RESUMO

Many genes associated with familial forms of the amyotrophic lateral sclerosis (fALS) have been identified in European and North American cohorts. However, little is known about the genetic bases of fALS in Latin America and Brazil, in particular. To address this question, we recruited 107 patients with fALS from 93 unrelated families from Southeastern, Southern, and Northeastern regions of the country. A 3-step diagnostic approach was used: 1) Triplet repeat primed polymerase chain reaction to search for C9orf72 expansions, then 2) fragment digestion to search for the c.166 C>T VAPB variant, and finally, 3) whole exome sequencing for those who tested negative. We identified the genetic cause for fALS in 70% of the families. VAPB and C9orf72 were the most frequent genes (30% and 22%, respectively), followed by SOD1, TARDBP, ANXA11, and FUS. Five novel variants in known ALS genes were found, including the SOD1 Val120Leu and ANXA11 Asp40Tyr, which were seen in 2 unrelated families each. In conclusion, VAPB and then C9orf72 are the genes most commonly related to fALS in Brazil.

Assuntos

Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Proteínas de Transporte Vesicular/genética , Brasil/epidemiologia , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Reação em Cadeia da Polimerase , Proteína FUS de Ligação a RNA/genética , Superóxido Dismutase-1/genética , Sequenciamento do Exoma

RESUMO

Oxidative stress is one of the main mechanisms associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). Copper can affect cellular oxidation and lipid metabolism. The aim of this study was to evaluate the association of copper status with lipid profile and functional status in patients with ALS. A cross-sectional study was carried out including 27 patients with ALS (case group) and 26 healthy individuals (control group). Copper status was evaluated by habitual dietary copper intake, plasma copper, and serum ceruloplasmin concentrations. The lipid profile included analysis of serum total cholesterol (TC), LDL-cholesterol (LDL-c), HDL-cholesterol (HDL-c), and triglycerides (TGL). The functional status of patients with ALS was assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R). In the case group, plasma copper was lower compared with the control group (133.9 versus 164.1 µg/dL, p=0.0001) and was positively correlated with HDL-c (rs=0.398, p=0.044). In the control group, plasma copper was positively correlated with serum ceruloplasmin (rs=0.646, p < 0.001), TC (rs=0.446, p=0.025), LDL-c (rs=0.445, p=0.029), and HDL-c (rs=0.479, p=0.015), and serum ceruloplasmin was positively correlated only with LDL-c (rs=0.407, p=0.043). In the case group, dietary copper intake (B=-0.373, p < 0.001), plasma copper (B=-0.005, p=0.033), and TC (B=-0.312, p=0.001) were inversely associated with the functional status of patients with ALS. In contrast, serum ceruloplasmin (B=0.016, p=0.044), LDL-c (B=0.314, p=0.001), HDL-c (B=0.308, p=0.001), and TGL (B=0.062; p=0.001) were positively associated with their functional status. In conclusion, this study suggests a disturbance of copper status and its connection with the lipid profile in patients with ALS. Furthermore, copper status and lipid profile may influence the functional status of patients with ALS, standing out as potential biomarkers of disease severity.