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Stéphanie Baulac and colleagues report the identification of mutations in the DEPDC5 gene that cause focal epilepsies. The main familial focal epilepsies are autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy and familial focal epilepsy with variable foci. A frameshift mutation in the DEPDC5 gene (encoding DEP domain–containing protein 5) was identified in a family with focal epilepsy with variable foci by linkage analysis and exome sequencing. Subsequent pyrosequencing of DEPDC5 in a cohort of 15 additional families with focal epilepsies identified 4 nonsense mutations and 1 missense mutation. Our findings provided evidence of frequent (37%) loss-of-function mutations in DEPDC5 associated with a broad spectrum of focal epilepsies. The implication of a DEP (Dishevelled, Egl-10 and Pleckstrin) domain–containing protein that may be involved in membrane trafficking and/or G protein signaling opens new avenues for research.

Johannes Lemke, Holger Lerche and colleagues report the identification of de novo mutations in the potassium channel gene KCNA2 in patients with epileptic encephalopathies. The authors confirm in vitro that two mutations cause dominant loss of channel function, whereas the other two mutations induce gain-of-function effects, leading to permanently open channels. Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features 1 , 2 , 3 , 4 , 5 , 6 . Using next-generation sequencing, we identified four different de novo mutations in KCNA2 , encoding the potassium channel K V 1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of K V 1.2-expressing neurons.

We prove an analogue statement to an estimate by De Lellis–Müller in R 3 on the standard Minkowski lightcone. More precisely, we show that under some additional assumptions, any spacelike cross section of the standard lightcone is W 2 , 2 -close to a round surface provided the trace-free part of a scalar second fundamental form A is sufficiently small in L 2 . To determine the correct intrinsically round cross section of reference, we define an associated 4-vector, which transforms equivariantly under Lorentz transformations in the restricted Lorentz group. A key step in the proof consists of a geometric, scaling invariant estimate, and we give two different proofs. One utilizes a recent characterization of singularity models of null mean curvature flow along the standard lightcone by the author, while the other is heavily inspired by an almost-Schur lemma by De Lellis–Topping.

Background This study measured sleep quality among caregivers of patients with Dravet syndrome (DS) and assessed the impacts of mental health problems and caregiver burden on sleep quality. Methods This multicenter, cross-sectional study of patients with DS and their caregivers throughout Germany consisted of a questionnaire and a prospective 4-week diary querying disease characteristics, demographic data, living conditions, nocturnal supervision, and caregivers’ work situations. Sleep quality was assessed using the Pittsburgh Sleeping Quality Index (PSQI). The Hospital Anxiety and Depression Scale (HADS) and the Burden Scale for Family Caregivers (BSFC) were used to measure anxiety, symptoms of depression, and caregiver burden. Results Our analysis included 108 questionnaires and 82 four-week diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 ± 10.0 years. Caregivers were 92.6% (n = 100) female, with a mean age of 44.7 ± 10.6 years. The overall mean PSQI score was 8.7 ± 3.5, with 76.9% of participants (n = 83) scoring 6 or higher, indicating abnormal sleep quality. The HADS for anxiety and depression had overall mean scores of 9.3 ± 4.3 and 7.9 ± 3.7, respectively; 61.8% and 50.9% of participants scored above the cutoff value of 8 for anxiety and depression, respectively. Statistical analyses revealed caregiver anxiety levels and patients’ sleep disturbances as major factors influencing PSQI scores. The overall mean BSFC score of 41.7 ± 11.7 indicates a moderate burden, with 45.3% of caregivers scoring 42 or higher. Conclusions Sleep quality is severely affected among caregivers of patients with DS, correlating with anxiety, comorbidities, and patients’ sleep disturbances. A holistic therapeutic approach should be implemented for patients with DS and their caregivers, focusing on the sleep quality and mental health of caregivers. Trial registration : German Clinical Trials Register (DRKS), DRKS00016967. Registered 27 May 2019, http://www.drks.de/DRKS00016967 Key points Sleep quality is severely affected in caregivers of patients with Dravet syndrome (DS). Anxiety level, caregiver burden, and patients’ comorbidities have major impacts on caregiver sleep quality. We recommend a holistic therapy approach beyond seizures, including mental health challenges faced by caregivers of patients with DS. The holistic therapeutic approach should target caregivers’ sleep disorders and any concomitant causes.

Identifying any conformally round metric on the 2-sphere with a unique cross section of the standard lightcone in the 3 + 1 -Minkowski spacetime, we gain a new perspective on 2 d -Ricci flow on topological spheres. It turns out that in this setting, Ricci flow is equivalent to a null mean curvature flow first studied by Roesch–Scheuer along null hypersurfaces. Exploiting this equivalence, we can translate well-known results from 2 d -Ricci flow first proven by Hamilton into a full classification of the singularity models for null mean curvature flow in the Minkowski lightcone. Conversely, we obtain a new proof of Hamilton’s classical result using only the maximum principle.

We study the effects of the null energy condition on totally umbilic hypersurfaces in a class of static spacetimes, both in the spacelike and the timelike case, respectively. In the spacelike case, we study totally umbilic warped product graphs and give a full characterization of embedded surfaces with constant spacetime mean curvature using an Alexandrov Theorem by Brendle and Borghini–Fogagnolo–Pinamonti. In the timelike case, we achieve a characterization of photon surfaces with constant umbilicity factor similar to a result by Cederbaum–Galloway.

In SCN2A- related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clamp (DAPC) and voltage clamp. Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between individuals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage clamp in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the α 1 and β 2 subunits of the Na v 1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage clamp reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity. A comprehensive biophysical analysis of disease-associated mutations in the voltage-gated sodium channel gene, SCN2A , suggests that dynamic action potential clamp may be a better predictor than voltage clamp of how these mutations alter neuronal excitability, though other approaches are needed to predict severity.

In Dravet syndrome (DS), a rare epileptic and developmental encephalopathy, the effectiveness of a new treatment is predominantly measured in terms of seizure frequency. However, this may not fully capture the impact of a treatment on the broader aspects of the syndrome and patients' health-related quality of life (HRQoL). Using a previously published survey which collected data from DS patients and their carers on the broader manifestations of their syndrome, their HRQoL, and their experience of seizures, this study created composite measures of symptom severity to offer new perspectives on the multifaceted aspects of this rare condition. Survey responses on the severity of physical and psychosocial symptoms were combined with independent assessments of disability and care need, to generate three composite symptom scores assessing the manifestations of DS (physical, psychosocial and care requirements). Variation in HRQoL was investigated in multiple regression analyses to assess the strength of association between each of these composite measures and three forms of seizure measures (seizure frequency, days with no seizures and longest interval without seizures), as experienced over a 4- and 12-week period. Composite scores were calculated for a cohort of 75 primarily paediatric patients who were enrolled in the study. Strong associations were found between each of the three composite symptom scores and each of the three seizure measures, with the regression coefficient on symptom score highly significant (p ≤ 0.001) in all nine comparisons. Separate regressions using predictors of HRQoL (Kiddy KINDL and Kid KINDL) as the dependent variable were inconclusive, identifying only behavioural/attention problems and status epilepticus as significant predictors of HRQoL. These results allow the development of a composite score that may be useful in developing a clinical understanding of the severity of DS for an individual patient and establishing their treatment goals. Where measurement of long-term sequalae of disease is not feasible, such as clinical trials, correlation of the composite score with experience of seizures and seizure-free periods may allow a better contextualisation of the results of short-term assessments. German Clinical Trials Register (DRKS), DRKS00011894. Registered 16 March 2017, http://www.drks.de/ DRKS00011894.

A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.