Abstract
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.
Highlights
Photosensitivity is a heritable abnormal cortical response to flickering light, often manifesting as EEG changes called a photoparoxysmal response (Walter et al, 1946)
We examined the frequency of all rare variants in the entire cohort, and the frequency of unique variants only separately in patients with eyelid myoclonia with absences (EMA), patients with genetic generalized epilepsies (GGE) excluding EMA, and patients with focal epilepsies
We show an enrichment of unique variants in CHD2 with photosensitivity in the common epilepsies overall, identifying CHD2 as a photosensitive epilepsy gene
Summary
Photosensitivity is a heritable abnormal cortical response to flickering light, often manifesting as EEG changes called a photoparoxysmal response (Walter et al, 1946). The photoparoxysmal response is age-dependent: prevalence in healthy children is between 1.4 and 8.3%, dropping to 51% in adults (Gregory et al, 1993; Quirk et al, 1995; Kasteleijn-Nolst Trenite et al, 2003; Verrotti et al, 2012). Photosensitive epilepsy is a reflex epilepsy, with seizures triggered by visual stimuli. A population-based study in Great Britain determined that the annual incidence of epilepsy with photoparoxysmal response was 1.1 per 100 000 in the overall population, and 5.7 per 100 000 between 7 and 19 years of age (Quirk et al, 1995). About 40% of people with photosensitive epilepsy only have seizures on exposure to visual stimuli. Photosensitive seizures feature in specific epilepsy syndromes, with other seizure types, and in nonsyndromic epilepsies. The archetypal photosensitive syndrome is eyelid myoclonia with absences (EMA), a GGE characterized by rapid eyelid jerks and upward eyeball deviation on eye closure: photosensitivity is an essential feature (Sadleir et al, 2012)
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