RESUMO
Purpose: The TRAK1 gene is mapped to chromosome 3p22.1 and encodes trafficking protein kinesin binding 1. The aim of this study was to investigate the genotype-phenotype of TRAK1-associated epilepsy. Methods: Trio-based whole-exome sequencing was performed on a cohort of 98 patients with epilepsy of unknown etiologies. Protein modeling and the VarCards database were used to predict the damaging effects of the variants. Detailed neurological phenotypes of all patients with epilepsy having TRAK1 variants were analyzed to assess the genotype-phenotype correlations. Results: A novel TRAK1 compound heterozygous variant comprising variant c.835C > T, p.Arg279Cys and variant c.2560A > C, p.Lys854Gln was identified in one pediatric patient. Protein modeling and VarCards database analyses revealed that the variants were damaging. The patient received a diagnosis of early infantile epileptic spasms with a developmental disorder; he became seizure-free through valproate and adrenocorticotropic hormone treatment. Further results for six variants in 12 patients with epilepsy indicated that biallelic TRAK1 variants (including homozygous or compound heterozygous variants) were associated with epilepsy with developmental disorders. Among these patients, eight (67%) had epileptic spasms and seven (58%) were intractable to anti-seizure medicines. Moreover, eight patients experienced refractory status epilepticus, of which seven (88%) died in early life. To our knowledge, this is the first reported case of epilepsy caused by TRAK1 compound heterozygous variants. Conclusion: Biallelic TRAK1 variants can cause epilepsy and developmental disorders. In these patients, seizures progress to status epilepticus, suggesting a high risk for poor outcomes and the requirement of early treatment.
RESUMO
BACKGROUND: Uncertainty remains regarding the association between body mass index (BMI) and the risk of bleeding in patients with non-valvular atrial fibrillation (NVAF). We aimed to investigate the association between BMI and the risk of bleeding in elderly NVAF patients taking dabigatran. METHODS: A total of 509 elderly NVAF patients, who were being treated at twelve centers in China from February 2015 to December 2017 and taking dabigatran, were analyzed. The exposure and outcome variables were BMI at baseline and bleeding events within the subsequent six months, respectively. Cox proportional hazards regression analysis was used to evaluate the association between BMI and the risk of bleeding. Moreover, the Cox proportional hazards regression with cubic spline functions and smooth curve fitting was conducted. RESULTS: During the six-month follow-up, 50 participants experienced bleeding. Every 1 kg/m2 increase in BMI was associated with a 12% increased risk of bleeding (P = 0.021). Compared to those with BMI values in Tertile 1 (< 22.5 kg/m2), the adjusted hazard ratio (HR) of bleeding for participants in Tertile 2 (22.5-25.3 kg/m2) and Tertile 3 (> 25.3 kg/m2) were 2.71 (95% CI: 1.02-7.17) and 3.5 (95% CI: 1.21-8.70), respectively. The P trend-value was significant in all models. The adjusted smooth curve showed a linear association between BMI and bleeding. None of the stratified variables showed significant effect modification on the association between BMI and bleeding (P interaction > 0.05). CONCLUSIONS: BMI was significantly and positively associated with the risk of bleeding in elderly NVAF patients treated with dabigatran.