RESUMO
OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Hipocampo , Esclerose , Humanos , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Esclerose/genética , Esclerose/patologia , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/patologia , Feminino , Masculino , Adulto , Adulto Jovem , Adolescente , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/patologia , Criança , Filaminas/genética , Pessoa de Meia-Idade , Pré-Escolar , Variação Genética/genética , Esclerose HipocampalRESUMO
Silicofluorides, widely used in water fluoridation, are unlicensed medicinal substances, administered to large populations without informed consent or supervision by a qualified medical practitioner. Fluoridation fails the test of reliability and specificity, and, lacking toxicity testing of silicofluorides, constitutes unlawful medical research. It is banned in most of Europe; European Union human rights legislation makes it illegal. Silicofluorides have never been submitted to the U.S. FDA for approval as medicines. The ethical validity of fluoridation policy does not stand up to scrutiny relative to the Nuremberg Code and other codes of medical ethics, including the Council of Europe's Biomedical Convention of 1999. The police power of the State has been used in the United States to override health concerns, with the support of the courts, which have given deference to health authorities.