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Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved. Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al . identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p  < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p  = 0.001) and females (OR = 3.0, p  < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p  = 0.001), absence seizures (OR = 6.0, p  < 0.001) and stress-precipitated seizures (OR = 5.3, p  = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p  = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12 . Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2 , indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion. This study identifies TTTCA- and TTTTA-repeat expansions in benign adult familial myoclonic epilepsy. Cortical neurons from affected people exhibit RNA foci containing these expanded repeats, suggesting RNA toxicity as the mechanism underlying disease pathogenesis.

Among children and young adults with the Dravet syndrome, a developmental disorder that is associated with treatment-resistant seizures, cannabidiol reduced the frequency of convulsive seizures but caused sleepiness and elevated liver enzymes in some patients. Seizures are difficult to control in the Dravet syndrome, a rare genetic form of epileptic encephalopathy primarily due to loss-of-function mutations in the SCN1A gene. Interest in cannabidiol for the treatment of epilepsy was generated by media reports of efficacy in children with the Dravet syndrome. 1 Four small trials of cannabidiol had yielded mixed results. 2 – 5 A series of in vitro and in vivo preclinical models of seizure showed that cannabidiol had activity against convulsive seizures. 6 Subsequently, the safety and effectiveness of a standardized oral solution of cannabidiol was tested in an open-label trial involving 214 children and young adults . . .

Structural neuroimaging studies of patients with Juvenile Myoclonic Epilepsy (JME) typically present two findings: 1‐volume reduction of subcortical gray matter structures, and 2‐abnormalities of cortical thickness. The general trend has been to observe increased cortical thickness primarily in medial frontal regions, but heterogeneity across studies is common, including reports of decreased cortical thickness. These differences have not been explained. The cohort of patients investigated here originates from the Juvenile Myoclonic Epilepsy Connectome Project, which included comprehensive neuropsychological testing, 3 T MRI, and high‐density 256‐channel EEG. 64 JME patients aged 12–25 and 41 age and sex‐matched healthy controls were included. Data‐driven approaches were used to compare cortical thickness and subcortical volumes between the JME and control participants. After differences were identified, supervised machine learning was used to confirm their classification power. K‐means clustering was used to generate imaging endophenotypes, which were then correlated with cognition, EEG frequency band lagged coherence from resting state high‐density EEG, and white and grey matter based spatial statistics from diffusion imaging. The volumes of subcortical gray matter structures, particularly the thalamus and the motor‐associated thalamic nuclei (ventral anterior), were found to be smaller in JME. In addition, the right hemisphere (primarily) sulcal pre‐motor cortex was abnormally thicker in an age‐dependent manner in JME with an asymmetry in the pre‐motor cortical findings. These results suggested that for some patients JME may be an asymmetric disease, at least at the cortical level. Cluster analysis revealed three discrete imaging endophenotypes (left, right, symmetric). Clinically, the groups were not substantially different except for cognition, where left hemisphere disease was linked with a lower performance on a general cognitive factor (“g”). HD‐EEG demonstrated statistically significant differences between imaging endophenotypes. Tract‐based spatial statistics showed significant changes between endophenotypes as well. The left dominant disease group exhibited diffuse white matter changes. JME patients present with heterogeneity in underlying imaging endophenotypes that are defined by the presence and laterality of asymmetric abnormality at the level of the pre‐motor sulcal cortex; these endophenotypes are linked to orderly relationships with cognition, EEG, and white matter pathology. The relationship of JME's adolescent onset, age‐dependent cortical thickness loss, and seizure upon awakening all suggest that synaptic pruning may be a key element in the pathogenesis of JME. Individualized treatment approaches for neuromodulation are needed to target the most relevant cortical and subcortical structures as well as develop disease‐modifying and neuroprotective strategies.

Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Background Familial adult myoclonic epilepsy (FAME), an autosomal dominant disorder, is characterized by cortical myoclonus and occasional generalized tonic–clonic seizures. To date, intronic pentanucleotide repeat expansions in at least seven genes, including SAMD12 , TNRC6A , YEATS2 , MARCHF6 , STARD7 , RAPGEF2 , and RAI1 , have been reported as causative. Detecting these repeat expansions using conventional sequencing techniques (Sanger or short-read next-generation sequencing) is not feasible as they cannot reliably span or characterize long repetitive elements. Although genetic testing has been performed in some research laboratories, comprehensive long read–based panel is unavailable for clinical application. To address this gap, we developed a targeted long-read sequencing panel and applied it in a clinical diagnostic context for the first time. Methods We designed a custom long-read sequencing panel targeting all seven known FAME-associated repeat loci using Oxford Nanopore Cas9-enrichment technology and applied it to a 47-year-old woman with familial cortical myoclonic tremor, clinically suspected to have FAME. Results The panel functioned as intended, providing robust on-target coverage across all loci, facilitating confident interrogation of each repeat region. At the SAMD12 locus, strand-aware histograms and read-level inspection demonstrated a clear pathogenic expansion, encompassing mixed TTTTA/TTTCA motifs with detectable TTTGA interruptions, consistent with FAME1. Using the crude allele prediction option of tandem-genotypes, the expanded allele contained approximately 689 additional repeats relative to the reference genome. The other six loci showed no pathogenic expansions. Conclusions This targeted long-read panel enabled the first clinical molecular diagnosis of FAME using a comprehensive assay, yielding allele-resolved characterization of the pathogenic repeat and its motif composition. With further validation, this approach may serve as a clinically practical tool for reliable detection of FAME1 and for broader screening of other FAME subtypes, potentially reducing reliance on prolonged clinical observation or specialized electrophysiological testing.

Objective To: (a) interrogate the concept of general mental ability reflected by “Spearman's g” factor in participants with Juvenile Myoclonic Epilepsy (JME) and control participants; (b) understand g's clinical, familial, socioeconomic, and brain structural correlates; and (c) determine g's relationship with variable cognitive pathology in JME and the neuroanatomical correlates of association. Methods Seventy‐seven JME and 43 typically developing unrelated control participants (mean ages 19.7 and 20.3 years, respectively) were administered a comprehensive neuropsychological battery with characterization of clinical epilepsy and familial features, determination of socioeconomic status, and structural neuroimaging. g was estimated through factor analysis and compared between participant groups, related to familial social factors (marital status, level of education, work status), socioeconomic environment (Area Deprivation Index), and brain morphological features (total intracranial volume [TIV], cortical and subcortical volumes, and cortical thickness). High and low cognitive reserve groups were defined by g and interrogated in a similar fashion. Results General mental ability (g) was significantly lower in JME than in controls and associated with a lower level of paternal education, greater disadvantage, smaller TIV and cortical and subcortical volumes, as well as with disruption of age‐appropriate cortical thinning in bifrontal lateral and medial regions. JME high and low g groups exhibited significantly different cognitive and academic profiles compared to controls, as well as to each other, with differences in familial and socioeconomic factors, as well as in brain morphological characteristics, all less favorable in the low compared to high g JME group. High g JME participants showed few differences compared to controls. Significance g is lower in JME than control participants and linked with definable features of familial and sociodemographic environment, as well as brain morphological patterns. g appears to provide an effective metric to characterize so‐called reserve for overall cognitive and academic function with associated brain structural features, notably the presence/absence of age‐appropriate cortical thinning in bifrontal regions. Plain language summary General mental ability, or g, is an important aspect of a person's cognitive ability. We found g to be lower in JME patients compared to controls and to be linked to features of their family, neighborhood, and brain. The protective effects of g could be shown by dividing participants into high and low g groups. High g participants exhibited few differences compared to controls, while, in contrast, low g participants showed poorer cognition, school performance, came from deprived neighborhoods, and had more problematic family features. Importantly, lower g was linked to measures of the brain, suggesting slowed neurodevelopment.

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model ( Scn1a   Stop/+ ) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Na v 1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells. Dravet syndrome is a devastating epileptic encephalopathy caused by Scn1a gene haploinsufficiency. Exploiting a novel knock-in mouse model, here the authors show that restoring Scn1a expression after symptom onset is sufficient to rescue main phenotypic manifestations of the syndrome.

Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2–52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Zogenix.