RESUMEN
The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.
Asunto(s)
Epilepsia Generalizada/genética , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Espasmos Infantiles/genética , Preescolar , Epilepsia Generalizada/diagnóstico por imagen , Epilepsia Generalizada/patología , Femenino , Humanos , Lactante , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Masculino , Mutación Missense/genética , Linaje , Sitios de Empalme de ARN/genética , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/patología , Secuenciación del ExomaRESUMEN
We present an 11-year-old female with bullous ichthyosiform erythroderma (BIE), learning disability, patent ductus arteriosus and mild stenosis of the aortic and pulmonary arteries. Chromosome analysis showed the expression of the rare folate-sensitive fragile site FRA12A at 12q13 in 8/20 (40%) of blood lymphocytes cultured in folate-deficient medium in the presence of trimethoprim. Her mother and maternal grandmother are phenotypically normal, but her mother shows expression of the same fragile site in 4/20 (20%) of cells cultured under the same conditions. Lymphocytes from the grandmother only showed expression of the fragile site when cultured in the presence of methotrexate in folate deficient medium. Interestingly, two genes (keratin 1 and keratin 2e) which are known to cause BIE map to 12q13. Molecular data is presented excluding three candidate (CCG)n repeats within keratin 1 gene. We present a review of previously reported FRA12A cases and discuss possible molecular explanations for the clinical findings in this patient.