<i>GBA</i> mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

Amaral, Carlos Eduardo de Melo; Lopes, Patrick Farias; Ferreira, Juliana Cristina Cardoso; Alves, Erik Artur Cortinhas; Montenegro, Marcella Vieira Barroso; Costa, Edmar Tavares da; Yamada, Elizabeth Sumi; Cavalcante, Fernando Otávio Quaresma; Santana-da-Silva, Luiz Carlos

doi:10.1590/0004-282X20190006

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Article • Arq. Neuro-Psiquiatr. 77 (2) • Feb 2019 • https://doi.org/10.1590/0004-282X20190006 copy

GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

Mutações p.N370S e p.L444P no gene GBA estão associadas com doença de Parkinson em pacientes do norte do Brasil

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Mutations of the GBA gene have been reported in patients with Parkinson's disease (PD) from a number of different countries, including Brazil. In order to confirm this pattern in a sample of PD patients from northern Brazil, we conducted a case-control study of the occurrence of the two most common mutations of the GBA gene (c.1226A>G; p.N370S and c.1448T>C; p.L444P) in a group of 81 PD patients and 81 control individuals, using PCR-RFLP, confirmed by the direct sequencing of the PCR products. In the patient group, three patients (3.7%) were heterozygous for the GBA c.1226A>G; p.N370S mutation, and three (3.7%) for GBA c.1448T>C; p.L444P Neither mutation was detected in the control group (p =0.0284). Patients with the c.1448T>C; p.L444P mutation showed a tendency to have an earlier disease onset, but a larger sample number is required to confirm this observation. Our results suggest an association between the GBA c.1226A>G; p.N370S and c.1448T>C; p.L444P mutations and the development of PD in the population of patients from the Northern Brazil.

Keywords:
Gaucher disease; mutation; Parkinson's disease

Patients (mutation)	Sex	Age of onset	Current age	First symptoms	Familiar history
1 (N370S/Normal allele)	M	71	80	Rigidity and weakness in legs	Absent
2 (N370S/Normal allele)	F	42	69	Tremor in arm, initially just one side	Absent
3 (N370S/Normal allele)	F	67	75	Tremor on left side	Present (mother)
4 (L444P/Normal allele)	M	35	52	Impaired gait on left side	Present (paternal grandparents, paternal uncles and father)
5 (L444P/Normal allele)	M	28	44	Tremor on right side	Absent
6 (L444P/Normal allele)	M	55	65	Tremor on right side	Absent

Variable		Mutation (+)	Mutation (-)	p-value
Total		6 (74%)	75 (92.6%)
	Male	4 (66.7%)	66 (88.0%)
	Female	2 (33.3%)	29 (12.0%)
Age at onset		49.66 ± 1747	54.96 ± 11.94	0.20
Initial symptoms
Tremor		4 (66.7%)	47 (62.7%)	0.99
	Bradykinesia	0 (0%)	4 (5.3%)	1.00
	Rigidity	1 (25.0%)	6 (8.0%)	0.44
	Postural instability	0 (0%)	2 (2.7%)	1.00
Family history		2 (3.3%)	6 (8.0%)	0.15

Studies	Population studied	PD inclusion criteria	Method	Mutation analyzed	Patient mutation frequency	Control mutation frequency	Age of onset	GBA mutated PD and family history
Spitz et al.¹⁷17. Spitz M, Rozenberg R, Pereira LV, Barbosa ER. Association between Parkinson's disease and glucocerebrosidase mutations in Brazil. Parkinsonism RelatDisord. 2008;14(1):58-62. https://doi.org/10.1016/j.parkreldis.2007.06.010 https://doi.org/10.1016/j.parkreldis.200...	65 PD patients and 267 control individuals from southeastern Brazil	Early onset (<55 years)	PCR-RFLP, restriction endonucleases and electrophoresis	N370S and L444P	2/65 (3%); L444P 2/2 (100%); N370S 0/2 (0%)	0/267	Patient 1 at 46 years old and Patient 2 at 42 years old.	The two patients had family history, no statistical test was applied.
Socal et al.²⁴24. Socal MP, Bock H, Michelin-Tirelli K, Hilbig A, Saraiva-Pereira ML, Rieder CR, et al. Parkinson's disease and the heterozygous state for glucocerebrosidase mutations among Brazilians. Parkinsonism RelatDisord. 2009 Jan;15(1):76-8. https://doi.org/10.1016/j.parkreldis.2008.01.019 https://doi.org/10.1016/j.parkreldis.200...	62 PD patients from southern Brazil	All patients diagnosed were included	PCR-RFLP, restriction endonucleases	N370S, L444P and IVS2þ1	2/62 (3.5%); L444P 1/2 (50%); N370S 1/2 (50%)	Not informed	Patients with mutation 37 ± 4 years. Patients without mutation 41.4 ± 10.8 years.	Not informed
Guimarães et al.²⁶26. Guimarães BC, Pereira AC, Rodrigues FC, Santos AV, Campos Junior M, Santos JM, et al. Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson's disease in Brazilian patients. Parkinsonism RelatDisord. 2012 Jun;18(5):688-9. https://doi.org/10.1016/j.parkreldis.2011.11.028 https://doi.org/10.1016/j.parkreldis.201...	347 PD patients and 341 control individuals from southeastern, midwestern and northern Brazil.	All patients diagnosed were included.	direct sequencing	N370S and L444P	13/347 (3.7%); L444P 8/13 (62%); N370S 5/13 (38%)	0/341	Patients with mutation 49.9 ± 11.3 y years Patients without mutation 52.5 ± 13.3 years.	Those with family history and those without family history did not show statistical significance.
Amaral et al. (Present study	81 PD patients and 81 control individuals from northern Brazil.	All patients diagnosed were included	Amplification of the exons 8 to exon 11, PCR-RFLP for N370S and L444P restriction endonucleases and direct sequencing of N370S and L444P	N370S and L444P	6/81 (7.4%); L444P 3/6 (50%); N370S 3/6 (50%)	0/81	Patients with mutation 49.6 ± 174 years. Patients without mutation 55.1 ± 11.6 years.	Of the 6 patients, 2 had family history. No statistical test was used.

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[1] Correspondence: Luiz Carlos Santana da Silva; Av. Pedro Miranda, 1807; 66085-024 Belém PA, Brasil; E-mail: lcsantana-pa@hotmail.com