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GBA1 variants and Parkinson’s Disease: A dual approach combining clinical data and literature review

Yıl 2025, Cilt: 64 Sayı: 2, 231 - 242, 10.06.2025

Sezin Canbek , Goncagül Mert , Muhammed Fatih Gülseven , Mehmet Güney Şenol

https://doi.org/10.19161/etd.1583422

Öz

Aim: The GBA1 (ENSG00000177628) gene, a key susceptibility gene in Parkinson’s disease (PD) and closely linked to Gaucher disease, has garnered significant research attention over the past two decades. Mutations in GBA1 are associated with an elevated risk of developing PD. This study aims to elucidate genetic mutations related to PD in a cohort of patients undergoing clinical exome analysis. We aimed to investigate the clinical and genetic profiles of patients with Parkinson’s disease, focusing on GBA1 gene mutations and additional neurodegenerative-related genetic alterations.
Materials and Methods: Fourteen patients with a preliminary diagnosis of Parkinson's disease underwent clinical exome analysis. The research included genetic testing to identify variants of uncertain significance, likely pathogenic mutations, and pathogenic mutations in the GBA1 gene. Further genetic alterations were evaluated in patients with positive GBA1 mutation results.
Results: 14 out of 177 diagnosed individuals had GBA1 mutations. The group had 8 men and 6 women with a mean onset age of 53.7 years. Tremor, stiffness, bradykinesia, hypomimia, and postural instability predominated. Dopamine agonists were often administered for symptoms. Disorders like depression, anxiety, hypercholesterolemia, and diabetes were frequent. GBA1 gene study found many missense variants, with the p.Asn409Ser (N370S) mutation being the most common. Four individuals also had mutations in EIF4G1, APP, and SLC20A2, demonstrating a complex genetic landscape affecting PD.
Conclusion: Our research highlights PD's genetic diversity, particularly GBA1 mutations' role in disease onset and progression. Additional genetic variants may worsen PD symptoms. Further research is needed on these mutations' pathogenicity and consequences on patient care.

Anahtar Kelimeler

Parkinson’s disease GBA gene glucocerebrosidase clinical exome analysis motor symptoms

Kaynakça

  • Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest. 2006;116(7):1744-54.
  • Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009;18(R1):R48-59.
  • Halperin A, Elstein D, Zimran A. Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cells Mol Dis. 2006;36(3):426-8.
  • Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015;138(Pt 9):2648-58.
  • Beavan M, Schapira AH. Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease-Reply. JAMA Neurol. 2015;72(6):724.
  • Macerollo A. Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease. JAMA Neurol. 2015;72(6):723-4.
  • Chatterjee D, Krainc D. Mechanisms of Glucocerebrosidase Dysfunction in Parkinson's Disease. J Mol Biol. 2023;435(12):168023.
  • Huang Y, Yu F, Feng L, Wang X. The Association between E326K of GBA and the Risk of Parkinson's Disease. Parkinsons Dis. 2018;2018:1048084.
  • Wang DX, Shi Q, Wang Z, Zhang Y. (GBA mutations and Parkinson's disease). Sheng Li Xue Bao. 2018;70(3):294-300.
  • Brooker SM, Krainc D. Glucocerebrosidase dysfunction in neurodegenerative disease. Essays Biochem. 2021;65(7):873-83.
  • Dos Santos JCC, Dos Santos LR, Ferreira RR, Costa RB. The Molecular Impact of Glucosylceramidase Beta 1 (GBA1) in Parkinson's Disease: a New Genetic State of the Art. Mol Neurobiol. 2024.
  • Wang D, Wang L, Wang Z. Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease. Front Pharmacol. 2023;14:1288894.
  • Gabbert C, Lu J, Ennis K, Zhang X. GBA1 in Parkinson's disease: variant detection and pathogenicity scoring matters. BMC Genomics. 2023;24(1):322.
  • Hatano T, Okuzumi A, Aoyama M, Hattori N. Alpha-Synuclein: A Promising Biomarker for Parkinson's Disease and Related Disorders. J Mov Disord. 2024.
  • Sobreira-Neto MA, Fukusaki C, Angelim A, Sobreira E. REM sleep behavior disorder: update on diagnosis and management. Arq Neuropsiquiatr. 2023;81(12):1179-94.
  • Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci. 2010;1184:15-54.
  • Iftikhar IH, Smith MC, Neubauer DN, Kasper JL. Alpha-synuclein pathology in isolated rapid eye movement sleep behaviour disorder: a meta-analysis. J Sleep Res. 2024;e14204.
  • Adler CH, Hentz JG, Shill HA, Caviness JN. Conjugal Synucleinopathies: A Clinicopathologic Study. Mov Disord. 2024.
  • Liu L, Xue L, Huang X, Chen S. Effect of GBA gene variants on clinical characteristics of dementia with Lewy bodies: a review and meta-analyses. Neurol Sci. 2022;43(6):3541-50.
  • Wernick AI, Aasly J, Blaeser CD, Mathias C. GBA variation and susceptibility to multiple system atrophy. Parkinsonism Relat Disord. 2020;77:64-9.
  • Usenko TS, Prokhorova EA, Chernykh AV, Krylova TD. Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy. Mol Neurobiol. 2022;59(4):2277-87.
  • Matsukawa T, Ito M, Inoue Y, Okada Y. Clinical and Genetic Features of Multiplex Families with Multiple System Atrophy and Parkinson's Disease. Cerebellum. 2024;23(1):22-30.
  • Saffie Awad P, Guerrero-Jaramillo Y, Campos-Arriola D, Rivas D. Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis. Mov Disord. 2024;39(1):6-16.
  • Zhang X, Yin Z, Yu X, Li J. Clinical Characteristics and GBA Gene Mutation Analysis of Gaucher Disease Type I. Clin Lab. 2023;69(4).
  • Parlar SC, Guven MM, Ciftci B, Akcan C. Classification of GBA1 Variants in Parkinson's Disease: The GBA1-PD Browser. Mov Disord. 2023;38(3):489-95.
  • Senkevich K, Rudakova A, Sudarkina O, Gureev A. Genetic mechanism vs genetic subtypes: The example of GBA. Handb Clin Neurol. 2023;193:155-70.
  • Long GL, Winichagoon P, Fucharoen S, Fucharoen G. Structure and organization of the human metaxin gene (MTX) and pseudogene. Genomics. 1996;33(2):177-84.
  • Toffoli M, Cenci S, Piacentini M, Tagliaferri L. Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene. Commun Biol. 2022;5(1):670.
  • Gan-Or Z, Bar-Shira A, Mirelman A, Gurevich T. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008;70(24):2277-83.
  • Colucci F, Ali M, Silva D, Massaroni S. Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. BMJ Neurol Open. 2023;5(2):e000535.
  • Kopytova AE, Proskurina SE, Kruglikov IS, Podlesnykh SI. Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism. Parkinsonism Relat Disord. 2021;84:112-21.
  • Crotty GF, Schwarzschild MA. What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs. Neurology. 2022;99(7 Suppl 1):34-41.
  • Zhao X, Chen X, Huang J, Wang Z. PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases. Proc Natl Acad Sci U S A. 2023;120(1):e2210442120.
  • Jones TA, Trinh J, Tagliati M, Schuler M. A cross-sectional survey of genetic counselors providing carrier screening regarding GBA variants and Parkinson disease susceptibility. J Assist Reprod Genet. 2022;39(3):747-55.
  • Deng H, Wu Y, Jankovic J. The EIF4G1 gene and Parkinson's disease. Acta Neurol Scand. 2015;132(2):73-8.
  • Sidransky E, Nalls MA, Aasly JO, Nichols WC. Glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009;361(17):1651-61.
  • Neumann J, Bohnen NI, Müller U, Schulz JB. Non-motor symptoms of Parkinson's disease: Depression, anxiety, and apathy in Parkinson's disease. Mov Disord. 2009;24(9):1212-9.
  • Brockmann K, GBA-associated Parkinson's disease: The effects of GBA mutations on the development of non-motor symptoms. Neurology. 2011;77(13):1221-6.
  • Alcalay RN, Glucocerebrosidase mutations and risk of Parkinson’s disease in Ashkenazi Jews. N Engl J Med. 2012;367(24):2332-9.
  • Singleton A, Gene expression in Parkinson’s disease. Lancet Neurol. 2013;12(11):1140-50.
  • Davis MY, Mutations in GBA1, EIF4G1, and PD risk: Exploring genetic overlap in neurodegenerative diseases. J Parkinsons Dis. 2016;6(4):759-73.
  • Mazzulli JR, α-Synuclein causes lysosomal dysfunction and impaired autophagic clearance in GBA mutation carriers. Science. 2011;333(6048):90-3.
  • Mullin S, Ambroxol for the treatment of patients with Parkinson disease and GBA1 mutations: A nonrandomized, noncontrolled trial. JAMA Neurol. 2020;77(4):427-34.
  • Gan-Or Z, The penetrance of GBA mutations in Parkinson’s disease: The importance of genetic counseling and individualized risk assessment. Mov Disord. 2015;30(1):14-7.

GBA1 varyantları ve Parkinson Hastalığı: Klinik veriler ve literatür incelemesini birleştiren çift yaklaşım

Yıl 2025, Cilt: 64 Sayı: 2, 231 - 242, 10.06.2025

Sezin Canbek , Goncagül Mert , Muhammed Fatih Gülseven , Mehmet Güney Şenol

https://doi.org/10.19161/etd.1583422

Öz

Amaç:
Parkinson hastalığında (PD) önemli bir duyarlılık geni olan ve Gaucher hastalığıyla yakından ilişkili olan GBA geni, son yirmi yılda önemli bir araştırma ilgisi topladı. GBA'daki mutasyonlar, PD geliştirme riskinin artmasıyla ilişkilidir. Bu çalışma, klinik ekzom analizi geçiren bir hasta kohortunda PD ile ilişkili genetik mutasyonları açıklamayı amaçlamaktadır.
GBA gen mutasyonlarına ve ek nörodejeneratif ilişkili genetik değişikliklere odaklanarak Parkinson hastalığı olan hastaların klinik ve genetik profillerini araştırmak.
Gereç ve Yöntem:
Parkinson hastalığı ön tanısı olan on dört hasta klinik ekzom analizinden geçti. Araştırma, belirsiz öneme sahip varyantları, olası patojenik mutasyonları ve GBA genindeki patojenik mutasyonları belirlemek için genetik test içeriyordu. Pozitif GBA mutasyonu sonuçları olan hastalarda daha fazla genetik değişiklik değerlendirildi.
Sonuçlar: Teşhis konulan 177 kişiden 14'ünde GBA mutasyonu vardı. Grupta ortalama başlangıç ​​yaşı 53,7 yıl olan 8 erkek ve 6 kadın vardı. Titreme, sertlik, bradikinezi, hipomimi ve duruş bozukluğu baskındı. Semptomlar için genellikle dopamin agonistleri uygulandı. Depresyon, anksiyete, hiperkolesterolemi ve diyabet gibi bozukluklar sıktı. GBA gen çalışması, p.Asn409Ser (N370S) mutasyonunun en yaygın olduğu birçok anlamsız varyant buldu. Dört kişide ayrıca EIF4G1, APP ve SLC20A2 mutasyonları vardı ve bu da PD'yi etkileyen karmaşık bir genetik manzarayı gösteriyor.
Sonuç:
Araştırmamız PD'nin genetik çeşitliliğini, özellikle GBA mutasyonlarının hastalığın başlangıcında ve ilerlemesindeki rolünü vurgulamaktadır. Ek genetik varyantlar PD semptomlarını kötüleştirebilir. Bu mutasyonların patojenitesi ve hasta bakımı üzerindeki sonuçları hakkında daha fazla araştırmaya ihtiyaç vardır.

Anahtar Kelimeler

Parkinson hastalığı GBA geni glukoserebrosidaz klinik ekzom analizi motor semptomlar

Etik Beyan

Etik kurul onayı alınmıştır.

Destekleyen Kurum

None

Teşekkür

Hasta ve yakınlarına teşekkürler.

Kaynakça

  • Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest. 2006;116(7):1744-54.
  • Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009;18(R1):R48-59.
  • Halperin A, Elstein D, Zimran A. Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cells Mol Dis. 2006;36(3):426-8.
  • Alcalay RN, Levy OA, Waters CC, Fahn S, Ford B, Kuo SH, et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015;138(Pt 9):2648-58.
  • Beavan M, Schapira AH. Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease-Reply. JAMA Neurol. 2015;72(6):724.
  • Macerollo A. Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease. JAMA Neurol. 2015;72(6):723-4.
  • Chatterjee D, Krainc D. Mechanisms of Glucocerebrosidase Dysfunction in Parkinson's Disease. J Mol Biol. 2023;435(12):168023.
  • Huang Y, Yu F, Feng L, Wang X. The Association between E326K of GBA and the Risk of Parkinson's Disease. Parkinsons Dis. 2018;2018:1048084.
  • Wang DX, Shi Q, Wang Z, Zhang Y. (GBA mutations and Parkinson's disease). Sheng Li Xue Bao. 2018;70(3):294-300.
  • Brooker SM, Krainc D. Glucocerebrosidase dysfunction in neurodegenerative disease. Essays Biochem. 2021;65(7):873-83.
  • Dos Santos JCC, Dos Santos LR, Ferreira RR, Costa RB. The Molecular Impact of Glucosylceramidase Beta 1 (GBA1) in Parkinson's Disease: a New Genetic State of the Art. Mol Neurobiol. 2024.
  • Wang D, Wang L, Wang Z. Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease. Front Pharmacol. 2023;14:1288894.
  • Gabbert C, Lu J, Ennis K, Zhang X. GBA1 in Parkinson's disease: variant detection and pathogenicity scoring matters. BMC Genomics. 2023;24(1):322.
  • Hatano T, Okuzumi A, Aoyama M, Hattori N. Alpha-Synuclein: A Promising Biomarker for Parkinson's Disease and Related Disorders. J Mov Disord. 2024.
  • Sobreira-Neto MA, Fukusaki C, Angelim A, Sobreira E. REM sleep behavior disorder: update on diagnosis and management. Arq Neuropsiquiatr. 2023;81(12):1179-94.
  • Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci. 2010;1184:15-54.
  • Iftikhar IH, Smith MC, Neubauer DN, Kasper JL. Alpha-synuclein pathology in isolated rapid eye movement sleep behaviour disorder: a meta-analysis. J Sleep Res. 2024;e14204.
  • Adler CH, Hentz JG, Shill HA, Caviness JN. Conjugal Synucleinopathies: A Clinicopathologic Study. Mov Disord. 2024.
  • Liu L, Xue L, Huang X, Chen S. Effect of GBA gene variants on clinical characteristics of dementia with Lewy bodies: a review and meta-analyses. Neurol Sci. 2022;43(6):3541-50.
  • Wernick AI, Aasly J, Blaeser CD, Mathias C. GBA variation and susceptibility to multiple system atrophy. Parkinsonism Relat Disord. 2020;77:64-9.
  • Usenko TS, Prokhorova EA, Chernykh AV, Krylova TD. Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy. Mol Neurobiol. 2022;59(4):2277-87.
  • Matsukawa T, Ito M, Inoue Y, Okada Y. Clinical and Genetic Features of Multiplex Families with Multiple System Atrophy and Parkinson's Disease. Cerebellum. 2024;23(1):22-30.
  • Saffie Awad P, Guerrero-Jaramillo Y, Campos-Arriola D, Rivas D. Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis. Mov Disord. 2024;39(1):6-16.
  • Zhang X, Yin Z, Yu X, Li J. Clinical Characteristics and GBA Gene Mutation Analysis of Gaucher Disease Type I. Clin Lab. 2023;69(4).
  • Parlar SC, Guven MM, Ciftci B, Akcan C. Classification of GBA1 Variants in Parkinson's Disease: The GBA1-PD Browser. Mov Disord. 2023;38(3):489-95.
  • Senkevich K, Rudakova A, Sudarkina O, Gureev A. Genetic mechanism vs genetic subtypes: The example of GBA. Handb Clin Neurol. 2023;193:155-70.
  • Long GL, Winichagoon P, Fucharoen S, Fucharoen G. Structure and organization of the human metaxin gene (MTX) and pseudogene. Genomics. 1996;33(2):177-84.
  • Toffoli M, Cenci S, Piacentini M, Tagliaferri L. Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene. Commun Biol. 2022;5(1):670.
  • Gan-Or Z, Bar-Shira A, Mirelman A, Gurevich T. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008;70(24):2277-83.
  • Colucci F, Ali M, Silva D, Massaroni S. Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. BMJ Neurol Open. 2023;5(2):e000535.
  • Kopytova AE, Proskurina SE, Kruglikov IS, Podlesnykh SI. Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism. Parkinsonism Relat Disord. 2021;84:112-21.
  • Crotty GF, Schwarzschild MA. What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs. Neurology. 2022;99(7 Suppl 1):34-41.
  • Zhao X, Chen X, Huang J, Wang Z. PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases. Proc Natl Acad Sci U S A. 2023;120(1):e2210442120.
  • Jones TA, Trinh J, Tagliati M, Schuler M. A cross-sectional survey of genetic counselors providing carrier screening regarding GBA variants and Parkinson disease susceptibility. J Assist Reprod Genet. 2022;39(3):747-55.
  • Deng H, Wu Y, Jankovic J. The EIF4G1 gene and Parkinson's disease. Acta Neurol Scand. 2015;132(2):73-8.
  • Sidransky E, Nalls MA, Aasly JO, Nichols WC. Glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009;361(17):1651-61.
  • Neumann J, Bohnen NI, Müller U, Schulz JB. Non-motor symptoms of Parkinson's disease: Depression, anxiety, and apathy in Parkinson's disease. Mov Disord. 2009;24(9):1212-9.
  • Brockmann K, GBA-associated Parkinson's disease: The effects of GBA mutations on the development of non-motor symptoms. Neurology. 2011;77(13):1221-6.
  • Alcalay RN, Glucocerebrosidase mutations and risk of Parkinson’s disease in Ashkenazi Jews. N Engl J Med. 2012;367(24):2332-9.
  • Singleton A, Gene expression in Parkinson’s disease. Lancet Neurol. 2013;12(11):1140-50.
  • Davis MY, Mutations in GBA1, EIF4G1, and PD risk: Exploring genetic overlap in neurodegenerative diseases. J Parkinsons Dis. 2016;6(4):759-73.
  • Mazzulli JR, α-Synuclein causes lysosomal dysfunction and impaired autophagic clearance in GBA mutation carriers. Science. 2011;333(6048):90-3.
  • Mullin S, Ambroxol for the treatment of patients with Parkinson disease and GBA1 mutations: A nonrandomized, noncontrolled trial. JAMA Neurol. 2020;77(4):427-34.
  • Gan-Or Z, The penetrance of GBA mutations in Parkinson’s disease: The importance of genetic counseling and individualized risk assessment. Mov Disord. 2015;30(1):14-7.
Toplam 44 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Tıbbi Genetik (Kanser Genetiği hariç), Nöroloji ve Nöromüsküler Hastalıklar
Bölüm Araştırma Makaleleri
Yazarlar

Sezin Canbek 0000-0001-9516-0047

Goncagül Mert 0009-0005-8597-8802

Muhammed Fatih Gülseven 0009-0000-0520-6794

Mehmet Güney Şenol 0000-0001-6397-9293

Yayımlanma Tarihi 10 Haziran 2025
Gönderilme Tarihi 12 Kasım 2024
Kabul Tarihi 27 Ocak 2025
Yayımlandığı Sayı Yıl 2025 Cilt: 64 Sayı: 2

Kaynak Göster

Vancouver Canbek S, Mert G, Gülseven MF, Şenol MG. GBA1 variants and Parkinson’s Disease: A dual approach combining clinical data and literature review. ETD. 2025;64(2):231-42.
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