Prophecy or empiricism? Clinical value of predicting versus determining genetic variant functions.

The recent explosion of epilepsy genetic testing has created challenges for interpretation of gene variants. Assessments of the functional consequences of genetic variants either by predictive or experimental strategies can contribute to estimating pathogenicity, but there is no consensus on which approach is best. The Special Interest Group on Epilepsy Genetics hosted a session during the Annual American Epilepsy Society Meeting in December 2022 to discuss this topic. The session featured a debate of the relative advantages and limitations of predicting (prophecy) versus experimentally determining (empiricism) variant function using ion channel gene variants as examples. This commentary summarizes these discussions.

A somatic mutation in MEN1 gene detected in periventricular nodular heterotopia tissue obtained from depth electrodes.

Periventricular nodular heterotopia (PNH) is a common structural malformation of cortical development. Mutations in the filamin A gene are frequent in familial cases with X-linked PNH. However, many cases with sporadic PNH remain genetically unexplained. Although medically refractory epilepsy often brings attention to the underlying PNH, patients are often not candidates for surgical resection. This limits access to neuronal tissue harboring causal mutations. We evaluated a patient with PNH and medically refractory focal epilepsy who underwent a presurgical evaluation with stereotactically placed electroencephalographic (SEEG) depth electrodes. Following SEEG explantation, we collected trace tissue adherent to the electrodes and extracted the DNA. Whole-exome sequencing performed in a Clinical Laboratory Improvement Amendments-approved genetic diagnostic laboratory uncovered a de novo heterozygous pathogenic variant in novel candidate PNH gene MEN1 (multiple endocrine neoplasia type 1; c.1546dupC, p.R516PfsX15). The variant was absent in an earlier exome profiling of the venous blood-derived DNA. The MEN1 gene encodes the ubiquitously expressed, nuclear scaffold protein menin, a known tumor suppressor gene with an established role in the regulation of transcription, proliferation, differentiation, and genomic integrity. Our study contributes a novel candidate gene in PNH generation and a novel practical approach that integrates electrophysiological and genetic explorations of epilepsy.

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Observations in witnessed Sudden Unexpected Death in Epilepsy (SUDEP) suggest that a fatal breakdown of the central autonomic control could play a major role in SUDEP. A previous MR study found volume losses in the mesencephalon in focal epilepsy that were more severe and extended into the lower brainstem in two patients who later died of SUDEP. The aims of this study were to demonstrate an association (1) between brainstem volume loss and impaired autonomic control (reduced heart rate variability [HRV]); (2) between brainstem damage and time to SUDEP in patients who later died of SUDEP. Two populations were studied: (1) Autonomic system function population (ASF, 18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3 T MR exams. (2) SUDEP population (26 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion indicating significant volume loss or atrophy. The total number of regions with excessive expansion in ASF was negatively correlated with HRV (r = -.37, p = .03), excessive volume loss in periaqueductal gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r2 = -.82/.67, p < .001). The total number of regions with excessive expansion in SUDEP was negatively correlated with time to SUDEP (r = -.39, p = .03), excessive volume loss in the raphe/medulla oblongata at the obex level explained most of the variation of the time between MRI to SUDEP (r/r2 = -.60/.35,p = .001). Epilepsy is associated with brainstem atrophy that impairs autonomic control and can increase the risk for SUDEP if it expands into the mesencephalon.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention.

Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death.

Mechanisms of sudden unexplained death in epilepsy.

PURPOSE OF REVIEW: Human and experimental research has identified cardioautonomic and respiratory dysfunction as a frequent accompaniment in human and animal model events of sudden unexpected death in epilepsy (SUDEP). This review aims to provide an overview of the scientific evidence behind the currently accepted risk factors and working hypotheses regarding SUDEP pathophysiology. RECENT FINDINGS: Epidemiological analysis of public health burden of SUDEP has shown that it rates second only to stroke in the years of potential life lost. Clinical and experimental studies uncovered the dynamic cardiorespiratory dysfunction interictally and imminently to SUDEP, and model systems have facilitated discoveries in SUDEP mechanistic understanding and application of pilot therapeutic interventions. Pilot molecular profiling of human SUDEP has uncovered complex genomic structure in the candidate gene network. SUMMARY: Extensive clinical and experimental work has established a rationale for the conceptual thinking about SUDEP mechanisms. The application of the global molecular profiling will be invaluable in unraveling the individually unique genomic complexities and interactions that underlie the physiological signature of each patient. At the same time, sophisticated model systems will be critical in the iterative translation of human genetics, physiology, pharmacological interventions, and in testing preventive interventions.

Benchmarking signal quality and spatiotemporal distribution of interictal spikes in prolonged human iEEG recordings using CorTec wireless brain interchange.

Neuromodulation through implantable pulse generators (IPGs) represents an important treatment approach for neurological disorders. While the field has observed the success of state-of-the-art interventions, such as deep brain stimulation (DBS) or responsive neurostimulation (RNS), implantable systems face various technical challenges, including the restriction of recording from a limited number of brain sites, power management, and limited external access to the assessed neural data in a continuous fashion. To the best of our knowledge, for the first time in this study, we investigated the feasibility of recording human intracranial EEG (iEEG) using a benchtop version of the Brain Interchange (BIC) unit of CorTec, which is a portable, wireless, and externally powered implant with sensing and stimulation capabilities. We developed a MATLAB/SIMULINK-based rapid prototyping environment and a graphical user interface (GUI) to acquire and visualize the iEEG captured from all 32 channels of the BIC unit. We recorded prolonged iEEG (~ 24 h) from three human subjects with externalized depth leads using the BIC and commercially available clinical amplifiers simultaneously in the epilepsy monitoring unit (EMU). The iEEG signal quality of both streams was compared, and the results demonstrated a comparable power spectral density (PSD) in all the systems in the low-frequency band (< 80 Hz). However, notable differences were primarily observed above 100 Hz, where the clinical amplifiers were associated with lower noise floor (BIC-17 dB vs. clinical amplifiers < - 25 dB). We employed an established spike detector to assess and compare the spike rates in each iEEG stream. We observed over 90% conformity between the spikes rates and their spatial distribution captured with BIC and clinical systems. Additionally, we quantified the packet loss characteristic in the iEEG signal during the wireless data transfer and conducted a series of simulations to compare the performance of different interpolation methods for recovering the missing packets in signals at different frequency bands. We noted that simple linear interpolation has the potential to recover the signal and reduce the noise floor with modest packet loss levels reaching up to 10%. Overall, our results indicate that while tethered clinical amplifiers exhibited noticeably better noise floor above 80 Hz, epileptic spikes can still be detected successfully in the iEEG recorded with the externally powered wireless BIC unit opening the road for future closed-loop neuromodulation applications with continuous access to brain activity.

SCN1A testing for epilepsy: application in clinical practice.

This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage-gated sodium channels (protein name: Nav 1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions; therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.

Epigenetic genes and epilepsy - emerging mechanisms and clinical applications.

An increasing number of epilepsies are being attributed to variants in genes with epigenetic functions. The products of these genes include factors that regulate the structure and function of chromatin and the placing, reading and removal of epigenetic marks, as well as other epigenetic processes. In this Review, we provide an overview of the various epigenetic processes, structuring our discussion around five function-based categories: DNA methylation, histone modifications, histone-DNA crosstalk, non-coding RNAs and chromatin remodelling. We provide background information on each category, describing the general mechanism by which each process leads to altered gene expression. We also highlight key clinical and mechanistic aspects, providing examples of genes that strongly associate with epilepsy within each class. We consider the practical applications of these findings, including tissue-based and biofluid-based diagnostics and precision medicine-based treatments. We conclude that variants in epigenetic genes are increasingly found to be causally involved in the epilepsies, with implications for disease mechanisms, treatments and diagnostics.

To share or not to share: a randomized trial of consent for data sharing in genome research.

PURPOSE: Despite growing concerns toward maintaining participants' privacy, individual investigators collecting tissue and other biological specimens for genomic analysis are encouraged to obtain informed consent for broad data sharing. Our purpose was to assess the effect on research enrollment and data sharing decisions of three different consent types (traditional, binary, or tiered) with varying levels of control and choices regarding data sharing. METHODS: A single-blinded, randomized controlled trial was conducted with 323 eligible adult participants being recruited into one of six genome studies at Baylor College of Medicine in Houston, Texas, between January 2008 and August 2009. Participants were randomly assigned to one of three experimental consent documents (traditional, n = 110; binary, n = 103; and tiered, n = 110). Debriefing in follow-up visits provided participants a detailed review of all consent types and the chance to change data sharing choices or decline genome study participation. RESULTS: Before debriefing, 83.9% of participants chose public data release. After debriefing, 53.1% chose public data release, 33.1% chose restricted (controlled access database) release, and 13.7% opted out of data sharing. Only one participant declined genome study participation due to data sharing concerns. CONCLUSION: Our findings indicate that most participants are willing to publicly release their genomic data; however, a significant portion prefers restricted release. These results suggest discordance between existing data sharing policies and participants' judgments and desires.

X-linked serotonin 2C receptor is associated with a non-canonical pathway for sudden unexpected death in epilepsy.

Sudden Unexpected Death in Epilepsy is a leading cause of epilepsy-related mortality, and the analysis of mouse Sudden Unexpected Death in Epilepsy models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. Serotonin (5-HT) signalling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of Sudden Unexpected Death in Epilepsy. Most monogenic models of Sudden Unexpected Death in Epilepsy invoke a failure of inhibitory synaptic drive as a critical pathogenic step. Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Here, we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioural seizures culminating in late onset sudden mortality predominantly in male mice. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. Analysis of human Sudden Unexpected Death in Epilepsy and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in Sudden Unexpected Death in Epilepsy cases. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying Sudden Unexpected Death in Epilepsy risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. These results strengthen the evidence for the serotonin hypothesis of Sudden Unexpected Death in Epilepsy risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy.

Epigenetics explained: a topic "primer" for the epilepsy community by the ILAE Genetics/Epigenetics Task Force.

Epigenetics refers broadly to processes that influence medium to long-term gene expression by changing the readability and accessibility of the genetic code. The Neurobiology Commission of the International League Against Epilepsy (ILAE) recently convened a Task Force to explore and disseminate advances in epigenetics to better understand their role and intersection with genetics and the neurobiology of epilepsies and their co-morbidities, and to accelerate translation of these findings into the development of better therapies. Here, we provide a topic primer on epigenetics, explaining the key processes and findings to date in experimental and human epilepsy. We review the growing list of genes with epigenetic functions that have been linked with epilepsy in humans. We consider potential practical applications, including using epigenetic signals as biomarkers for tissue- and biofluid-based diagnostics and the prospects for developing epigenetic-based treatments for epilepsy. We include a glossary of terms, FAQs and other supports to facilitate a broad understanding of the topic for the non-expert. Last, we review the limitations, research gaps and the next challenges. In summary, epigenetic processes represent important mechanisms controlling the activity of genes, providing opportunities for insight into disease mechanisms, biomarkers and novel therapies for epilepsy.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Spectrum and time course of epilepsy and the associated cognitive decline in MECP2 duplication syndrome.

OBJECTIVE: We characterized the epilepsy features and contribution to cognitive regression in 47 patients with MECP2 duplication syndrome (MDS) and reviewed these characteristics in over 280 MDS published cases. METHODS: The institutional review board approved this retrospective review of medical records and case histories of patients with MDS. RESULTS: The average age at enrollment was 10 ± 7 years. Patients with epilepsy were older (13 ± 7 years vs 8 ± 5 years, p = 0.004) and followed for a longer time (11.8 ± 6.5 years vs 6.3 ± 4.2 years, p = 0.003) than patients without a seizure disorder. Epilepsy affected 22/47 (47%) patients with MDS. It was treatment-refractory and consistent with epileptic encephalopathy in 18/22 (82%) cases. Lennox-Gastaut syndrome (LGS) was present in 12/22 (55%) patients and manifested between late childhood and adulthood in 83% of cases. The emergence of neurologic regression coincided with the onset of epilepsy. The MECP2 duplication size and gene content did not correlate with epilepsy presence, type, age at onset, or treatment responsiveness. CONCLUSION: Epilepsy in MDS is common, often severe, and medically refractory. LGS occurs frequently and may have a late onset. Developmental regression often follows the onset of epilepsy. The MECP2 duplication extent and gene content do not discriminate between patients with or without epilepsy. Our findings inform clinical care and family counseling with respect to early epilepsy recognition, diagnosis, specialty referral, and implementation of aggressive seizure therapy to minimize detrimental effect of uncontrolled seizures on cognitive functions or preexisting neurologic deficits.

Brainstem atrophy in focal epilepsy destabilizes brainstem-brain interactions: Preliminary findings.

BACKGROUND: MR Imaging has shown atrophy in brainstem regions that were linked to autonomic dysfunction in epilepsy patients. The brainstem projects to and modulates the activation state of several wide-spread cortical/subcortical regions. The goal was to investigate 1. Impact of brainstem atrophy on gray matter connectivity of cortical/subcortical structures and autonomic control. 2. Impact on the modulation of cortical/subcortical functional connectivity. METHODS: 11 controls and 18 patients with non-lesional focal epilepsy (FE) underwent heart rate variability (HRV) measurements and a 3 T MRI (T1 in all subjects, task-free fMRI in 7 controls/ 12 FE). The brainstem was extracted, and atrophy assessed using deformation-based-morphometry. The age-corrected z-scores of the mean Jacobian determinants were extracted from 71 5x5x5 mm grids placed in brainstem regions associated with autonomic function. Cortical and non-brainstem subcortical gray matter atrophy was assessed with voxel-based-morphometry and mean age corrected z-scores of the modulated gray matter volumes extracted from 380 cortical/subcortical rois. The profile similarity index was used to characterize the impact of brainstem atrophy on gray matter connectivity. The fMRI was preprocessed in SPM12/Conn17 and the BOLD signal extracted from 398 ROIs (16 brainstem). A dynamic task-free analysis approach was used to identify activation states. Connectivity HRV relationship were assessed with Spearman rank correlations. RESULTS: HRV was negatively correlated with reduced brainstem right hippocampus/parahippocampus gray matter connectivity in controls (p < .05, FDR) and reduced brainstem to right parietal cortex, lingual gyrus, left hippocampus/amygdala, parahippocampus, temporal pole, and bilateral anterior thalamus connectivity in FE (p < .05, FDR). Dynamic task-free fMRI analysis identified 22 states. The strength of the functional brainstem/cortical connectivity of state 15 was negatively associated with HRV (r = -0.5, p = .03) and positively with decreased brainstem-cortical (0.49, p = .03) gray matter connectivity. CONCLUSION: The findings of this small pilot study suggest that impaired brainstem-cortex gray matter connectivity in FE negatively affects the brainstem's ability to control cortical activation.

De novo missense variant in the GTPase effector domain (GED) of DNM1L leads to static encephalopathy and seizures.

DNM1L encodes a GTPase of the dynamin superfamily, which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of DNM1L have been implicated in encephalopathy because of defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27-yr-old woman with static encephalopathy, a history of seizures, and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase effector domain (GED) of DNM1L (c.2072A>G, p.Tyr691Cys). Functional studies in Drosophila demonstrate large, abnormally distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of DNM1L-related disorders.

Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes.

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A, resulting in Nav1.1 haploinsufficiency. Because SCN1A is expressed in heart and in brain, we proposed that cardiac arrhythmia contributes to SUDEP in DS. We generated DS patient and control induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). We observed increased sodium current (INa) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in INa, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased INa density in iPSC-CMs similar to that seen in patient cells. Thus, the high risk of SUDEP in DS may result from a predisposition to cardiac arrhythmias in addition to seizures, reflecting expression of SCN1A in heart and brain.