Maria J Miranda

Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

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.

Will seizure control improve by switching from the modified Atkins diet to the traditional ketogenic diet

It has been reported that children can maintain seizure control when the ketogenic diet (KD) is transitioned to the less‐restrictive modified Atkins diet (MAD). What is unknown, however, is the likelihood of additional seizure control from a switch from the MAD to the KD. Retrospective information was obtained from 27 patients who made this dietary change from four different institutions. Ten (37%) patients had ≥10% additional seizure reduction with the KD over the MAD, of which five became seizure‐free. The five children who did not improve on the MAD failed to improve when transitioned to the KD. A higher incidence of improvement with the KD occurred for those with myoclonic–astatic epilepsy (70% vs. 12% for all other etiologies, p = 0.004), including all who became seizure‐free. These results suggest that the KD probably represents a “higher dose” of dietary therapy than the MAD, which may particularly benefit those with myoclonic–astatic epilepsy.

Ketogenic diet in the treatment of refractory continuous spikes and waves during slow sleep.

Purpose:  To evaluate the effect of the ketogenic diet on electroclinical characteristics and cognitive function in children with continuous spikes and waves during slow sleep (CSWS).

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

Effectiveness of the ketogenic diet used to treat resistant childhood epilepsy in Scandinavia

BACKGROUND This Scandinavian collaborative retrospective study of children treated with ketogenic diet (KD) highlights indications and effectiveness over two years follow-up. METHODS Five centres specialised in KD collected data retrospectively on 315 patients started on KD from 1999 to 2009. Twenty-five patients who stopped the diet within four weeks because of compliance-problems and minor side-effects were excluded. Seizure-type(s), seizure-frequency, anti-epileptic drugs and other treatments, mental retardation, autism-spectrum disorder and motor-dysfunction were identified and treatment-response was evaluated. RESULTS An intention-to-treat analysis was used. Responders (>50% seizure-frequency reduction) at 6, 12 and 24 months were 50%, 46% and 28% respectively, seizure-free were 16%, 13% and 10%. Still on the diet were 80%, 64% and 41% after 6, 12 and 24 months. No child had an increased seizure-frequency. The best seizure outcome was seen in the group with not-daily seizures at baseline (n = 22), where 45%, 41% and 32% became seizure-free at 6, 12 and 24 months A significant improvement in seizure-frequency was seen in atonic seizures at three months and secondary generalised seizures at three and six months. Side-effects were noted in 29 subjects; most could be treated and only two stopped due to hyperlipidaemia and two due to kidney-stones. In 167 patients treated with potassium-citrate, one developed kidney-stones, compared with six of 123 without potassium-citrate treatment (relative risk = 8.1). CONCLUSIONS As the first study of implementing KD in children in the Scandinavian countries, our survey of 290 children showed that KD is effective and well tolerated, even in such severe patients with therapy-resistant epilepsy, more than daily seizures and intellectual disability in the majority of patients. Long-term efficacy of KD was comparable or even better than reported in newer AEDs. Addition of potassium citrate reduced risk of kidney-stones. Our data indicate that the response might be predicted by seizure-frequency before initiation of the diet but not by age, seizure-type or aetiology.

Investigation of 4q-deletion in two unrelated patients using array CGH

S.S. Kaalund, R.S. Møller, A. Tészás, M. Miranda, G. Kosztolanyi, R. Ullmann, N. Tommerup, and Z. Tümer* Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark Danish Epilepsy Centre, Dianalund, Dianalund, Denmark Department of Medical Genetics and Child Development, University of Pécs, Pécs, Hungary Max-Planck Institute for Molecular Genetics, Berlin, Germany

Letter to the editor: confirming neonatal seizure and late onset ataxia in SCN2A Ala263Val

We read with interest the paper by Schwarz et al. [4] in the 2016 February issue. The authors describe four patients with SCN2A mutations, neonatal onset epilepsy and later onset ataxia. A recurrent mutation Ala263Val was found in two of the patients, one of which had previously been published [2]. The two boys presented with intractable tonic seizures within the first week of life. Both had spontaneous remission of seizures within the first year of life, and developed normally, until approximately 1.5 years of age when they both had onset of episodic ataxia. Interestingly we identified the same Ala263Val SCN2A mutation in a 19-month-old girl with a similar clinical history. The girl was born at term after an uncomplicated pregnancy. She had onset of seizures at day 1 of life. The initial seizures were tonic, and progressed to generalized tonic–clonic seizures, which were often prolonged and came in clusters. Her EEG initially showed sharpwaves frontotemporal, but was normal on follow-up at 4 months of age. A gene panel testing revealed a de novo SCN2A Ala263Val mutation. The girl became seizure free at the age of 7 months, despite several hospitalizations with status epilepticus. She has reached all motor milestones in due time, and is developing normal in every way. At the age of 15 months she started developing episodes characterized by dizziness, poor balance and motor disturbances. Interictal EEG was normal and the episodes were classified as episodic ataxia. The girl continues to be seizure free, but has ataxic episodes 3–5 times per week. The episodes appear in clusters with 2–3 episodes within a 2-h period. Each episode lasts a couple of minutes, and can be triggered by stress or sleep deprivation. Videos of the ataxia are available in videos 1, 2 and 3. As shown in the first report by Liao et al. [2] the Ala263Val mutation is a clear gain-of-function mutation, leading to an increased persistent Na current. As with the two previous cases, the presented girl exhibited more severe and long-lasting seizures in her neonatal and infantile period compared to other benign SCN2A-associated neonatal-infantile epilepsies [1]. She became seizure free at a similar age as the other two cases, and also presented with ataxia in the second year of life, as described. Liao et al. [4] have proposed that the delayed expression of the Nav1.2 channel in unmyelinated parallel fibers projecting from granule to purkinje cells could be responsible for this specific phenotype. In contrast, the early expression in axon initial segments of principal neurons with myelinated fibers, which diminishes later in development, and the gradual increase of Nav1.6 channel expression which partially replaces the Nav1.2 channels within the AIS could explain the occurrence and remission of neonatal-infantile seizures [3, 5]. Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8149-5) contains supplementary material, which is available to authorized users.

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant: CUX2 and Epilepsy With Intellectual Disability

Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE).