Protective and susceptibility effects of hSKCa3 allelic variants on juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME; OMIM 606904) is a subtype of common idiopathic generalised epilepsy (IGE) and affects up to 26% of all individuals with IGE.1–3 JME is characterised by the onset in adolescence of bilateral myoclonic jerks usually affecting the upper limbs.1,4 Patients also have generalised tonic-clonic seizures and about one third experience absence seizures. Genetic factors are known to play an important role in the etiology of JME.3,4 While identification of genes underlying predisposition to JME has been relatively slow due to clinical and genetic heterogeneity,5,6 progress made so far in the isolation and characterisation of genes associated with other monogenic subtypes of IGE, provides evidence that most idiopathic epilepsy syndromes are caused by mutations in genes encoding ion channels.7 The implications of these findings in monogenic subtypes of the disorder for the complex polygenic subset are now being increasingly appreciated.8 Two types of voltage gated potassium channels have been associated with seizure disorders, the KCNQ channels and the Kv channels. Loss of function mutations for the potassium channels KCNQ2 and KCNQ3 have been identified in families with a rare autosomal dominant subtype of IGE called benign familial neonatal convulsions (BFNC).9,10 Allelic association of JME with KCNQ3 has been suggested in a South Indian cohort of JME patients.11 Mutation in human KCN1A predisposes to episodic ataxia and partial epilepsy.12 These findings emphasise the importance of potassium channels in controlling neuronal excitability and thus make potassium channel genes potentially interesting candidates for idiopathic epilepsy syndromes. The calcium activated potassium channels are an interesting class of potassium channels that regulate neuronal excitability.13,14 These are gated by intracellular calcium ions and their activity is responsible in part for the afterpolarisation that follows a single action …