UNC13B variants associated with partial epilepsy with favourable outcome

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13–2 (Munc13-2), that is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of UNC13B mutation in human disease is not known. In this study we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed favorable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant, and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database. Computational modeling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favorable outcome under antiepileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

PROMISING DIRECTIONS FOR THE APPLICATION OF PIPERIDINE DERIVATIVES AS STRUCTURAL COMPONENTS OF NEUROTROPIC DRUGS

Piperidine is one of the most common heterocycles, and its derivatives are found in many pharmacological groups, including neurotropic drugs. These compounds are numerous among analgesics, and, in addition to “classical” promedol, fentanyl and its derivatives, the paper presents the results of studying new compounds with analgesic activity and piperidine cycle. Reviews of such piperidine antipsychotics as haloperidol and risperidone have been considered, and new compounds showing antipsychotic activity through their effects on dopamine and serotonin receptors have been elucidated. The data on the influence of methylphenidate on the brain in case of attention deficit/ hyperactivity disorder (ADHD) have been analyzed, which help to understand the disturbances occurring in this disease. Tiagabine has been considered as an antiepileptic agent reducing the number of seizures in resistant forms of partial epilepsy, as well as the activation of microglia and may be effective in neurodegenerative diseases. The last section is devoted to drugs for the treatment of Alzheimer’s disease (AD), namely donepezil, its modifications, and some new compounds potentially capable of inhibiting AD progression through the inhibition of Aβ42 protein synthesis.

Atypical benign partial epilepsy and a new variant of SLC35A3 gene plus 2p25.1 duplication. Phenotypic-Genotypic correlation?

Background Atypical Benign Partial Epilepsy (ABPE), recognized also as pseudo-Lennox syndrome, is an uncommon form of epilepsy characterized by generalized minor seizures such as atonic, absences, or myoclonic seizures, and electroencephalographic pattern of focal or multifocal sharp waves with activation of epileptiform discharges during sleep. ABPE is indicated as a variant of ESES (ILAE classification 2017). ESES is a clinical entity that is characterized by encephalopathy with cognitive/ behavioral regression and EEG pattern of electrical status epilepticus during slow sleep. Fine and gross motor, language and social/behavioral impairment are associated symptoms, which may have reversible or persistent course. ABPE has been ascribed to the group of the “epilepsy aphasia spectrum” disorders, which includes also Rolandic Epilepsy, Landau-Kleffner syndrome, and electrical status epilepticus during sleep/continuous spike-wave during sleep. We report a young boy with a previous mild motor and language delay, who at 2-year-old presented with recurrent atonic seizures and an EEG pattern consisting of continuous spike and waves during sleep. Methods Next Generation Sequencing and microarray technology were used to investigate the molecular background of the proband, and the findings were then analyzed and integrated with clinical data. Results The child has been followed up to 7 years of age showing a progressive, complete EEG resolution and a normalization of the previous motor and cognitive impairment in association to the levetiracetam treatment. Genetic diagnosis displayed a novel heterozygous mutation c.310G>A of the SLC35A3 gene and a partial duplication of the short arm of chromosome 2, which might have pathogenic correlation with the neurological signs presented by the child. Conclusions Data generated by a genomic approach disclose a more comprehensive view of the genotype-phenotype correlation analysis for the novel pathogenic variant and ABPE. The relationship between the phenotypic manifestations of the child and genetic data is discussed.

Effect of carbamazepine on emotional intelligence and mindfulness in patients with partial epilepsy

Objective: To assess the effectiveness of carbamazepine on emotional intelligence and mindfulness in patients with epilepsy. Method: The repeated-measure case-control study was conducted at the Nishter Hospital, Multan, Bahawal Victoria Hospital, Bahawalpur, and Civil Hospital, Bahawalpur, Pakistan, from April 2017 to March 2018, and comprised patients with partial epilepsy and healthy controls. Baseline data was collected using BarOn Emotional Quotient Inventory and Cognitive and Affective Mindfulness Scale-Revised. Subsequent data was collected twice in titration and maintenance phases during carbamazepine therapy for patients, while the controls were on no medication. . Data was analysed using SPSS 20. Results: Of the 80 subjects, 40(50%) were cases with a mean age of 37.92±9.09 years, and 40(50%) were controls with a mean age of 37.80±9.00 years. The patients had significantly lower emotional intelligence and mindfulness compared to the controls (p<0.001). Patients showed improved emotional intelligence and mindfulness after the therapy compared to their baseline scores (p<0.05). Conclusion: Carbamazepine was found to be effective in improving emotional intelligence and mindfulness in patients with epilepsy. Key Words: Epilepsy, Carbamazepine, Mindfulness, Cognition, Continuous...

Temporal Lobe Epilepsy Misdiagnosed as Schizophrenia: A Case Report

Temporal lobe epilepsy is a neurological disorder of an unprovoked type of focal (partial) epilepsy that begins in the temporal lobe of the brain. Patients with this condition are often misdiagnosed due to similarities in presentation to other conditions. In this case report, we presented a 34-year-old male, who had symptoms of hallucination, anxiety, and depression which can be seen in patients with temporal lobe epilepsy. Due overlap in symptoms, he was misdiagnosed to have schizophrenia. Following subsequent review of his medical history and findings seen in his laboratory work and imaging studies, it was determined that his symptoms were caused by seizures originating from an atrophic lesion in his hippocampus found on magnetic resonance imaging of his temporal lobe.