De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Sleep Habits, Academic Performance and Health Behaviors of Adolescents in Southern Greece.

Adolescents often experience insufficient sleep and have unhealthy sleep habits. Our aim was to investigate the sleep patterns of secondary education students in Heraklion, Crete, Greece and their association with school performance and health habits. We conducted a community-based cross-sectional study with 831 students aged 13-19 years who completed an online self-reported questionnaire related to sleep and health habits. The data are mostly numerical or categorical, and an analysis was performed using t-tests, chi-square tests and multiple logistic regression. During weekdays, the students slept for an average of 7 ± 1.1 h, which is significantly lower than the 7.8 ± 1.5 h average on weekends (p < 0.001). Nearly 79% reported difficulty waking up and having insufficient sleep time, while 73.8% felt sleepy at school at least once a week. Having sufficient sleep time ≥ 8 h) was positively correlated with better academic performance (OR: 1.48, CI: 1.06-2.07, p = 0.022) and frequent physical exercise (never/rarely: 13.5%, sometimes: 21.2%, often: 65.3%; p = 0.002). Conversely, there was a negative correlation between adequate sleep and both smoking (OR: 0.29, CI: 0.13-0.63) and alcohol consumption (OR: 0.51, CI: 0.36-0.71, p = 0.001). In conclusion, this study shows that students in Heraklion, Crete frequently experience sleep deprivation, which is associated with compromised academic performance, reduced physical activity and an increased likelihood of engaging in unhealthy behaviors like smoking and alcohol consumption.

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.