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

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) • Fev 2019 • https://doi.org/10.1590/0004-282X20190006 copiar

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

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

Mutações no gene GBA têm sido reportadas em pacientes com doença de Parkinson (DP) em diferentes países, incluindo o Brasil. Com o objetivo de confirmar esse padrão em uma amostra de pacientes com DP provenientes do Norte brasileiro, foi conduzindo esse estudo caso-controle investigando a frequência das duas mutações mais comuns do gene GBA (c.1226A>G; p.N370S e c.1448T>C; p.L444P) em um grupo de 81 pacientes com DP e 81 controles, usando PCR-RFLP e confirmado pelo sequenciamento direto de produtos de PCR. No grupo experimental, três pacientes (3,7%) foram heterozigotos para a mutação c.1226A>G; p.N370S e três (3,7%), para a mutação c.1448T>C; p.L444P Nenhuma das duas mutações foi detectada no grupo controle (p =0,0284). Pacientes com a mutação c.1448T>C; p.L444P demonstraram uma tendência a apresentar os sintomas mais precocemente, porém um número amostrai maior é necessário para confirmar essa observação. Nossos resultados sugerem uma associação entre essas duas mutações no gene GBA e o desenvolvimento de DP na população de pacientes do norte Brasileiro.

Palavras-chave:
Doença de Gaucher; mutação; doença de Parkinson

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