To explore the socio-economic burden associated with Dravet syndrome (DS) in Germany. DS patients and their caregivers completed questionnaires covering 3–12 months (retrospective cohort) and diaries covering 3 months (prospective cohort, a subset of the retrospective) assessing clinical characteristics, patient and caregiver QoL, and direct (healthcare professional time, inpatient, emergency care, medicine), indirect (productivity) and out-of-pocket costs. Descriptive data were summarised statistically and direct, indirect and out-of-pocket costs were calculated using literature- or participant-reported costs, as appropriate. 70 of 93 patients (75%) in the retrospective cohort (mean age 10.0 years) experienced ≥1 seizure in the past month, and patients possessed multiple, problematic impairments in cognitive, behavioural and motor functioning. Seventy-eight percent of patients were recognised according to the formal German disability care rating scale, with substantial (level 1; 24%), severe (level 2; 27%) or extreme (level 3; 27%) care needs. Most patients possessed multiple impairments in cognitive, behavioural and motor functioning, and lower than average QoL (kiddy-KINDL). Around half of caregivers showed some degree of depression (BDI-II). Total annual per-patient direct costs in the retrospective cohort were €24,944 (of which €2,764 were copayments). Maternal and paternal indirect costs were €17,594 and €1,565, respectively. Patient seizure burden was a major driver of direct costs, with other costs such as specialist care and therapy for additional symptoms substantial. Prospective data (n=77) validated retrospective data, based on comparison in various areas (seizure frequency, healthcare resource use). This is the first study to measure the socio-economic impact of DS over a period up to 15 months using retrospective and prospective methodology. Substantial seizure burden, as well as physical and intellectual impairments associated with the condition, place a notable QoL burden on DS patients and their caregivers. Managing the consequences of DS consumes substantial healthcare resources resulting in significant costs.

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

Epileptic encephalopathies (EE) are a heterogeneous group of epilepsy syndromes associated with severe cognitive and behavioral disturbances. Amongst others, genes encoding neuronal ion channels have been identified as candidate genes for EE. Using next generation sequencing, we identified four different de novo mutations in KCNA2, encoding the voltage-gated potassium channel KV1.2. Voltage-gated potassium channels play an essential role in neuronal excitability, control the resting membrane potential and thresholds for action potential generation of a neuron and are responsible for repolarizing membranes back to resting values after action potential generation. Therefore, mutations in potassium channel-encoding genes have been shown to alter the neuronal excitability and cause different epilepsy syndromes, including EE. Here, we identified four independently occurring de novo KCNA2 mutations in six EE patients, with one mutation recurring three times. Four of the studied patients presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild-moderate ID, delayed speech development and sometimes ataxia. Functional studies were performed using an automated two-microelectrode voltage-clamp oocyte system. The two mutations associated with this phenotype revealed an almost complete loss-of-function with a dominant negative effect. Two further cases with KCNA2 mutations in the voltage sensor presented with an even more severe EE phenotype. These mutations caused a dramatic gain-of-function effect leading to permanent opening of KV1.2 channels. Therefore, KCNA2 is a novel gene involved in human neurodevelopmental disorders causing the clinical phenotype by two different mechanisms: (i) increasing the excitability or (ii) electrical silencing of KV1.2-expressing neurons.

Aim: Myoclonic astatic epilepsy (MAE) is a rare type of epilepsy occurring in early childhood with a clinical spectrum from easy-to-treat epilepsy to therapy-resistant epilepsy with severe developmental problems. The aim of this study was to identify clinical and genetic risk factors determining the prognosis of MAE.

OBJECTIVE:To identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations.METHODS:Using a panel approach, we screened 357 patients comprising a vast spectrum of epileptic disorders for defects in genes known to contribute to epilepsy and/or intellectual disability (ID). After detection of mutations in a novel epilepsy gene, we investigated functional effects in Xenopus laevis oocytes and screened a follow-up cohort.RESULTS:We revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay as well as 1 individual with ID and focal epilepsy. The patient with ID and focal epilepsy had a missense mutation in the extracellular glutamate-binding domain (p.Arg540His), whereas both West syndrome patients carried missense mutations within the NR2B ion channel-forming re-entrant loop (p.Asn615Ile, p.Val618Gly). Subsequent screening of 47 patients with unexplained infantile spasms did not reveal additional de novo mutations, but detected a carrier of a novel inherited GRIN2B splice site variant in close proximity (c.2011-5_2011-4delTC). Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg(2+) block and higher Ca(2+) permeability, leading to a dramatically increased Ca(2+) influx, whereas p.Arg540His caused less severe disturbance of channel function, corresponding to the milder patient phenotype.INTERPRETATION:We identified GRIN2B gain-of-function mutations as a cause of West syndrome with severe developmental delay as well as of ID with childhood onset focal epilepsy. Severely disturbed channel function corresponded to severe clinical phenotypes, underlining the important role of facilitated NMDA receptor signaling in epileptogenesis.

Purpose: Mutations in the sodium channel gene SCN2A have been associated with benign epileptic phenotypes such as benign familial neonatal-infantile seizures. Recently, several de novo SCN2A mutations have been found in children with more severe forms of epilepsy. Here, we describe the phenotypic spectrum of a cohort of children with drug resistant epilepsies due to de novo SCN2A mutations.

Aims: Myoclonic-astatic epilepsy (MAE, Doose syndrome) represents a generalized epilepsy syndrome starting early in childhood. The aim of this study is to further characterize this rare and poorly understood epilepsy syndrome.