Summary
Mutations in the NaV1.1 neuronal sodium channel alpha‐subunit (SCN1A) gene have been documented in a spectrum of epilepsy syndromes, ranging from the relatively benign generalized epilepsy ...with febrile seizures plus (GEFS+) to severe myoclonic epilepsy in infancy (SMEI), and rare cases of familial migraine. More than 300 new mutations have been identified to date, with missense mutations being the most common in GEFS+ and more deleterious mutations (nonsense, frameshift) representing the majority of SMEI mutations. Microchromosomal abnormalities including SCN1A deletions, amplifications, and duplications are also found in patients with SMEI. Deletions range in size from one single exon to abnormalities extending beyond SCN1A and involving contiguous genes. The majority of SCN1A mutations in SMEI arise de novo. SCN1A mutations are found throughout the protein structure, and some clustering of mutations is observed in the C‐terminus and the loops between segments 5 and 6 of the first three domains of the protein. Functional studies so far show no consistent relationship between changes to channel properties and clinical phenotype.
See Lerche (doi:10.1093/brain/awy073) for a scientific commentary on this article.
PRRT2 mutations cause heterogeneous paroxysmal neurological disorders. Using iPSC-derived neurons from patients ...homozygous for a nonsense PRRT2 mutation and cortical neurons from PRRT2-knockout mice, Fruscione et al. show that PRRT2 is a negative modulator of voltage-dependent NaV1.2/1.6 channels. Increased neuronal excitability may contribute to the paroxysmal nature of PRRT2-linked diseases.
Abstract
See Lerche (doi:10.1093/brain/awy073) for a scientific commentary on this article.
Proline-rich transmembrane protein 2 (PRRT2) is the causative gene for a heterogeneous group of familial paroxysmal neurological disorders that include seizures with onset in the first year of life (benign familial infantile seizures), paroxysmal kinesigenic dyskinesia or a combination of both. Most of the PRRT2 mutations are loss-of-function leading to haploinsufficiency and 80% of the patients carry the same frameshift mutation (c.649dupC; p.Arg217Profs*8), which leads to a premature stop codon. To model the disease and dissect the physiological role of PRRT2, we studied the phenotype of neurons differentiated from induced pluripotent stem cells from previously described heterozygous and homozygous siblings carrying the c.649dupC mutation. Single-cell patch-clamp experiments on induced pluripotent stem cell-derived neurons from homozygous patients showed increased Na+ currents that were fully rescued by expression of wild-type PRRT2. Closely similar electrophysiological features were observed in primary neurons obtained from the recently characterized PRRT2 knockout mouse. This phenotype was associated with an increased length of the axon initial segment and with markedly augmented spontaneous and evoked firing and bursting activities evaluated, at the network level, by multi-electrode array electrophysiology. Using HEK-293 cells stably expressing Nav channel subtypes, we demonstrated that the expression of PRRT2 decreases the membrane exposure and Na+ current of Nav1.2/Nav1.6, but not Nav1.1, channels. Moreover, PRRT2 directly interacted with Nav1.2/Nav1.6 channels and induced a negative shift in the voltage-dependence of inactivation and a slow-down in the recovery from inactivation. In addition, by co-immunoprecipitation assays, we showed that the PRRT2-Nav interaction also occurs in brain tissue. The study demonstrates that the lack of PRRT2 leads to a hyperactivity of voltage-dependent Na+ channels in homozygous PRRT2 knockout human and mouse neurons and that, in addition to the reported synaptic functions, PRRT2 is an important negative modulator of Nav1.2 and Nav1.6 channels. Given the predominant paroxysmal character of PRRT2-linked diseases, the disturbance in cellular excitability by lack of negative modulation of Na+ channels appears as the key pathogenetic mechanism.
Functional seizures (FS) are classified as conversion disorders in the DSM-5 and dissociative disorders in the ICD-11, showing a multifactorial psychopathology with various psychiatric comorbidities, ...such as depression and anxiety. Several studies have found a correlation between FS and personality disorders, mainly those in cluster B. Within this cluster, borderline personality disorder (BPD) or borderline personality traits are the most prevalent in FS. Emotion dysregulation is a hallmark of BPD and is commonly reported in individuals with FS. Cluster C personality disorders, such as avoidant or obsessive-compulsive disorders, have also been reported in FS. In this review, we aim to evaluate the relationship between FS and personality disorders. Assessing personality disorders in the context of FS is relevant for determining the most appropriate intervention. Cognitive-behavioral therapy (CBT) is considered the first-line approach to treating FS. Among various CBT strategies, dialectical behavior therapy, which specifically targets emotion dysregulation, may be helpful for individuals with BPD. Future research should assess the advantages of systematically evaluating personality disorders in FS to address specific treatment planning and evaluate its effectiveness on seizure recurrence, psychological comorbidities, and quality of life. Systematic review registration https://www.crd.york.ac.uk/PROSPEROFILES/509286_STRATEGY_20240203.pdf , identifier CRD42024509286.
Epilepsy includes a group of disorders of the brain characterized by an enduring predisposition to generate epileptic seizures. Although familial epilepsy has a genetic component and heritability, ...the etiology of the majority of non-familial epilepsies has no known associated genetic mutations. In epilepsy, recent epigenetic profiles have highlighted a possible role of microRNAs in its pathophysiology. In particular, molecular profiling identifies a significant number of microRNAs (miRNAs) altered in epileptic hippocampus of both animal models and human tissues. In this review, analyzing molecular profiles of different animal models of epilepsy, we identified a group of 20 miRNAs commonly altered in different epilepsy-animal models. As emerging evidences highlighted the poor overlap between signatures of animal model tissues and human samples, we focused our analysis on miRNAs, circulating in human biofluids, with a principal role in epilepsy hallmarks, and we identified a group of 8 diagnostic circulating miRNAs. We discussed the functional role of these 8 miRNAs in the epilepsy hallmarks. A few of them have also been proposed as therapeutic molecules for epilepsy treatment, revealing a great potential for miRNAs as theranostic molecules in epilepsy.
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Doublecortin, encoded by the
gene, plays a crucial role in the neuronal migration process during brain development. Pathogenic variants of the
gene are the major causes of the "lissencephaly (LIS) ...spectrum", which comprehends a milder phenotype like Subcortical Band Heterotopia (SBH) in heterozygous female subjects. We performed targeted sequencing in three unrelated female cases with SBH. We identified three DCX-related variants: a novel missense (c.601A>G: p.Lys201Glu), a novel nonsense (c.210C>G: p.Tyr70*), and a previously identified nonsense (c.907C>T: p.Arg303*) variant. The novel c.601A>G: p.Lys201Glu variant shows a mother-daughter transmission pattern across four generations. The proband exhibits focal epilepsy and achieved seizure freedom with a combination of oxcarbazepine and levetiracetam. All other affected members have no history of epileptic seizures. Brain MRIs of the affected members shows predominant fronto-central SBH with mixed pachygyria on the overlying cortex. The two nonsense variants were identified in two unrelated probands with SBH, severe drug-resistant epilepsy and intellectual disability. These novel DCX variants further expand the genotypic-phenotypic correlations of lissencephaly spectrum disorders. Our documented phenotypic descriptions of three unrelated families provide valuable insights and stimulate further discussions on DCX-SBH cases.
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy; it is considered a network disorder associated with structural changes. Incomplete knowledge of the pathological changes in TLE ...complicates a therapeutic approach; indeed, 30 to 50% of patients with TLE are refractory to drug treatment. Non-coding RNAs (ncRNAs), acting as epigenetic factors, participate in the regulation of the pathophysiological processes of epilepsy and are dysregulated during epileptogenesis. Abnormal expression of ncRNA is observed in patients with epilepsy and in animal models of epilepsy. Furthermore, ncRNAs could also be used as biomarkers for the diagnosis and prognosis of treatment response in epilepsy. In summary, ncRNAs can represent important mechanisms and targets for the modulation of brain excitability and can provide information on pathomechanisms, biomarkers and novel therapies for epilepsy. In this review, we summarize the latest research advances concerning mainly molecular mechanisms, regulated by ncRNA, such as synaptic plasticity, inflammation and apoptosis, already associated with the pathogenesis of TLE. Moreover, we discuss the role of ncRNAs, such as microRNAs, long non-coding RNAs and circular RNAs, in the pathophysiology of epilepsy, highlighting their use as potential biomarkers for future therapeutic approaches.
MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as new potential epigenetic biomarkers. Here, we evaluate the efficacy of six circulating miRNA previously described in the literature as ...biomarkers for the diagnosis of temporal lobe epilepsy (TLE) and/or as predictive biomarkers to antiepileptic drug response. We measured the differences in serum miRNA levels by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays in a cohort of 27 patients (14 women and 13 men; mean ± SD age: 43.65 ± 17.07) with TLE compared to 20 healthy controls (HC) matched for sex, age and ethnicity (11 women and 9 men; mean ± SD age: 47.5 ± 9.1). Additionally, patients were classified according to whether they had drug-responsive (n = 17) or drug-resistant (n = 10) TLE. We have investigated any correlations between miRNAs and several electroclinical parameters. Three miRNAs (miR-142, miR-146a, miR-223) were significantly upregulated in patients (expressed as average expression ± SD). In detail, miR-142 expression was 0.40 ± 0.29 vs. 0.16 ± 0.10 in TLE patients compared to HC (t-test, p < 0.01), miR-146a expression was 0.15 ± 0.11 vs. 0.07 ± 0.04 (t-test, p < 0.05), and miR-223 expression was 6.21 ± 3.65 vs. 1.23 ± 0.84 (t-test, p < 0.001). Moreover, results obtained from a logistic regression model showed the good performance of miR-142 and miR-223 in distinguishing drug-sensitive vs. drug-resistant TLE. The results of this pilot study give evidence that miRNAs are suitable targets in TLE and offer the rationale for further confirmation studies in larger epilepsy cohorts.
Background
SARS-CoV-2 is a novel infectious agent causing coronavirus disease 2019, which has been declared as pandemic in March 2020. Personal protective equipment has been mandatory for healthcare ...workers in order to contain the outbreak of pandemic disease. Mild neurological disturbances such as headache have been related to the extensive utilization of facemask. This study aims to examine headache variations related to the intensive utilization of facemask among a cohort of healthcare professionals in a setting of low-medium risk of exposure to SARS-CoV-2.
Methods
This is a cross-sectional study among healthcare providers from different hospital and clinics in Italy. Each participant completed a specifically designed self-administered questionnaire. Headache features and outcome measures’ change from baseline were evaluated over a 4-month period, in which wearing facemask has become mandatory for Italian healthcare workers.
Results
A total of 400 healthcare providers completed the questionnaire, 383 of them met the inclusion criteria. The majority were doctors, with a mean age of 33.4 ± 9.2 years old. Among 166/383 subjects, who were headache free at baseline, 44 (26.5%) developed de novo headache. Furthermore, 217/383 reported a previous diagnosis of primary headache disorder: 137 were affected by migraine and 80 had tension-type headache. A proportion (31.3%) of these primary headache sufferers experienced worsening of their pre-existing headache disorder, mainly for migraine frequency and attack mean duration.
Conclusions
Our data showed the appearance of de novo associated facemask headache in previous headache-free subjects and an exacerbation of pre-existing primary headache disorders, mostly experienced by people with migraine disease.
: In geriatric age, cognitive impairment and cardiovascular disorders are frequent comorbidities. Age-related anatomical and functional cardiac changes, including the autonomic system, could ...interfere with the control of different cognitive domains. Therefore, we assess the relationship between long-term heart rate variability (HRV), as a measure of autonomic nervous system (ANS) functioning, and cognitive performance in elderly patients representative of outpatients in a real-life setting.
: Of 155 elderly outpatients (aged >65 years) screened, 117 enrolled patients underwent anthropometric evaluation, cardiac assessment by 12-lead electrocardiogram, 24-h ECG recording, and blood pressure (BP) measurement, as well as global cognitive evaluation by a standardized multidimensional assessment, including the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment test (MoCA). HRV analysis was performed on 24-h ECG recordings focusing on time-domain indices Standard deviation of the NN intervals (SDNN), standard deviations of 5-min mean values of the NN intervals for each 5-min interval (SDANN), and root mean squares of successive differences of the NN intervals (RMSSD) and on frequency-domain measurements heart rate (HR), low frequency (LF), high frequency (HF), and LF/HF. Multivariate linear analysis was used to explore the influence of the HRV significant variables on MMSE and MoCA test values.
: The MMSE and MoCA scores were both significantly and positively correlated with the sympathetic system parameters (SDNN, SDANN, LF, and LF/HF ratio), but not with the parasympathetic system parameters (RMSSD and HF). Multivariate analysis confirms this relationship.
: Our results show that, in a representative real-life community elderly population, an increased sympathetic activity, but not decreased vagal activity, is associated with better cognitive performances. These results support the sympathetic autonomic function, in that the relationship between better cognitive performances and a moderate prevalence of autonomic function appears dependent on long-term changes in heart rate, mediated by sympathetic activation.
Several studies have focused on the emerging role of immunity and inflammation in a wide range of neurological disorders. Autoimmune diseases involving central nervous system share well defined ...clinical features including epileptic seizures and additional neuropsychiatric symptoms, like cognitive and psychiatric disturbances. The growing evidence about the role of immunity in the pathophysiologic mechanisms underlying these conditions lead to the concept of autoimmune epilepsy. This relatively-new term has been introduced to highlight the etiological and prognostic implications of immunity in epileptogenesis. In this review, we aim to discuss the role of autoimmunity in epileptogenesis and its clinical, neurophysiological, neuroimaging and therapeutic implications. Moreover, we wish to address the close relationship between immunity and additional symptoms, particularly cognitive and psychiatric features, which deeply impact clinical outcomes in these patients. To assess these aspects, we first analyzed Rasmussen’s encephalitis. Subsequently, we have covered autoimmune encephalitis, particularly those associated with autoantibodies against surface neuronal antigens, as these autoantibodies express a direct immune-mediated mechanism, different from those against intracellular antigens. Then, we discussed the connection between systemic immune disorders and neurological manifestations. This review aims to highlight the need to expand knowledge about the role of inflammation and autoimmunity in the pathophysiology of neurological disorders and the importance to early recognize these clinical entities. Indeed, early identification may result in faster recovery and a better prognosis.
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