Gabriela Reyes Valenzuela

Alterations in genes involved in glutamatergic neurotransmission are associated with developmental and epileptic encephalopathies (DEE). One of the most extensively studied pathways involves N‐methyl‐D‐aspartate receptors (NMDAR), which play a key role in brain development, synaptic plasticity, learning and memory. We present the case of an 11‐month‐old boy with DEE who began at 2 months of age with afebrile focal‐to‐generalized tonic seizures and focal activity on electroencephalography (EEG). The patient showed developmental delay, resistance to antiseizure medications and frequent, multiple seizure types—including motor focal seizures, epileptic spasms with and without hypsarrhythmia and generalized seizures—together with abnormal movements and EEG findings consistent with epileptic encephalopathy. Whole‐exome sequencing identified a de novo likely pathogenic variant in the GRIN2D gene, affecting one of the transmembrane domains (M3), which is essential for normal NMDAR function and harbours most of the pathogenic variants reported to date. Our case represents the 14th documented case in the literature to date of a patient with GRIN2D ‐related DEE, contributing to the phenotypic characterization of this entity.

The HECW2 gene, essential for neurodevelopment, plays a critical role in maintaining cellular homeostasis and regulating key pathways in the nervous system. Deleterious variants in the HECW2 gene have been associated with developmental delay, intellectual disability, hypotonia and epilepsy, as well as dysmorphic features. We present the case of an infant with a novel variant in HECW2 with an unusual clinical presentation and a progressive disease course, showing three successive electroclinical patterns, consisting of burst suppression characteristic of early infantile developmental and epileptic encephalopathy, subcontinuous myoclonic seizures and infantile epileptic spasms syndrome without hypsarrhythmia, occurring over a short period of time. This case expands the clinical spectrum associated with this gene and highlights the intrafamilial phenotypic variability. It also underscores the importance of personalized therapeutic strategies, as demonstrated by the use of perampanel in this patient. These findings emphasize the need to include HECW2 as a possible aetiology in the diagnostic evaluation of developmental and epileptic encephalopathies.

Background: Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition. Methods: We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 -related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed. Results: The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 – 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 – 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (PATP1A3 -related phenotypes and baseline QTc 4 seconds. Conclusions: Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contributes to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction. Clinical Perspective: What is Known: Individuals with ATP1A3-D801N have a short baseline QTc. Two individuals with AHC experienced ventricular fibrillation following bradycardia. What the Study Adds: The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

The identification of factors that affect cannabidiol (CBD) systemic exposure may aid in optimizing treatment efficacy and safety in clinical practice. In this study, we aimed to correlate CBD plasma concentrations at a steady state to demographic, clinical, and pharmacological characteristics as well as seizure frequency after the administration of a purified CBD oil solution in a real-world setting of children with drug-resistant developmental and epileptic encephalopathies (DEEs). Patients receiving oral CBD pharmaceutical products at maintenance were enrolled. Venous blood samples were drawn before the CBD morning dose, 12 h apart from the last evening dose (C0 or CBD trough concentration). A linear mixed-effect analysis was implemented to assess the correlation between C0 and clinical, laboratory, pharmacological, and lifestyle factors. Fifteen females and seven males with a median age of 12.8 years (ranging between 4.7 and 17.2) were included. The median CBD dose was 8.8 mg/kg/day (ranging between 2.6 and 22.5), and the CBD C0 median (range) was 48.2 ng/mL (3.5–366.3). The multivariate model showed a 109.6% increase in CBD C0 in patients with concomitant levothyroxine (β = 0.74 ± 0.1649, p < 0.001), 56.8% with food (β = 0.45 ± 0.1550, p < 0.01), and 116.0% after intake of a ketogenic diet (β = 0.77 ± 0.3141, p < 0.05). All patients included were responders without evidence of an association between C0 and response status. In children with DEEs, systemic concentrations of CBD may be significantly increased when co-administered with levothyroxine, food, or a ketogenic diet.

Introduction: Epilepsy is a neurological disorder characterized by an increased susceptibility to seizures. The ketogenic diet (KD) is currently the most important alternative non-pharmacological treatment. Despite its long history of clinical use, it is not clear how this diet affects longitudinal growth in children. Methods: A prospective study was designed to evaluate growth and nutritional status in 45 children on KD. Growth was assessed by measuring weight, height, and body mass index (BMI). Standard deviation scores (SDS) were calculated for all measurement parameters at KD initiation and at a two-year follow-up. Results: Overall, 45 patients who completed 24 months on KD were enrolled. Median age was 6.6 years (0.8 to 17.3), with a male predominance (n = 23); 74% of the 45 patients were responders on seizure reduction at three months; 26% of patients were non-responders. In our study, using −1 SDS as a cut-off point, growth deceleration was observed in 9% (n: 4) of the patients; however, the nutritional status was maintained or even improved. No correlation with age, sex, or ambulatory status was found. Conclusions: The nutritional follow-up of these patients was helpful to improve overweight and thinness but could not avoid growth deceleration in some of them. These findings confirm that children with refractory epilepsy on KD treatment require careful growth monitoring.