RESUMEN
Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 × 10-6 for the European controls; odds ratio = 2.42, p-value = 6.33 × 10-3 for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence.
Asunto(s)
Trastorno del Espectro Autista/genética , Moléculas de Adhesión Celular Neuronal/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Alelos , Trastorno del Espectro Autista/diagnóstico , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Haplotipos , Humanos , Italia , Masculino , Oportunidad Relativa , Factores SexualesRESUMEN
OBJECTIVE: To investigate the relevance of serum topiramate (TPM) levels (SL) monitoring in the clinical management of epileptic patients. METHODS: Twenty-seven patients with different epileptic syndromes on TPM therapy were studied. TPM was used as add-on in 26 patients, only in one as monotherapy de novo; one case changed from TPM as add-on to TPM monotherapy. The mean follow-up time was 11 months. TPM SL were measured by fluorescence polarization immunoassay. RESULTS: We analyzed the TPM SL in 43 samples from 27 patients. Mean TPM dose was 3.9mg/kg, mean TPM SL 13.43mumol/l. The mean level to dose ratio (LDR) was 3.63mumol/l/mg/kg. Four patients became seizure-free, all with TPM dosages lower than the mean. Eleven patients had at least 50% seizure reduction. The comedication with enzyme-inducing AED significantly reduced TPM SL and LDR. On the other hand, the influence of valproic acid (VPA) on TPM LDR was not univocal. Indeed, patients younger than 15 years showed SL values lower than the adults did, although not significant. CONCLUSION: We could not detect a direct relationship between high TPM SL and efficacy neither between high TPM SL and tolerability. However, the data we collected seem to favour the hypothesis that high TPM dosage and SL might be associated to a greater probability to reduce seizure severity.