Epilepsy is a common and potentially severe neurological disorder, the consequences of which include stigmatization and psychiatric comorbidities. This study aims (a) to evaluate stigma, seizure severity, quality of life, anxiety and depression in a sample of individuals diagnosed with epilepsy (IDWE), (b) to examine their associations with sociodemographic characteristics (age, sex, income, and education), and (b) to identify potential predictors of stigma. Eighty IDWE were assessed using the Epilepsy Stigma Scale (ESS), the Seizure Severity Questionnaire (SSQ), the Beck Depression Inventory (BDI), the Beck Anxiety Inventory (BAI), and the Quality of Life in Epilepsy Inventory (QOLIE-31). Correlation and regression analyses were conducted to explore the relationships among these variables. Stigma (ESS) was positively correlated with seizure severity (SSQ), depression (BDI), and anxiety (BAI), while it was negatively correlated with quality of life (QOLIE-31). No significant associations were observed between stigma and sex, marital status, education level, or age of onset. In the multiple regression analysis, quality of life emerged as the strongest predictor of stigma, with higher QOLIE-31 scores being associated with lower ESS scores (β = -0.641, p < 0.001). Our findings highlight the significant psychosocial burden of epilepsy, demonstrating that stigma is strongly linked to seizure severity, depression, and anxiety, while quality of life plays a crucial role in mitigating stigma. Addressing these factors is essential for improving the overall well-being of IDWE.

Carrier screening is a long-standing genetic testing process offered to at-risk couples, with or without a family history, who might have pregnancies affected by an autosomal recessive (AR) or X-linked (XL) disorder. A total of 276 unrelated individuals, initially referred for rare disorder screening by clinicians, were enrolled in this study and tested by Exome sequencing (ES). Expanded carrier screening (ECS) was performed for 176 disorders that met the inclusion criteria of the ACMG and ACOG. Genes with single nucleotide variants (SNVs) identified with a carrier rate > 1% for AR disorders included HBB, CFTR, PMM2, NPHS2, GJB2, ACADM, ALDOB, MEFV, MKS1, NEB, PAH, ATM, CPT2, CYP21A2, AGXT, BBS1, CAPN3, COL4A4, DHCR7, GAA, IVD, LAMA2, SLC22A5, SLC26A4, USH2A. For XL disorders, variants were detected in the RS1 gene. ECS offers a wealth of information about SNVs related to AR and XL disorders in specified populations. The information obtained from ECS provides multiple advantages: (a) it identifies the most prominent risks in health care in a given population and contributes to the prevention of genetic disorders, (b) it enriches available databases with pathogenic or likely pathogenic SNVs, and (c) it records novel targets for molecular clinical genetic testing.

Spinal cord injury is strongly associated with male infertility, traditionally attributed to erectile and ejaculatory dysfunction. However, accumulating evidence demonstrates that infertility in this population extends beyond neurogenic impairment and involves profound biochemical and molecular alterations within the male reproductive system. The objective of this review is to synthesize current evidence on the role of oxidative stress, inflammation, and sperm DNA damage as central mechanisms driving impaired fertility in men with spinal cord injury. A comprehensive evaluation of clinical and experimental studies indicates that seminal plasma in affected individuals is characterized by elevated reactive oxygen species, reduced antioxidant capacity, and a pro-inflammatory cytokine profile, including increased levels of tumor necrosis factor alpha, interleukin 6, and interleukin 1 beta. These alterations are closely linked to leukocytospermia, mitochondrial dysfunction, and disruption of the blood-testis barrier, creating a toxic microenvironment that compromises sperm function. As a consequence, spermatozoa exhibit reduced motility, impaired membrane integrity, and significantly increased DNA fragmentation and chromatin abnormalities. Elevated sperm DNA damage has been consistently associated with poor fertilization outcomes, reduced embryo quality, and increased risk of pregnancy loss in assisted reproductive settings. Importantly, these molecular defects persist even when sperm are retrieved using advanced techniques such as electroejaculation or surgical extraction, highlighting the need for targeted therapeutic strategies. Interventions aimed at reducing oxidative stress and modulating inflammation, including antioxidant supplementation and advanced sperm selection methods, show promise but remain insufficiently standardized. Future research should focus on the development of personalized approaches integrating molecular diagnostics and targeted therapies to improve reproductive outcomes in this population. Collectively, this review reframes spinal cord injury-related infertility as a complex inflammatory and oxidative disorder and underscores the importance of addressing sperm DNA integrity in clinical management.

Assisted reproductive technologies (ART) and, in particular, intracytoplasmic sperm injection (ICSI) transformed the management of male infertility by making fertility possible in previously untreatable cases. However, the bypassing of natural selection mechanisms at fertilization is fraught with the danger of transmission of genetic and epigenetic abnormalities. Male infertility is now a multifactorial disorder with notable contributions from single-gene defects, chromosomal abnormalities, and Y-chromosome microdeletions. The recent advances in next-generation sequencing and sperm omics have identified mutations and copy-number variations in genes critical for spermatogenesis, flagellar structure, and endocrine regulation. Along with these findings, an increasing body of evidence suggests that ART procedures can lead to a disruption of epigenetic reprogramming during gametogenesis and early embryogenesis, resulting in imprinting disorders and altered patterns of gene expression in the offspring. This review synthesizes recent progress in the molecular underpinnings of genetic and epigenetic hazards of ART, with an emphasis on clinical significance for reproductive counselling and ethical considerations for future generations.

More than 600 different metabolic disorders can lead to a clinical picture, where seizures are a main neurological manifestation, either as the primary clinical finding or as a part of a more complex phenotype. For these metabolic disorders, the term “metabolic epilepsy” is commonly used. About one in six metabolic epilepsies is treatable, constituting a well-defined subset of metabolic disorders, which is amenable to treatment targeting the primary cause of the seizures and reducing or preventing associated complications. However, the majority of metabolic disorders currently lack effective treatment, making them a major challenge both in clinical practice and in research. Herein, we provide an overview of both treatable and non-treatable metabolic epilepsies and discuss our current understanding of these disorders. We also perform pathway analysis in order to compare the pathways in which the genes associated with treatable and non-treatable metabolic epilepsies take part. This approach may orientate the research to particular pathways and explore novel treatment algorithms.

Exome sequencing (ES) is an essential part in clinical diagnosis of hereditary disorders. However, ES can reveal secondary findings (SFs) in medically actionable genes that are not related to the patient’s phenotype. In this study, we performed ES to 280 unrelated individuals of a Greek cohort and calculated the frequency of SFs in 81 ACMG SF v3.2 genes. Variants were classified using the standards and guidelines established by the American College of Medical Genetics and Genomics (ACMG). We identified 12 individuals (4.3%) who carried a pathogenic (P)/likely pathogenic (LP) variant in genes associated with dominant disorders. The variants were found in genes BRCA1, BRCA2, MSH6, LDLR, MYH7, and TTN. Notably, we discovered a P founder variant for the Greek population and one P variant with high prevalence in BRCA1 gene. Additionally, we observed a high prevalence of P/LP variants in the LDLR gene. In conclusion, this is the first study that calculates the prevalence of P/LP variants in the ACMG actionable gene list for SFs in Greece. The results of our study could serve as a guide for the national carrier screening program and may contribute to the precise treatment of certain human disorders.

Retrotransposable elements are implicated in genome rearrangements and gene expression alterations that result in various human disorders. In the current study, we sought to investigate the potential effects of long interspersed elements-1 (LINE-1) overexpression on the integrity and methylation of DNA and on the expression of three major pluripotency factors (OCT4, SOX2, NANOG) during the preimplantation stages of human embryo development. Human MI oocytes were matured in vitro to MII and transfected through intracytoplasmic sperm injection (ICSI) either with an EGFP vector carrying a cloned active human LINE-1 retroelement or with the same EGFP vector without insert as control. The occurrence of retrotransposition events was screened by fluorescent microscopy. The in vitro preimplantation development as well as the methylation, pluripotency, and DNA double-strand breaks (DSBs) of the transfected embryos were examined. LINE-1 retrotransposons gave rise to new retrotransposition events in the transfected embryos. LINE-1 injected embryos were characterized by accelerated asymmetrical cell division, multiple cellular fragments, cleavage arrest, and degeneration. Early OCT4 expression remained unaltered, but cleavage arrest and a high fragmentation rate hindered the expression of SOX2/NANOG at the morula stage. Increased DNA DSBs were observed in cleavage-stage blastomeres, while no methylation changes were detected before the cleavage arrest. Our data provide evidence that LINE-1 retrotransposition in human preimplantation embryos may induce DNA DSBs, while at the same time, it appears to interfere with the expression patterns of pluripotency factors. The morphological, structural, and cleavage abnormalities of the transfected embryos show that aberrant retroelement expression may negatively affect human embryo development.

Holliday junctions are the first recognized templates of legitimate recombination. Their prime physiological role is meiotic homologous recombination, resulting in rearrangements of the genetic material. In humans, recombination hotspots follow a distinct epigenetic pattern designated by the presence of PR domain-containing protein 9 (PRDM9). Repetitive DNA elements can replicate in the genome and can pair with short inverted repeats (SIRs) that form Holliday junctions in a significantly high frequency in vitro. Remarkably, PRDM9 and SIR sequence motifs, which may have the potential to act as recombination primers associated with transposable elements (TEs) and their presence, may lead to gradual spreading of recombination events in human genomes. Microdeletion and microduplication syndromes (MMSs) constitute a significant entity of genetic abnormalities, almost equal in frequency to aneuploidies. Based on our custom database, which includes all MMSs shorter than 5 Mbs in length which is the cut-off point for the standard cytogenetic resolution, we found that the majority of MMSs were present in sequences shorter than 0.5 Mbs. A high probability of TE-associated and non-TE-associated PRDM9/SIR sequence motifs was found in short and long MMSs. Significantly, following the Reactome pathway analysis, a number of affected genes have been associated with the pathophysiological pathways linked to MMSs. In conclusion, PRDM9 or SIR sequence motifs in regions spanning MMSs hotspots underlie a potential functional mechanism for MMS occurrences during recombination.

The PR domain-containing 9 or PRDM9 is a gene recognized for its fundamental role in meiosis, a process essential for forming reproductive cells. Recent findings have implicated alterations in the PRDM9, particularly its zinc finger motifs, in the onset and progression of cancer. This association is manifested through genomic instability and the misregulation of genes critical to cell growth, proliferation, and differentiation. In our comprehensive study, we harnessed advanced bioinformatic mining tools to delve deep into the intricate relationship between PRDM9F and cancer. We analyzed 136,752 breakpoints and found an undeniable association between specific PRDM9 motifs and the occurrence of double-strand breaks, a phenomenon evidenced in every cancer profile examined. Utilizing R statistical querying and the Regioner package, 55 unique sequence variations of PRDM9 were statistically correlated with cancer, from a pool of 1024 variations. A robust analysis using the Enrichr tool revealed prominent associations with various cancer types. Moreover, connections were noted with specific phenotypic conditions and molecular functions, underlining the pervasive influence of PRDM9 variations in the biological spectrum. The Reactome tool identified 25 significant pathways associated with cancer, offering insights into the mechanistic underpinnings linking PRDM9 to cancer progression. This detailed analysis not only confirms the pivotal role of PRDM9 in cancer development, but also unveils a complex network of biological processes influenced by its variations. The insights gained lay a solid foundation for future research aimed at deciphering the mechanistic pathways of PRDM9, offering prospects for targeted interventions and innovative therapeutic approaches in cancer management.

Background: The aim of the present study was to compare the myocardial perfusion imaging (MPI) with [99mTc]tetrofosmin stress — rest single-photon emission computer tomography (SPECT) of patients with epilepsy with matched control individuals. Material and methods: All 29 adult epileptic patients were receiving antiepileptic drugs (AEDs) for epilepsy. Thirty-two individuals matched for gender and age consisted of the control group. MPIs SPECT were performed, and myocardial summed scores were obtained during stress (SSS) and rest (SRS) images. Abnormal MPI was considered when SSS was ≥ 4. In addition, the difference (SDS) between SSS and SRS was also assessed, which represents a rate of reversibility after stress. Results: Twenty of 29 (68.97%) patients with epilepsy had abnormal MPI and 14/32 (43.75%) of the controls (p = 0.04). Among males, 18/23 patients and 11/25 controls had abnormal MPI (p = 0.01), with quite a significant difference for mean SSS between male patients and controls (p = 0.002). Furthermore, SDS comparison showed that irreversible abnormalities were more common in patients than in control individuals. A difference of inadequately compensated myocardial ischemia between patients treated with enzyme inducing AEDs and patients treated with valproic acid was also detected. Conclusions: Single-photon emission computer tomography (SPECT) may detect increased risk for coronary artery disease and further cardiovascular events in patients with epilepsy. Our findings favor the conclusion that SPECT could be used for the early identification of cardiovascular comorbidity in epilepsy.

The completion of the human genome sequencing in 2003 redefined the molecular basis for understanding many diseases and illnesses at the genetic level. Sequencing of the human genome has led to a radical change in genetic medicine as well as the association of genes with diseases. The application of genetic knowledge in clinical practice in the last 4 years is due to the development of next generation sequencing systems (NGS). NGS technology, also known as massive parallel sequencing, is an innovative high throughput DNA sequencing methodology. NGS technology is the new genetic “weapon” enabling the sequencing of all genes (whole exome sequencing) and the entire human genome (whole genome sequencing) in just a few days, producing huge amounts of information. NGS is rapidly gaining ground in the field of genetic diagnosis and research. It can give combined results for both small gene damage and structural abnormalities of chromosomes. Based on this technology, the goal of GeneScreening project is to create a genetic platform for the detection of pathogenic variants in the copy number variations (CNVs) of wide clinical utility and application in order to prevent and diagnose developmental disorders and mental illnesses. Sub-objectives are: (i) the mapping of repetitive sequences in which the recombination points that cause deficits and microplications are identified, (ii) the creation of biomarkers of pathogenic recombinations, (iii) creating a database of sequences involved in pathogenic recombinations and (iv) the creation of standard recombination point detection software in NGS data.

Brivaracetam (BRV) is the latest approved antiepileptic drug. The aim of the study was to evaluate the efficacy and tolerability of BRV in everyday clinical practice. In this retrospective, observational, multicenter study, data from epilepsy patients receiving BRV from January 2018 to July 2019 were analyzed. Patients with age ≥16 suffering from any type of epilepsy and having at least one follow up encounter after dose titration were included. 156 consecutive patients were included in the study. The mean age was 40 (16–84 years) and the mean duration of epilepsy was 21 years. Of the 156 patients, 81% were diagnosed with focal-onset seizures, 16% with generalized seizures, while 3% suffered from unclassified seizures. Nine patients received BRV as monotherapy as a switching therapy. At the first follow up visit, seizure cessation was achieved in 56 (36%) patients and the rate of ≥50% responders was 36%. Twenty four patients (15%) remained unchanged; six patients (4%) were recorded with increased seizure frequency, while the remaining 9% had a response of less than 50%. Twenty-six patients (17%) showed clinically significant adverse events, but none were life threatening. Brivaracetam seems to be an effective, easy to use and safe antiepileptic drug in the clinical setting.

Epilepsy is a risk factor for the development of psychogenic non-epileptic seizures (PNES) and comorbid epilepsy is recognized as a comorbidity in about 10–30% of patients with PNES. The combination of epileptic and nonepileptic seizures poses a particular diagnostic challenge. In patients with epilepsy, additional PNES may be suspected on the basis of their typical semiology. The possibility of additional PNES should also be considered if seizures fail to respond to antiepileptic drug treatment, in patients with frequent emergency admissions with seizures and in those who develop new types of seizures. The description of semiological details by patients and witnesses can suggest additional PNES. Home video recordings can support an initial diagnosis, however, especially in patients with mixed seizure disorders it is advisable to seek further diagnostic confirmation by capturing all habitual seizure types with video-EEG. The clinical features of PNES associated with epilepsy are similar to those in isolated PNES disorders and include longer duration, fluctuating course, asynchronous movements, pelvic thrusting, side-to-side head or body movement, persistently closed eyes and mouth, ictal crying, recall of ictal experiences and absence of postictal confusion. PNES can also present as syncope-like episodes with unresponsiveness and reduced muscle tone. There is no unique epileptological or brain pathology profile putting patients with epilepsy at risk of additional PNES. However, patients with epilepsy and PNES typically have lower educational achievements and higher levels of psychiatric comorbidities than patients with epilepsy alone. Psychological trauma, including sexual abuse, appears to be a less relevant aetiological factor in patients with mixed seizure disorders than those with isolated PNES, and the gender imbalance (i.e. the greater prevalence in women) is less marked in patients with PNES and additional epilepsy than those with PNES alone. PNES sometimes develop after epilepsy surgery. A diagnosis of ‘known epilepsy’ should never be accepted without (at least brief) critical review. This narrative review summarises clinical, electrophysiological and historical features that can help identify patients with epilepsy and additional PNES.

Background/Aim: The expression of reverse transcriptase (RT) in ovaries, testes, gametes and embryos highlights its critical role in cell growth and differentiation. We sought to investigate the effects of the potent RT inhibitor lamivudine in gametogenesis and mouse embryo preimplantation development. Materials and Methods: Male and female FVB/N mice were treated with the reverse transcriptase inhibitor Lamivudine for seven consecutive weeks. Following treatment, mouse sperm parameters, testicular and ovarian morphology as well as post-IVF embryo development were evaluated. Results: Lamivudine impaired the sperm parameters and the testicular structure in male mice, the number of primordial germ cells and primary oocytes in ovaries of female mice, and the embryos' morphology and development up to the blastocyst stage during in vitro culture. Conclusion: The administration of lamivudine affected the processes of spermatogenesis and oogenesis as well as the in vitro preimplantation development of mouse embryos.

The aim of the present study was to test whether inhibition of ovarian primordial follicles and subsequent activation can be achieved by transient mTOR inhibition. In this preclinical investigation, forty-five female immature Wistar rats were randomized in 5 groups. The control group received subcutaneous saline injections. The other groups received Everolimus, Everolimus plus Verapamil, Everolimus plus Fisetin, and Fisetin alone. Primary and secondary outcomes were measured in the left ovary after a treatment period of 8 weeks. Ten days later, animals received 35 IU FSH for 4 days and 35 IU of hCG on the 5th day. The same parameters were examined in the right ovary. AMH, estradiol, and progesterone levels were assessed at the end of both interventions. Significantly, more primordial and less atretic follicles were observed in the Everolimus plus Verapamil group. AMH and progesterone levels were substantially lower in the Everolimus group. Interestingly, after ovarian stimulation higher levels of AMH and progesterone were observed in the Everolimus plus Verapamil group. Immunoblot analysis of ovarian extracts revealed that the administration of Everolimus led to a significant reduction in the mTORC1-mediated phosphorylation of the 70-kDa ribosomal protein S6 kinase 1. This decrease was reversed in the presence of FSH after stopping drug administration. The expression of the anti-apoptotic molecule Bcl2 as well as of LC3-II and ATG12 was increased after removal of the Everolimus plus Verapamil combination, indicating reduced apoptosis and increased autophagy, whereas the levels of the proliferation marker PCNA in the granulosa cells were elevated, consistent with initiation of follicular growth.Thus, the combination of Everolimus plus Verapamil is capable of increasing the number of competent primordial follicles while reducing atresia.

•Maladaptive defenses and depression were related to the adverse events of AEDs.•Almost half of the severity of the adverse effects of AEDs was explained.•Gender, AEDs load, depression, and adaptive style remained significant coefficients.

Purpose: To present an unusual case of posterior encephalopathy syndrome (PRES) preceded by intracranial hypotension. Materials and Methods: We present a case of a 27-year-old parturient with an uneventful pregnancy that shortly after labor developed a persistent headache with characteristics compatible with intracranial hypotension. The patient had undergone epidural anesthesia for caesarian section. Results: The symptomatology of intracranial hypotension was attributed to inadvertent dural puncture during epidural anesthesia. The MRI revealed multiple white matter lesions located in frontal, temporal and parietal regions of both hemispheres. The type of lesions was suggestive of PRES. Pachymeningeal enhancement was also observed. The patient was managed conservatively. The symptoms improved gradually and the imaging findings resolved completely. Conclusions: This case demonstrates the need for clinical alertness for PRES in patients with prolonged and possibly atypical symptoms of intracranial hypotension. As probable causal relationship between these disorders we propose a sympathetic over-activation as a result of cerebrospinal fluid leakage leading to vasospasm and manifestation of PRES.

Limbic encephalitis is an inflammatory process involving the limbic structures of the brain, manifested with short-term memory deficits, confusion, depression and seizures. It is usually a paraneoplastic condition but it may also appear as a nonparaneoplastic syndrome. Patients with this condition may exhibit a variety of antibodies in their serum or/and cerebrospinal fluid targeting basement membrane components that bind to a variety of neurotransmitter receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and GABA B and proteins associated to the ion channels such as LGI1, Caspr2 or intracellular components. Flurodeoxyglucose PET/computed tomography usually demonstrates increased uptake in the limbic structures, and it may reveal the site of the primary tumor. Treatment consists of tumor removal if possible. Symptomatic treatment includes steroids, gamma immune globulin, plasma exchange, immunosuppressive therapies and anti-epileptic drugs. Prognosis is better when it is associated with antibodies against basement membrane rather than intracellular antibodies.

Background: In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures outcome and the clinical management. We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES. Methods: We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project. Results: Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 (+/- 19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 +/- 7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project. Conclusion: Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES. (C) 2020 Elsevier Inc. All rights reserved.