RESUMEN
OBJECTIVE: We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature. METHODS: A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed. RESULTS: Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively. CONCLUSIONS: There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.
Asunto(s)
Distonía , Trastornos Distónicos , Adulto , Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al ADN/genética , Distonía/epidemiología , Distonía/genética , Trastornos Distónicos/epidemiología , Trastornos Distónicos/genética , Humanos , Chaperonas Moleculares/genética , Mutación , España/epidemiologíaRESUMEN
BACKGROUND: A recent genome-wide association study (GWAS) has identified a putative association, not statistically confirmed, of cervical dystonia within several regions in a British population. Hence, the authors proposed dysfunction of the ion channel NALCN (for sodium leak channel, nonselective) as a plausible cause of cervical dystonia. The objective of our study was to investigate the association of five single nucleotide polymorphisms (SNPs) previously reported with high signals as putative genetic risk factors for cervical dystonia in a British GWAS, including two located in the NALCN gene region. METHODS: We performed a case-control association study in a Spanish population. The SNPs selected for genotyping were two SNPS in the NALCN gene (rs61973742 and rs1338041), one SNP in the OR4X2 gene (rs67863238), one SNP in the COL4A1 region (rs619152), and one intergenic SNP (rs1249277). Genomic DNA was collected from 252 patients with cervical dystonia, with a mean age of 55.3 ± 14.1 years (mean age at onset, 43.5 ± 15.7 years), and 342 unrelated control subjects with a mean age of 56.3 ± 14.3 years. Genotyping of SNPs was performed using TaqMan assays and SimpleProbe assays. RESULTS: The SNP rs619152 had to be excluded because of assay failure. No significant differences were found in allele distribution between cases and controls for all analyzed SNPs. Therefore, we found no association with cervical dystonia for the analyzed SNPs in our Spanish population. CONCLUSIONS: We did not find any evidence supporting the association of NALCN with cervical dystonia, indicating that this gene is not implicated in the pathogenesis of this disorder in our cervical dystonia population.
Asunto(s)
Distonía/genética , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Adulto , Edad de Inicio , Anciano , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Persona de Mediana Edad , Riesgo , Población BlancaRESUMEN
BACKGROUND: A polymorphism in brain-derived neurotrophic factor (BDNF) (Val66Met) has been reported as a risk factor in primary dystonia. However, overall the results have been inconclusive. Our aim was to clarify the association of Val66Met with primary dystonia, and with the most prevalent clinical subtypes, cervical dystonia and blepharospasm. METHODS: We conducted a Spanish multicenter case-control study (including 680 primary dystonia patients and 788 healthy controls) and performed a meta-analysis integrating our study and six previously published studies (including a total of 1,936 primary dystonia patients and 2,519 healthy controls). RESULTS: We found no allelic or genotypic association with primary dystonia, cervical dystonia, or blepharospasm risks, for the allele A (Met) from a BDNF Val66Met polymorphism in our case-control study. This was confirmed by results from our meta-analysis in white and mixed ethnic populations in any genetic model. CONCLUSION: We did not find any evidence supporting the association of the BDNF Val66Met polymorphism with primary dystonia.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Trastornos Distónicos/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Metionina/genética , Persona de Mediana Edad , Valina/genéticaAsunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Bevacizumab , Neoplasias del Colon/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Imagen por Resonancia Magnética , Masculino , Síndrome de Leucoencefalopatía Posterior/patologíaRESUMEN
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