotype. Parkinsonism Relat Disord 3647–51. https://doi.org/10.1016/j.parkreldis.2016.12.014

  41. Bras J, Guerreiro R, Darwent L et al (2014) Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 23(23):6139–6146. https://doi.org/10.1093/hmg/ddu334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gan-Or Z, Alcalay RN, Makarious MB et al (2019) Classification of GBA variants and their effects in synucleinopathies. Mov Disord 34(10):1581–1582. https://doi.org/10.1002/mds.27803

    Article  PubMed  Google Scholar 

  43. Lesage S, Anheim M, Condroyer C et al (2011) Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum Mol Genet 20(1):202–210. https://doi.org/10.1093/hmg/ddq454

    Article  CAS  PubMed  Google Scholar 

  44. Beutler E, Gelbart T, Scott CR (2005) Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis 35(3):355–364. https://doi.org/10.1016/j.bcmd.2005.07.005

    Article  CAS  PubMed  Google Scholar 

  45. Gan-Or Z, Amshalom I, Kilarski LL et al (2015) Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology 84(9):880–887. https://doi.org/10.1212/wnl.0000000000001315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Neumann J, Bras J, Deas E et al (2009) Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 132(Pt 7):1783–1794. https://doi.org/10.1093/brain/awp044

    Article  PubMed  PubMed Central  Google Scholar 

  47. Berge-Seidl V, Pihlstrøm L, Maple-Grødem J et al (2017) The GBA variant E326K is associated with Parkinson’s disease and explains a genome-wide association signal. Neurosci Lett 65848–52. https://doi.org/10.1016/j.neulet.2017.08.040

Download references

Acknowledgements

We would like to thank all the participants for their helpful comments on this paper.

Author information

Authors and Affiliations

  1. Department of Neurology, China–Japan Union Hospital of Jilin University, Changchun, 130000, Jilin, China

    Li Liu, Jia Li, Wei Quan, Yidan Qin, Qinghui Zhang, Xiaochen Pei, Hang Su, Jing Xu & Jiajun Chen

Authors
  1. Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yidan Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qinghui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaochen Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hang Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiajun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiajun Chen.

Ethics declarations

Ethical approval

Does not involve ethical content.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Li Liu and Jia Li contributed equally to this work and are co-first authors.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 99 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, L., Li, J., Quan, W. et al. Effect of GBA gene variants on clinical characteristics of dementia with Lewy bodies: a review and meta-analyses. Neurol Sci 43, 3541–3550 (2022). https://doi.org/10.1007/s10072-022-06031-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-022-06031-w

Keywords

Search

Navigation