RESUMEN
Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.
Asunto(s)
Proteínas de Unión al ADN/genética , Epilepsia Refleja/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Animales , Electroencefalografía , Técnicas de Silenciamiento del Gen/métodos , Humanos , Estimulación Luminosa/métodos , Factores de Riesgo , Pez CebraRESUMEN
BACKGROUND: The emergence of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated recognition of microdeletions and microduplications as risk factors for both generalised and focal epilepsies. Furthermore, there is evidence that some microdeletions/duplications, such as the 15q13.3 deletion predispose to a range of neuropsychiatric disorders, including intellectual disability (ID), autism, schizophrenia and epilepsy. We hypothesised that array CGH would reveal relevant findings in an adult patient group with epilepsy and complex phenotypes. METHODS: 82 patients (54 from the National Hospital for Neurology and Neurosurgery and 28 from King's College Hospital) with drug-resistant epilepsy and co-morbidities had array CGH. Separate clinicians ordered array CGH and separate platforms were used at the two sites. RESULTS: In the two independent groups we identified copy number variants judged to be of pathogenic significance in 13.5% (7/52) and 20% (5/25) respectively, noting that slightly different selection criteria were used, giving an overall yield of 15.6%. Sixty-nine variants of unknown significance were also identified in the group from the National Hospital for Neurology and Neurosurgery and 5 from the King's College Hospital patient group. CONCLUSION: We conclude that array CGH be considered an important investigation in adults with complicated epilepsy and, at least at present for selected patients, should join the diagnostic repertoire of clinical history and examination, neuroimaging, electroencephalography and other indicated investigations in generating a more complete formulation of an individual's epilepsy.
Asunto(s)
Anomalías Múltiples/genética , Hibridación Genómica Comparativa , Epilepsia/genética , Anomalías Múltiples/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Cromosomas Humanos/genética , Estudios de Cohortes , Comorbilidad , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/genética , Resistencia a Medicamentos , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Femenino , Genes , Humanos , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
Current practice favors imaging of people with myasthenia gravis (MG) at the time of diagnosis to look for evidence of thymoma or thymic hyperplasia. However, there is no evidence to allow any recommendation about repeat imaging in people with normal scans at presentation, and there is little evidence to recommend surgical exploration in such cases. We present a patient with a delayed presentation of invasive thymoma 11 years after a normal thoracic computerized tomography.