Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.

ObjectiveTo develop and prospectively evaluate a method of epileptic seizure detection combining heart rate and movement.MethodsIn this multicenter, in-home, prospective, video-controlled cohort study, nocturnal seizures were detected by heart rate (photoplethysmography) or movement (3-D accelerometry) in persons with epilepsy and intellectual disability. Participants with >1 monthly major seizure wore a bracelet (Nightwatch) on the upper arm at night for 2 to 3 months. Major seizures were tonic-clonic, generalized tonic >30 seconds, hyperkinetic, or others, including clusters (>30 minutes) of short myoclonic/tonic seizures. The video of all events (alarms, nurse diaries) and 10% completely screened nights were reviewed to classify major (needing an alarm), minor (needing no alarm), or no seizure. Reliability was tested by interobserver agreement. We determined device performance, compared it to a bed sensor (Emfit), and evaluated the caregivers’ user experience.ResultsTwenty-eight of 34 admitted participants (1,826 nights, 809 major seizures) completed the study. Interobserver agreement (major/no major seizures) was 0.77 (95% confidence interval [CI] 0.65–0.89). Median sensitivity per participant amounted to 86% (95% CI 77%–93%); the false-negative alarm rate was 0.03 per night (95% CI 0.01–0.05); and the positive predictive value was 49% (95% CI 33%–64%). The multimodal sensor showed a better sensitivity than the bed sensor (n = 14, median difference 58%, 95% CI 39%–80%, p < 0.001). The caregivers' questionnaire (n = 33) indicated good sensor acceptance and usability according to 28 and 27 participants, respectively.ConclusionCombining heart rate and movement resulted in reliable detection of a broad range of nocturnal seizures.

SummaryObjectiveAutomated seizure detection and alarming could improve quality of life and potentially prevent sudden, unexpected death in patients with severe epilepsy. As currently available systems focus on tonic–clonic seizures, we want to detect a broader range of seizure types, including tonic, hypermotor, and clusters of seizures.MethodsIn this multicenter, prospective cohort study, the nonelectroencephalographic (non‐EEG) signals heart rate and accelerometry were measured during the night in patients undergoing a diagnostic video‐EEG examination. Based on clinical video‐EEG data, seizures were classified and categorized as clinically urgent or not. Seizures included for analysis were tonic, tonic–clonic, hypermotor, and clusters of short myoclonic/tonic seizures. Features reflecting physiological changes in heart rate and movement were extracted. Detection algorithms were developed based on stepwise fulfillment of conditions during increases in either feature. A training set was used for development of algorithms, and an independent test set was used for assessing performance.ResultsNinety‐five patients were included, but due to sensor failures, data from only 43 (of whom 23 patients had 86 seizures, representing 402 h of data) could be used for analysis. The algorithms yield acceptable sensitivities, especially for clinically urgent seizures (sensitivity = 71–87%), but produce high false alarm rates (2.3–5.7 per night, positive predictive value = 25–43%). There was a large variation in the number of false alarms per patient.SignificanceIt seems feasible to develop a detector with high sensitivity, but false alarm rates are too high for use in clinical practice. For further optimization, personalization of algorithms may be necessary.

Background: Loss-of-function amyloid precursor protein (APP) and Nav1.6 transgenic mice share similar phenotypes. Results: APP interacts with Nav1.6 and enhances its cell surface expression through a G o -coupled JNK pathway. Conclusion: APP regulates Nav1.6 function, likely through a G o -coupled JNK pathway. Significance: This finding advances the current understanding of APP functions and has implications for novel therapies for neurodegenerative disorders.

Relaxin-3 or insulin-like peptide 7 (INSL7) is the most recently discovered relaxin/insulin-like family peptide. Mature relaxin-3 consists of an A chain and a B chain held by disulphide bonds. According to structure activity relationship studies, the relaxin-3 B chain is more important in binding and activating the receptor. RXFP3 (also known as Relaxin-3 receptor 1, GPCR 135, somatostatin- and angiotensin- like peptide receptor or SALPR) was identified as the cognate receptor for relaxin-3 by expression profiles and binding studies. Recent studies imply roles of this system in mediating stress and anxiety, feeding, metabolism and cognition. Stapling of peptides is a technique used to develop peptide drugs for otherwise undruggable targets. The main advantages of stapling include, increased activity due to reduced proteolysis, increased affinity to receptors and increased cell permeability. Stable agonists and antagonists of RXFP3 are crucial for understanding the physiological significance of this system. So far, agonists and antagonists of RXFP3 are peptides. In this study, for the first time, we have introduced stapling of the relaxin-3 B chain at 14th and 18th positions (14s18) and 18th and 22nd position (18s22). These stapled peptides showed greater helicity than the unstapled relaxin-3 B chain in circular dichroism analysis. Both stapled peptides bound RXFP3 and activated RXFP3 as observed in an inhibition of forskolin-induced cAMP assay and a ERK1/2 activation assay, although with different potencies. Therefore, we conclude that stapling of the relaxin3 B chain does not compromise its ability to activate RXFP3 and is a promising method for developing stable peptide agonists and antagonists of RXFP3 to aid relaxin-3/RXFP3 research.