Objective: To identify the prevalence of pathogenic variants of the GBA1 mutation among patients with parkinsonism who have undergone genetic testing.

Background: GBA gene encodes the lysosomal enzyme glucocerebrosidase (GCase), responsible for maintaining glycosphingolipid homeostasis, mutations in this gene can result in gain or loss of enzyme function, which can impair alpha-synuclein metabolism. GBA1 gene mutation is considered the most important genetic risk factor for Parkinson’s disease (PD), with a reported prevalence of up to 5-15%.(1) In Latin America, a meta-analysis identified a prevalence of 4.17%.(2)

Method: A retrospective study was conducted in outpatients from a Movement Disorders Clinic in a 3-million population city on the northeast of Brazil. Genetic testing was performed on routine patients to identify possible genetic causes related to Parkinsonism. Patients who presented at least 1 of the following criteria were included: 1) Symptoms onset before 40 years-old; 2) symptoms onset before 50 years-old with a positive family history; 3) Patients who had 2 or more family members with a positive history of PD. Variants were classified as pathogenic according to the genes cited by the MDS update on Nomenclature of Genetic Movement Disorders. (3)

Results: A total of 103 patients suspected of having a genetic forms of parkinsonism were screened, including 57 women (55,33%). Among them, 12 pathogenic mutations were detected, with the GBA1 mutation present in 7 patients (6,79% of our sample). All patients met criteria for Parkinson’s disease according to the MDS clinical diagnostic criteria (4). GBA1 mutation was the most prevalent mutation in our sample, 58,3% of our genetic forms of PD, followed by PRKN (2,91%), SNCA (0,97%) and LRRK2 (0,97%). Mean age at onset of parkinsonian symptoms was 34.5 years [IQR, 28-51] with women being the main carriers of the pathogenic GBA mutation (n=5, 71,4%). The most common variant in GBA1 gene was c.1448T>C (p.Leu483Pro) (n=3, 42,8%), followed by c.721G>A (p.Gly241Arg), c.680A>G (p.Asn227Ser), c.1246G>A (p.Gly416Ser) and c.1251G>C p.(Trp417Cys), each of these last mutation variants was detected in one patient.

Conclusion: Our sample showed a prevalence higher than the prevalence previously described in Latin America. Prospective studies are needed to strengthen this hypothesis, and thus contribute to future therapies.

References: Smith L, Schapira AHV. GBA Variants and Parkinson Disease: Mechanisms and Treatments. Cells. 2022 Apr 8;11(8):1261.
Saffie Awad P, Teixeira-Dos-Santos D, Santos-Lobato BL, Camargos S, Cornejo-Olivas M, de Mello Rieder CR, Mata IF, Chaná-Cuevas P, Klein C, Schumacher Schuh AF. Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis. Mov Disord. 2024 Jan;39(1):6-16.
Lange LM, Gonzalez-Latapi P, Rajalingam R, et al. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society Task Force – an update. Mov Disord 2022;37(5):905–935.
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015 Oct;30(12):1591-601.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-mutation-profile-in-parkinsons-disease-insights-from-a-movement-disorders-center-in-brazil/