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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.

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.

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.

Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.

Mutations in the SCN1A gene, which encodes for the voltage-gated sodium channel NaV1.1, cause Dravet syndrome, a severe developmental and epileptic encephalopathy. Genetic testing of this gene is recommended early in life. However, predicting the outcome of de novo missense SCN1A mutations is difficult, since milder epileptic syndromes may also be associated. In this study, we correlated clinical severity with functional in vitro electrophysiological testing of channel activity and bioinformatics prediction of damaging mutational effects. Three patients, bearing the mutations p.Gly177Ala, p.Ser259Arg and p.Glu1923Arg, showed frequent intractable seizures that had started early in life, with cognitive and behavioral deterioration, consistent with classical Dravet phenotypes. These mutations failed to produce measurable sodium currents in a mammalian expression system, indicating complete loss of channel function. A fourth patient, who harbored the mutation p.Met1267Ile, though presenting with seizures early in life, showed lower seizure burden and higher cognitive function, matching borderland Dravet phenotypes. In correlation with this, functional analysis demonstrated the presence of sodium currents, but with partial loss of function. In contrast, six bioinformatics tools for predicting mutational pathogenicity suggested similar impact for all mutations. Likewise, homology modeling of the secondary and tertiary structures failed to reveal misfolding. In conclusion, functional studies using patch clamp are suggested as a prognostic tool, whereby detectable currents imply milder phenotypes and absence of currents indicate an unfavorable prognosis. Future development of automated patch clamp systems will facilitate the inclusion of such functional testing as part of personalized patient diagnostic schemes.

The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising.