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1. Whole genome sequencing identifies putative associations between genomic polymorphisms and clinical response to the antiepileptic drug levetiracetam

Author: Vavoulis, DV, Pagnamenta, AT, Knight, SJL, Pentony, MM, Armstrong, M, Galizia, EC, Balestrini, S, Sisodiya, SM, and Taylor, JC
Subjects: Quantitative Biology - Genomics
Abstract: In the context of pharmacogenomics, whole genome sequencing provides a powerful approach for identifying correlations between response variability to specific drugs and genomic polymorphisms in a population, in an unbiased manner. In this study, we employed whole genome sequencing of DNA samples from patients showing extreme response (n=72) and non-response (n=27) to the antiepileptic drug levetiracetam, in order to identify genomic variants that underlie response to the drug. Although no common SNP (MAF>5%) crossed the conventional genome-wide significance threshold of 5e-8, we found common polymorphisms in genes SPNS3, HDC, MDGA2, NSG1 and RASGEF1C, which collectively predict clinical response to levetiracetam in our cohort with ~91% predictive accuracy. Among these genes, HDC, NSG1, MDGA2 and RASGEF1C are potentially implicated in synaptic neurotransmission, while SPNS3 is an atypical solute carrier transporter homologous to SV2A, the known molecular target of levetiracetam. Furthermore, we performed gene- and pathway-based statistical analysis on sets of rare and low-frequency variants (MAF<5%) and we identified associations between the following genes or pathways and response to levetiracetam: a) genes PRKCB and DLG2, which are involved in glutamatergic neurotransmission, a known target of anticonvulsants, including levetiracetam; b) genes FILIP1 and SEMA6D, which are involved in axon guidance and modelling of neural connections; and c) pathways with a role in synaptic neurotransmission, such as WNT5A-dependent internalization of FZD4 and disinhibition of SNARE formation. In summary, our approach to utilise whole genome sequencing on subjects with extreme response phenotypes is a feasible route to generate plausible hypotheses for investigating the genetic factors underlying drug response variability in cases of pharmaco-resistant epilepsy.
Published: 2019

2. National compliance with UK wide guidelines for usage of valproate in women of childbearing potential

Author: Eriksson, SH, Tittensor, P, and Sisodiya, SM
Published: 2022
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3. The phenotypic continuum of ATPLA3-related disorders

Author: Vezyroglou, A, Akilapa, R, Barwick, K, Koene, S, Brownstein, CA, Holder-Espinasse, M, Fry, AE, Nemeth, AH, Tofaris, GK, Hay, E, Hughes, I, Mansour, S, Mordekar, SR, Splitt, M, Turnpenny, PD, Demetriou, D, Koopmann, TT, Ruivenkamp, CAL, Agrawal, PB, Carr, L, Clowes, V, Ghali, N, Holder, SE, Radley, J, Male, A, Sisodiya, SM, Kurian, MA, Cross, JH, and Balasubramanian, M
Abstract: Background and Objectives ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. Methods Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term “ATP1A3” from 2004 to 2021. Results Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2–3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint. Discussion Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.
Published: 2022

4. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Author: Campbell, C, McCormack, M, Patel, S, Stapleton, C, Bobbili, D, Krause, R, Depondt, C, Sills, GJ, Koeleman, BP, Striano, P, Zara, F, Sander, JW, Lerche, H, Kunz, WS, Stefansson, K, Stefansson, H, Doherty, CP, Heinzen, EL, Scheffer, IE, Goldstein, DB, O'Brien, T, Cotter, D, Berkovic, SF, Sisodiya, SM, Delanty, N, Cavalleri, GL, Campbell, C, McCormack, M, Patel, S, Stapleton, C, Bobbili, D, Krause, R, Depondt, C, Sills, GJ, Koeleman, BP, Striano, P, Zara, F, Sander, JW, Lerche, H, Kunz, WS, Stefansson, K, Stefansson, H, Doherty, CP, Heinzen, EL, Scheffer, IE, Goldstein, DB, O'Brien, T, Cotter, D, Berkovic, SF, Sisodiya, SM, Delanty, N, and Cavalleri, GL
Abstract: OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.
Published: 2022

5. Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy

Author: Park, B-Y, Lariviere, S, Rodriguez-Cruces, R, Royer, J, Tavakol, S, Wang, Y, Caciagli, L, Caligiuri, ME, Gambardella, A, Concha, L, Keller, SS, Cendes, F, Alvim, MKM, Yasuda, C, Bonilha, L, Gleichgerrcht, E, Focke, NK, Kreilkamp, BAK, Domin, M, von Podewils, F, Langner, S, Rummel, C, Rebsamen, M, Wiest, R, Martin, P, Kotikalapudi, R, Bender, B, O'Brien, TJ, Law, M, Sinclair, B, Vivash, L, Kwan, P, Desmond, PM, Malpas, CB, Lui, E, Alhusaini, S, Doherty, CP, Cavalleri, GL, Delanty, N, Kalviainen, R, Jackson, GD, Kowalczyk, M, Mascalchi, M, Semmelroch, M, Thomas, RH, Soltanian-Zadeh, H, Davoodi-Bojd, E, Zhang, J, Lenge, M, Guerrini, R, Bartolini, E, Hamandi, K, Foley, S, Weber, B, Depondt, C, Absil, J, Carr, SJA, Abela, E, Richardson, MP, Devinsky, O, Severino, M, Striano, P, Parodi, C, Tortora, D, Hatton, SN, Vos, SB, Duncan, JS, Galovic, M, Whelan, CD, Bargallo, N, Pariente, J, Conde-Blanco, E, Vaudano, AE, Tondelli, M, Meletti, S, Kong, X-Z, Francks, C, Fisher, SE, Caldairou, B, Ryten, M, Labate, A, Sisodiya, SM, Thompson, PM, McDonald, CR, Bernasconi, A, Bernasconi, N, Bernhardt, BC, Park, B-Y, Lariviere, S, Rodriguez-Cruces, R, Royer, J, Tavakol, S, Wang, Y, Caciagli, L, Caligiuri, ME, Gambardella, A, Concha, L, Keller, SS, Cendes, F, Alvim, MKM, Yasuda, C, Bonilha, L, Gleichgerrcht, E, Focke, NK, Kreilkamp, BAK, Domin, M, von Podewils, F, Langner, S, Rummel, C, Rebsamen, M, Wiest, R, Martin, P, Kotikalapudi, R, Bender, B, O'Brien, TJ, Law, M, Sinclair, B, Vivash, L, Kwan, P, Desmond, PM, Malpas, CB, Lui, E, Alhusaini, S, Doherty, CP, Cavalleri, GL, Delanty, N, Kalviainen, R, Jackson, GD, Kowalczyk, M, Mascalchi, M, Semmelroch, M, Thomas, RH, Soltanian-Zadeh, H, Davoodi-Bojd, E, Zhang, J, Lenge, M, Guerrini, R, Bartolini, E, Hamandi, K, Foley, S, Weber, B, Depondt, C, Absil, J, Carr, SJA, Abela, E, Richardson, MP, Devinsky, O, Severino, M, Striano, P, Parodi, C, Tortora, D, Hatton, SN, Vos, SB, Duncan, JS, Galovic, M, Whelan, CD, Bargallo, N, Pariente, J, Conde-Blanco, E, Vaudano, AE, Tondelli, M, Meletti, S, Kong, X-Z, Francks, C, Fisher, SE, Caldairou, B, Ryten, M, Labate, A, Sisodiya, SM, Thompson, PM, McDonald, CR, Bernasconi, A, Bernasconi, N, and Bernhardt, BC
Abstract: Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine ou
Published: 2022

6. Local molecular and global connectomic contributions to cross-disorder cortical abnormalities.

Author: Hansen, JY, Shafiei, G, Vogel, JW, Smart, K, Bearden, CE, Hoogman, M, Franke, B, van Rooij, D, Buitelaar, J, McDonald, CR, Sisodiya, SM, Schmaal, L, Veltman, DJ, van den Heuvel, OA, Stein, DJ, van Erp, TGM, Ching, CRK, Andreassen, OA, Hajek, T, Opel, N, Modinos, G, Aleman, A, van der Werf, Y, Jahanshad, N, Thomopoulos, SI, Thompson, PM, Carson, RE, Dagher, A, Misic, B, Hansen, JY, Shafiei, G, Vogel, JW, Smart, K, Bearden, CE, Hoogman, M, Franke, B, van Rooij, D, Buitelaar, J, McDonald, CR, Sisodiya, SM, Schmaal, L, Veltman, DJ, van den Heuvel, OA, Stein, DJ, van Erp, TGM, Ching, CRK, Andreassen, OA, Hajek, T, Opel, N, Modinos, G, Aleman, A, van der Werf, Y, Jahanshad, N, Thomopoulos, SI, Thompson, PM, Carson, RE, Dagher, A, and Misic, B
Abstract: Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.
Published: 2022

7. Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression

Author: Lariviere, S, Royer, J, Rodriguez-Cruces, R, Paquola, C, Caligiuri, ME, Gambardella, A, Concha, L, Keller, SS, Cendes, F, Yasuda, CL, Bonilha, L, Gleichgerrcht, E, Focke, NK, Domin, M, von Podewills, F, Langner, S, Rummel, C, Wiest, R, Martin, P, Kotikalapudi, R, O'Brien, TJ, Sinclair, B, Vivash, L, Desmond, PM, Lui, E, Vaudano, AE, Meletti, S, Tondelli, M, Alhusaini, S, Doherty, CP, Cavalleri, GL, Delanty, N, Kalviainen, R, Jackson, GD, Kowalczyk, M, Mascalchi, M, Semmelroch, M, Thomas, RH, Soltanian-Zadeh, H, Davoodi-Bojd, E, Zhang, J, Winston, GP, Griffin, A, Singh, A, Tiwari, VK, Kreilkamp, BAK, Lenge, M, Guerrini, R, Hamandi, K, Foley, S, Ruber, T, Weber, B, Depondt, C, Absil, J, Carr, SJA, Abela, E, Richardson, MP, Devinsky, O, Severino, M, Striano, P, Tortora, D, Kaestner, E, Hatton, SN, Vos, SB, Caciagli, L, Duncan, JS, Whelan, CD, Thompson, PM, Sisodiya, SM, Bernasconi, A, Labate, A, McDonald, CR, Bernasconi, N, Bernhardt, BC, Lariviere, S, Royer, J, Rodriguez-Cruces, R, Paquola, C, Caligiuri, ME, Gambardella, A, Concha, L, Keller, SS, Cendes, F, Yasuda, CL, Bonilha, L, Gleichgerrcht, E, Focke, NK, Domin, M, von Podewills, F, Langner, S, Rummel, C, Wiest, R, Martin, P, Kotikalapudi, R, O'Brien, TJ, Sinclair, B, Vivash, L, Desmond, PM, Lui, E, Vaudano, AE, Meletti, S, Tondelli, M, Alhusaini, S, Doherty, CP, Cavalleri, GL, Delanty, N, Kalviainen, R, Jackson, GD, Kowalczyk, M, Mascalchi, M, Semmelroch, M, Thomas, RH, Soltanian-Zadeh, H, Davoodi-Bojd, E, Zhang, J, Winston, GP, Griffin, A, Singh, A, Tiwari, VK, Kreilkamp, BAK, Lenge, M, Guerrini, R, Hamandi, K, Foley, S, Ruber, T, Weber, B, Depondt, C, Absil, J, Carr, SJA, Abela, E, Richardson, MP, Devinsky, O, Severino, M, Striano, P, Tortora, D, Kaestner, E, Hatton, SN, Vos, SB, Caciagli, L, Duncan, JS, Whelan, CD, Thompson, PM, Sisodiya, SM, Bernasconi, A, Labate, A, McDonald, CR, Bernasconi, N, and Bernhardt, BC
Abstract: Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.
Published: 2022

8. A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure

Author: Grinton, BE, Robertson, E, Fearnley, LG, Scheffer, IE, Marson, AG, O'Brien, TJ, Pickrell, WO, Rees, M, Sisodiya, SM, Balding, DJ, Bennett, MF, Bahlo, M, Berkovic, SF, Oliver, KL, Grinton, BE, Robertson, E, Fearnley, LG, Scheffer, IE, Marson, AG, O'Brien, TJ, Pickrell, WO, Rees, M, Sisodiya, SM, Balding, DJ, Bennett, MF, Bahlo, M, Berkovic, SF, and Oliver, KL
Abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.
Published: 2022

9. Cortical myoclonus and epilepsy in a family with a new SLC20A2 mutation

Author: Coppola A, Hernandez-Hernandez L, Balestrini S, Krithika S, Moran N, Hale B, Cordivari C, Sisodiya SM, Coppola, A, Hernandez-Hernandez, L, Balestrini, S, Krithika, S, Moran, N, Hale, B, Cordivari, C, and Sisodiya, Sm
Published: 2020

10. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author: Sonderby, IE, van der Meer, D, Moreau, C, Kaufmann, T, Walters, GB, Ellegaard, M, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Buelow, R, Boen, R, Cahn, W, Calhoun, VD, Caspers, S, Ching, CRK, Cichon, S, Ciufolini, S, Crespo-Facorro, B, Curran, JE, Dale, AM, Dalvie, S, Dazzan, P, de Geus, EJC, de Zubicaray, GI, de Zwarte, SMC, Desrivieres, S, Doherty, JL, Donohoe, G, Draganski, B, Ehrlich, S, Eising, E, Espeseth, T, Fejgin, K, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Ge, T, Glahn, DC, Grabe, HJ, Groenewold, NA, Gustafsson, O, Haavik, J, Haberg, AK, Hall, J, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Holmes, AJ, Homuth, G, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jahanshad, N, Jockwitz, C, Johansson, S, Joensson, EG, Jorgensen, NR, Kikuchi, M, Knowles, EEM, Kumar, K, Le Hellard, S, Leu, C, Linden, DEJ, Liu, J, Lundervold, A, Lundervold, AJ, Maillard, AM, Martin, NG, Martin-Brevet, S, Mather, KA, Mathias, SR, McMahon, KL, McRae, AF, Medland, SE, Meyer-Lindenberg, A, Moberget, T, Modenato, C, Sanchez, JM, Morris, DW, Muehleisen, TW, Murray, RM, Nielsen, J, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, GB, Prieto, C, Quinlan, EB, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Schork, AJ, Schumann, G, Shin, J, Shumskaya, E, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Suzuki, IK, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, van 't Ent, D, van den Bree, MBM, Vanderhaeghen, P, Vassos, E, Wen, W, Wittfeld, K, Wright, MJ, Agartz, I, Djurovic, S, Westlye, LT, Stefansson, H, Stefansson, K, Jacquemont, S, Thompson, PM, Andreassen, OA, Sonderby, IE, van der Meer, D, Moreau, C, Kaufmann, T, Walters, GB, Ellegaard, M, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Buelow, R, Boen, R, Cahn, W, Calhoun, VD, Caspers, S, Ching, CRK, Cichon, S, Ciufolini, S, Crespo-Facorro, B, Curran, JE, Dale, AM, Dalvie, S, Dazzan, P, de Geus, EJC, de Zubicaray, GI, de Zwarte, SMC, Desrivieres, S, Doherty, JL, Donohoe, G, Draganski, B, Ehrlich, S, Eising, E, Espeseth, T, Fejgin, K, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Ge, T, Glahn, DC, Grabe, HJ, Groenewold, NA, Gustafsson, O, Haavik, J, Haberg, AK, Hall, J, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Holmes, AJ, Homuth, G, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jahanshad, N, Jockwitz, C, Johansson, S, Joensson, EG, Jorgensen, NR, Kikuchi, M, Knowles, EEM, Kumar, K, Le Hellard, S, Leu, C, Linden, DEJ, Liu, J, Lundervold, A, Lundervold, AJ, Maillard, AM, Martin, NG, Martin-Brevet, S, Mather, KA, Mathias, SR, McMahon, KL, McRae, AF, Medland, SE, Meyer-Lindenberg, A, Moberget, T, Modenato, C, Sanchez, JM, Morris, DW, Muehleisen, TW, Murray, RM, Nielsen, J, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, GB, Prieto, C, Quinlan, EB, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Schork, AJ, Schumann, G, Shin, J, Shumskaya, E, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Suzuki, IK, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, van 't Ent, D, van den Bree, MBM, Vanderhaeghen, P, Vassos, E, Wen, W, Wittfeld, K, Wright, MJ, Agartz, I, Djurovic, S, Westlye, LT, Stefansson, H, Stefansson, K, Jacquemont, S, Thompson, PM, and Andreassen, OA
Abstract: Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
Published: 2021

11. Climate change and epilepsy: Insights from clinical and basic science studies

Author: Gulcebi, M, Bartolini, E, Lee, O, Lisgaras, CP, Onat, F, Mifsud, J, Striano, P, Vezzani, A, Hildebrand, MS, Jimenez-Jimenez, D, Junck, L, Lewis-Smith, D, Scheffer, IE, Thijs, RD, Zuberi, SM, Blenkinsop, S, Fowler, HJ, Foley, A, Sisodiya, SM, Balestrini, S, Berkovic, S, Cavalleri, G, Correa, DJ, Custodio, HM, Galovic, M, Guerrini, R, Henshall, D, Howard, O, Hughes, K, Katsarou, A, Koeleman, BPC, Krause, R, Lowenstein, D, Mandelenaki, D, Marini, C, O'Brien, TJ, Pace, A, De Palma, L, Perucca, P, Pitkanen, A, Quinn, F, Selmer, KK, Steward, CA, Swanborough, N, Thijs, R, Tittensor, P, Trivisano, M, Weckhuysen, S, Zara, F, Gulcebi, M, Bartolini, E, Lee, O, Lisgaras, CP, Onat, F, Mifsud, J, Striano, P, Vezzani, A, Hildebrand, MS, Jimenez-Jimenez, D, Junck, L, Lewis-Smith, D, Scheffer, IE, Thijs, RD, Zuberi, SM, Blenkinsop, S, Fowler, HJ, Foley, A, Sisodiya, SM, Balestrini, S, Berkovic, S, Cavalleri, G, Correa, DJ, Custodio, HM, Galovic, M, Guerrini, R, Henshall, D, Howard, O, Hughes, K, Katsarou, A, Koeleman, BPC, Krause, R, Lowenstein, D, Mandelenaki, D, Marini, C, O'Brien, TJ, Pace, A, De Palma, L, Perucca, P, Pitkanen, A, Quinn, F, Selmer, KK, Steward, CA, Swanborough, N, Thijs, R, Tittensor, P, Trivisano, M, Weckhuysen, S, and Zara, F
Abstract: Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, compl
Published: 2021

12. Postictal Psychosis in Epilepsy: A Clinicogenetic Study

Author: Braatz, V, Custodio, HM, Leu, C, Agro, L, Wang, B, Calafato, S, Rayner, G, Doyle, MG, Hengsbach, C, Bisulli, F, Weber, YG, Gambardella, A, Delanty, N, Cavalleri, G, Foong, J, Scheffer, IE, Berkovic, SF, Bramon, E, Balestrini, S, Sisodiya, SM, Braatz, V, Custodio, HM, Leu, C, Agro, L, Wang, B, Calafato, S, Rayner, G, Doyle, MG, Hengsbach, C, Bisulli, F, Weber, YG, Gambardella, A, Delanty, N, Cavalleri, G, Foong, J, Scheffer, IE, Berkovic, SF, Bramon, E, Balestrini, S, and Sisodiya, SM
Abstract: OBJECTIVE: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy-related psychoses, and has unknown causation. METHODS: We conducted a case-control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis; 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis; univariate associations with a p value < 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated. RESULTS: Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p < 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls (R2 = 3%, p = 6 × 10-3 ), but not significantly different from 945 independent patients with schizophrenia (R2 = 0.1%, p = 0.775). INTERPRETATION: Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021;90:464-476.
Published: 2021

13. A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies

Author: Altmann, A, Ryten, M, Di Nunzio, M, Ravizza, T, Tolomeo, D, Reynolds, RH, Somani, A, Bacigaluppi, M, Iori, V, Micotti, E, Di Sapia, R, Cerovic, M, Palma, E, Ruffolo, G, Botia, JA, Absil, J, Alhusaini, S, Alvim, MKM, Auvinen, P, Bargallo, N, Bartolini, E, Bender, B, Bergo, FPG, Bernardes, T, Bernasconi, A, Bernasconi, N, Bernhardt, BC, Blackmon, K, Braga, B, Caligiuri, ME, Calvo, A, Carlson, C, Carr, SJA, Cavalleri, GL, Cendes, F, Chen, J, Chen, S, Cherubini, A, Concha, L, David, P, Delanty, N, Depondt, C, Devinsky, O, Doherty, CP, Domin, M, Focke, NK, Foley, S, Franca, W, Gambardella, A, Guerrini, R, Hamandi, K, Hibar, DP, Isaev, D, Jackson, GD, Jahanshad, N, Kalviainen, R, Keller, SS, Kochunov, P, Kotikalapudi, R, Kowalczyk, MA, Kuzniecky, R, Kwan, P, Labate, A, Langner, S, Lenge, M, Liu, M, Martin, P, Mascalchi, M, Meletti, S, Morita-Sherman, ME, O'Brien, TJ, Pariente, JC, Richardson, MP, Rodriguez-Cruces, R, Rummel, C, Saavalainen, T, Semmelroch, MK, Severino, M, Striano, P, Thesen, T, Thomas, RH, Tondelli, M, Tortora, D, Vaudano, AE, Vivash, L, Podewils, F, Wagner, J, Weber, B, Wiest, R, Yasuda, CL, Zhang, G, Zhang, J, Leu, C, Avbersek, A, Thom, M, Whelan, CD, Thompson, P, McDonald, CR, Vezzani, A, Sisodiya, SM, Altmann, A, Ryten, M, Di Nunzio, M, Ravizza, T, Tolomeo, D, Reynolds, RH, Somani, A, Bacigaluppi, M, Iori, V, Micotti, E, Di Sapia, R, Cerovic, M, Palma, E, Ruffolo, G, Botia, JA, Absil, J, Alhusaini, S, Alvim, MKM, Auvinen, P, Bargallo, N, Bartolini, E, Bender, B, Bergo, FPG, Bernardes, T, Bernasconi, A, Bernasconi, N, Bernhardt, BC, Blackmon, K, Braga, B, Caligiuri, ME, Calvo, A, Carlson, C, Carr, SJA, Cavalleri, GL, Cendes, F, Chen, J, Chen, S, Cherubini, A, Concha, L, David, P, Delanty, N, Depondt, C, Devinsky, O, Doherty, CP, Domin, M, Focke, NK, Foley, S, Franca, W, Gambardella, A, Guerrini, R, Hamandi, K, Hibar, DP, Isaev, D, Jackson, GD, Jahanshad, N, Kalviainen, R, Keller, SS, Kochunov, P, Kotikalapudi, R, Kowalczyk, MA, Kuzniecky, R, Kwan, P, Labate, A, Langner, S, Lenge, M, Liu, M, Martin, P, Mascalchi, M, Meletti, S, Morita-Sherman, ME, O'Brien, TJ, Pariente, JC, Richardson, MP, Rodriguez-Cruces, R, Rummel, C, Saavalainen, T, Semmelroch, MK, Severino, M, Striano, P, Thesen, T, Thomas, RH, Tondelli, M, Tortora, D, Vaudano, AE, Vivash, L, Podewils, F, Wagner, J, Weber, B, Wiest, R, Yasuda, CL, Zhang, G, Zhang, J, Leu, C, Avbersek, A, Thom, M, Whelan, CD, Thompson, P, McDonald, CR, Vezzani, A, and Sisodiya, SM
Abstract: AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
Published: 2021

14. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author: Wolking, S, Moreau, C, McCormack, M, Krause, R, Krenn, M, Berkovic, S, Cavalleri, GL, Delanty, N, Depondt, C, Johnson, MR, Koeleman, BPC, Kunz, WS, Lerche, H, Marson, AG, O'Brien, TJ, Petrovski, S, Sander, JW, Sills, GJ, Striano, P, Zara, F, Zimprich, F, Sisodiya, SM, Girard, SL, Cossette, P, Wolking, S, Moreau, C, McCormack, M, Krause, R, Krenn, M, Berkovic, S, Cavalleri, GL, Delanty, N, Depondt, C, Johnson, MR, Koeleman, BPC, Kunz, WS, Lerche, H, Marson, AG, O'Brien, TJ, Petrovski, S, Sander, JW, Sills, GJ, Striano, P, Zara, F, Zimprich, F, Sisodiya, SM, Girard, SL, and Cossette, P
Abstract: OBJECTIVE: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. METHODS: We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. RESULTS: We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes - among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. INTERPRETATION: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.
Published: 2021

15. Structural brain imaging studies offer clues about the effects of the shared genetic etiology among neuropsychiatric disorders

Author: Radonjic, NV, Hess, JL, Rovira, P, Andreassen, O, Buitelaar, JK, Ching, CRK, Franke, B, Hoogman, M, Jahanshad, N, McDonald, C, Schmaal, L, Sisodiya, SM, Stein, DJ, van den Heuvel, OA, van Erp, TGM, van Rooij, D, Veltman, DJ, Thompson, P, Faraone, SV, Radonjic, NV, Hess, JL, Rovira, P, Andreassen, O, Buitelaar, JK, Ching, CRK, Franke, B, Hoogman, M, Jahanshad, N, McDonald, C, Schmaal, L, Sisodiya, SM, Stein, DJ, van den Heuvel, OA, van Erp, TGM, van Rooij, D, Veltman, DJ, Thompson, P, and Faraone, SV
Abstract: Genomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations are similar among disorders and, if so, the degree to which such similarities have a genetic etiology. From the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls. The SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.494). Our results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.
Published: 2021

16. Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study

Author: Gleichgerrcht, E, Munsell, BC, Alhusaini, S, Alvim, MKM, Bargallo, N, Bender, B, Bernasconi, A, Bernasconi, N, Bernhardt, B, Blackmon, K, Caligiuri, ME, Cendes, F, Concha, L, Desmond, PM, Devinsky, O, Doherty, CP, Domin, M, Duncan, JS, Focke, NK, Gambardella, A, Gong, B, Guerrini, R, Hatton, SN, Kalviainen, R, Keller, SS, Kochunov, P, Kotikalapudi, R, Kreilkamp, BAK, Labate, A, Langner, S, Lariviere, S, Lenge, M, Lui, E, Martin, P, Mascalchi, M, Meletti, S, O'Brien, TJ, Pardoe, HR, Pariente, JC, Rao, JX, Richardson, MP, Rodriguez-Cruces, R, Ruber, T, Sinclair, B, Soltanian-Zadeh, H, Stein, DJ, Striano, P, Taylor, PN, Thomas, RH, Vaudano, AE, Vivash, L, von Podewills, F, Vos, SB, Weber, B, Yao, Y, Yasuda, CL, Zhang, J, Thompson, PM, Sisodiya, SM, McDonald, CR, Bonilha, L, Gleichgerrcht, E, Munsell, BC, Alhusaini, S, Alvim, MKM, Bargallo, N, Bender, B, Bernasconi, A, Bernasconi, N, Bernhardt, B, Blackmon, K, Caligiuri, ME, Cendes, F, Concha, L, Desmond, PM, Devinsky, O, Doherty, CP, Domin, M, Duncan, JS, Focke, NK, Gambardella, A, Gong, B, Guerrini, R, Hatton, SN, Kalviainen, R, Keller, SS, Kochunov, P, Kotikalapudi, R, Kreilkamp, BAK, Labate, A, Langner, S, Lariviere, S, Lenge, M, Lui, E, Martin, P, Mascalchi, M, Meletti, S, O'Brien, TJ, Pardoe, HR, Pariente, JC, Rao, JX, Richardson, MP, Rodriguez-Cruces, R, Ruber, T, Sinclair, B, Soltanian-Zadeh, H, Stein, DJ, Striano, P, Taylor, PN, Thomas, RH, Vaudano, AE, Vivash, L, von Podewills, F, Vos, SB, Weber, B, Yao, Y, Yasuda, CL, Zhang, J, Thompson, PM, Sisodiya, SM, McDonald, CR, and Bonilha, L
Abstract: Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.
Published: 2021

17. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB
Abstract: Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
Published: 2021

18. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Author: Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, and Becker, F
Abstract: Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The character
Published: 2020

19. ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

Author: Thompson, PM, Jahanshad, N, Ching, CRK, Salminen, LE, Thomopoulos, SI, Bright, J, Baune, BT, Bertolin, S, Bralten, J, Bruin, WB, Buelow, R, Chen, J, Chye, Y, Dannlowski, U, de Kovel, CGF, Donohoe, G, Eyler, LT, Faraone, SV, Favre, P, Filippi, CA, Frodl, T, Garijo, D, Gil, Y, Grabe, HJ, Grasby, KL, Hajek, T, Han, LKM, Hatton, SN, Hilbert, K, Ho, TC, Holleran, L, Homuth, G, Hosten, N, Houenou, J, Ivanov, I, Jia, T, Kelly, S, Klein, M, Kwon, JS, Laansma, MA, Leerssen, J, Lueken, U, Nunes, A, Neill, JO, Opel, N, Piras, F, Postema, MC, Pozzi, E, Shatokhina, N, Soriano-Mas, C, Spalletta, G, Sun, D, Teumer, A, Tilot, AK, Tozzi, L, van der Merwe, C, Van Someren, EJW, van Wingen, GA, Voelzke, H, Walton, E, Wang, L, Winkler, AM, Wittfeld, K, Wright, MJ, Yun, J-Y, Zhang, G, Zhang-James, Y, Adhikari, BM, Agartz, I, Aghajani, M, Aleman, A, Althoff, RR, Altmann, A, Andreassen, OA, Baron, DA, Bartnik-Olson, BL, Bas-Hoogendam, J, Baskin-Sommers, AR, Bearden, CE, Berner, LA, Boedhoe, PSW, Brouwer, RM, Buitelaar, JK, Caeyenberghs, K, Cecil, CAM, Cohen, RA, Cole, JH, Conrod, PJ, De Brito, SA, de Zwarte, SMC, Dennis, EL, Desrivieres, S, Dima, D, Ehrlich, S, Esopenko, C, Fairchild, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Garavan, HP, Glahn, DC, Groenewold, NA, Gurholt, TP, Gutman, BA, Hahn, T, Harding, IH, Hernaus, D, Hibar, DP, Hillary, FG, Hoogman, M, Pol, HE, Jalbrzikowski, M, Karkashadze, GA, Klapwijk, ET, Knickmeyer, RC, Kochunov, P, Koerte, IK, Kong, X-Z, Liew, S-L, Lin, AP, Logue, MW, Luders, E, Macciardi, F, Mackey, S, Mayer, AR, McDonald, CR, McMahon, AB, Medland, SE, Modinos, G, Morey, RA, Mueller, SC, Mukherjee, P, Namazova-Baranova, L, Nir, TM, Olsen, A, Paschou, P, Pine, DS, Pizzagalli, F, Renteria, ME, Rohrer, JD, Saemann, PG, Schmaal, L, Schumann, G, Shiroishi, MS, Sisodiya, SM, Smit, DJA, Sonderby, IE, Stein, DJ, Stein, JL, Tahmasian, M, Tate, DF, Turner, JA, van den Heuvel, OA, van der Wee, NJA, van der Werf, YD, van Erp, TGM, van Haren, NEM, van Rooij, D, van Velzen, LS, Veer, IM, Veltman, DJ, Villalon-Reina, JE, Walter, H, Whelan, CD, Wilde, EA, Zarei, M, Zelman, V, Thompson, PM, Jahanshad, N, Ching, CRK, Salminen, LE, Thomopoulos, SI, Bright, J, Baune, BT, Bertolin, S, Bralten, J, Bruin, WB, Buelow, R, Chen, J, Chye, Y, Dannlowski, U, de Kovel, CGF, Donohoe, G, Eyler, LT, Faraone, SV, Favre, P, Filippi, CA, Frodl, T, Garijo, D, Gil, Y, Grabe, HJ, Grasby, KL, Hajek, T, Han, LKM, Hatton, SN, Hilbert, K, Ho, TC, Holleran, L, Homuth, G, Hosten, N, Houenou, J, Ivanov, I, Jia, T, Kelly, S, Klein, M, Kwon, JS, Laansma, MA, Leerssen, J, Lueken, U, Nunes, A, Neill, JO, Opel, N, Piras, F, Postema, MC, Pozzi, E, Shatokhina, N, Soriano-Mas, C, Spalletta, G, Sun, D, Teumer, A, Tilot, AK, Tozzi, L, van der Merwe, C, Van Someren, EJW, van Wingen, GA, Voelzke, H, Walton, E, Wang, L, Winkler, AM, Wittfeld, K, Wright, MJ, Yun, J-Y, Zhang, G, Zhang-James, Y, Adhikari, BM, Agartz, I, Aghajani, M, Aleman, A, Althoff, RR, Altmann, A, Andreassen, OA, Baron, DA, Bartnik-Olson, BL, Bas-Hoogendam, J, Baskin-Sommers, AR, Bearden, CE, Berner, LA, Boedhoe, PSW, Brouwer, RM, Buitelaar, JK, Caeyenberghs, K, Cecil, CAM, Cohen, RA, Cole, JH, Conrod, PJ, De Brito, SA, de Zwarte, SMC, Dennis, EL, Desrivieres, S, Dima, D, Ehrlich, S, Esopenko, C, Fairchild, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Garavan, HP, Glahn, DC, Groenewold, NA, Gurholt, TP, Gutman, BA, Hahn, T, Harding, IH, Hernaus, D, Hibar, DP, Hillary, FG, Hoogman, M, Pol, HE, Jalbrzikowski, M, Karkashadze, GA, Klapwijk, ET, Knickmeyer, RC, Kochunov, P, Koerte, IK, Kong, X-Z, Liew, S-L, Lin, AP, Logue, MW, Luders, E, Macciardi, F, Mackey, S, Mayer, AR, McDonald, CR, McMahon, AB, Medland, SE, Modinos, G, Morey, RA, Mueller, SC, Mukherjee, P, Namazova-Baranova, L, Nir, TM, Olsen, A, Paschou, P, Pine, DS, Pizzagalli, F, Renteria, ME, Rohrer, JD, Saemann, PG, Schmaal, L, Schumann, G, Shiroishi, MS, Sisodiya, SM, Smit, DJA, Sonderby, IE, Stein, DJ, Stein, JL, Tahmasian, M, Tate, DF, Turner, JA, van den Heuvel, OA, van der Wee, NJA, van der Werf, YD, van Erp, TGM, van Haren, NEM, van Rooij, D, van Velzen, LS, Veer, IM, Veltman, DJ, Villalon-Reina, JE, Walter, H, Whelan, CD, Wilde, EA, Zarei, M, and Zelman, V
Abstract: This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
Published: 2020

20. Focal epilepsy inSCN1A-mutation carrying patients: is there a role for epilepsy surgery?

Author: Vezyroglou, A, Varadkar, S, Bast, T, Hirsch, E, Strobl, K, Harvey, AS, Scheffer, IE, Sisodiya, SM, Cross, JH, Vezyroglou, A, Varadkar, S, Bast, T, Hirsch, E, Strobl, K, Harvey, AS, Scheffer, IE, Sisodiya, SM, and Cross, JH
Abstract: Variants in the gene SCN1A are a common genetic cause for a wide range of epilepsy phenotypes ranging from febrile seizures to Dravet syndrome. Focal onset seizures and structural lesions can be present in these patients and the question arises whether epilepsy surgery should be considered. We report eight patients (mean age 13y 11mo [SD 8y 1mo], range 3-26y; four females, four males) with SCN1A variants, who underwent epilepsy surgery. Outcomes were variable and seemed to be directly related to the patient's anatomo-electroclinical epilepsy phenotype. Patients with Dravet syndrome had unfavourable outcomes, whilst patients with focal epilepsy, proven to arise from a single structural lesion, had good results. We conclude that the value of epilepsy surgery in patients with an SCN1A variant rests on two issues: understanding whether the variant is pathogenic and the patient's anatomo-electroclinical phenotype. Careful evaluation of epilepsy phenotype integrated with understanding the significance of genetic variants is essential in determining a patient's suitability for epilepsy surgery. Patients with focal onset epilepsy may benefit from epilepsy surgery, whereas those with Dravet syndrome do not. WHAT THIS PAPER ADDS: Patients should not automatically be excluded from epilepsy surgery evaluation if they carry an SCN1A variant. Patients with focal epilepsy may benefit from epilepsy surgery; those with Dravet syndrome do not.
Published: 2020

21. Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study

Author: Lariviere, S, Rodriguez-Cruces, R, Royer, J, Caligiuri, ME, Gambardella, A, Concha, L, Keller, SS, Cendes, F, Yasuda, C, Bonilha, L, Gleichgerrcht, E, Focke, NK, Domin, M, von Podewills, F, Langner, S, Rummel, C, Wiest, R, Martin, P, Kotikalapudi, R, O'Brien, TJ, Sinclair, B, Vivash, L, Desmond, PM, Alhusaini, S, Doherty, CP, Cavalleri, GL, Delanty, N, Kalviainen, R, Jackson, GD, Kowalczyk, M, Mascalchi, M, Semmelroch, M, Thomas, RH, Soltanian-Zadeh, H, Davoodi-Bojd, E, Zhang, J, Lenge, M, Guerrini, R, Bartolini, E, Hamandi, K, Foley, S, Weber, B, Depondt, C, Absil, J, Carr, SJA, Abela, E, Richardson, MP, Devinsky, O, Severino, M, Striano, P, Tortora, D, Hatton, SN, Vos, SB, Duncan, JS, Whelan, CD, Thompson, PM, Sisodiya, SM, Bernasconi, A, Labate, A, McDonald, CR, Bernasconi, N, Bernhardt, BC, Lariviere, S, Rodriguez-Cruces, R, Royer, J, Caligiuri, ME, Gambardella, A, Concha, L, Keller, SS, Cendes, F, Yasuda, C, Bonilha, L, Gleichgerrcht, E, Focke, NK, Domin, M, von Podewills, F, Langner, S, Rummel, C, Wiest, R, Martin, P, Kotikalapudi, R, O'Brien, TJ, Sinclair, B, Vivash, L, Desmond, PM, Alhusaini, S, Doherty, CP, Cavalleri, GL, Delanty, N, Kalviainen, R, Jackson, GD, Kowalczyk, M, Mascalchi, M, Semmelroch, M, Thomas, RH, Soltanian-Zadeh, H, Davoodi-Bojd, E, Zhang, J, Lenge, M, Guerrini, R, Bartolini, E, Hamandi, K, Foley, S, Weber, B, Depondt, C, Absil, J, Carr, SJA, Abela, E, Richardson, MP, Devinsky, O, Severino, M, Striano, P, Tortora, D, Hatton, SN, Vos, SB, Duncan, JS, Whelan, CD, Thompson, PM, Sisodiya, SM, Bernasconi, A, Labate, A, McDonald, CR, Bernasconi, N, and Bernhardt, BC
Abstract: Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.
Published: 2020

22. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author: Perucca, P, Anderson, A, Jazayeri, D, Hitchcock, A, Graham, J, Todaro, M, Tomson, T, Battino, D, Perucca, E, Ferri, MM, Rochtus, A, Lagae, L, Canevini, MP, Zambrelli, E, Campbell, E, Koeleman, BPC, Scheffer, IE, Berkovic, SF, Kwan, P, Sisodiya, SM, Goldstein, DB, Petrovski, S, Craig, J, Vajda, FJE, O'Brien, TJ, Perucca, P, Anderson, A, Jazayeri, D, Hitchcock, A, Graham, J, Todaro, M, Tomson, T, Battino, D, Perucca, E, Ferri, MM, Rochtus, A, Lagae, L, Canevini, MP, Zambrelli, E, Campbell, E, Koeleman, BPC, Scheffer, IE, Berkovic, SF, Kwan, P, Sisodiya, SM, Goldstein, DB, Petrovski, S, Craig, J, Vajda, FJE, and O'Brien, TJ
Abstract: OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.
Published: 2020

23. The genetic architecture of the human cerebral cortex

Author: Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, Medland, SE, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, and Medland, SE
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Published: 2020

24. Medullary tyrosine hydroxylase catecholaminergic neuronal populations in sudden unexpected death in epilepsy

Author: Patodia, S, Tan, I, Ellis, M, Somani, A, Scheffer, IE, Sisodiya, SM, Thom, M, Patodia, S, Tan, I, Ellis, M, Somani, A, Scheffer, IE, Sisodiya, SM, and Thom, M
Abstract: Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure-related respiratory dysfunction. Medullary respiratory regulatory nuclei include the pre-Bötzinger complex (pre-BötC) in the ventrolateral medulla (VLM), the medullary raphé nuclei (MR) and nucleus of solitary tract in the dorsomedial medulla (DMM). The region of the VLM also contains intermingled tyrosine hydroxylase (TH) catecholaminergic neurones which directly project to the pre-BötC and regulate breathing under hypoxic conditions and our aim was to evaluate these neurones in SUDEP cases. In post-mortem cases from three groups [SUDEP (18), epilepsy controls (8) and non-epilepsy controls (16)] serial sections of medulla (obex + 2 to + 13 mm) were immunolabeled for TH. Three regions of interest (ROI) were outlined (VLM, DMM and MR) and TH-immunoreactive (TH-IR) neurones were evaluated using automated detection for overall labeling index (neurones and processes) and neuronal densities and compared between groups and relative to obex level. C-fos immunoreactivity was also semi-quantitatively evaluated in these regions. We found no significant difference in the density of TH-IR neurones or labeling index between the groups in all regions. Significantly more TH-IR neurones were present in the DMM region than VLM in non-epilepsy cases only (P < 0.01). Regional variations in TH-IR neurones with obex level were seen in all groups except SUDEP. We also identified occasional TH neurones in the MR region in all groups. There was significantly less c-fos labeling in the VLM and MR in SUDEP than non-epilepsy controls but no difference with epilepsy controls. In conclusion, in this series we found no evidence for alteration of total medullary TH-IR neuronal numbers in SUDEP but noted some differences in their relative distribution in the medulla and c-fos neurones compared to control groups which may be relevant to the mechanism of death.
Published: 2020

25. MRI and pathology correlations in the medulla in sudden unexpected death in epilepsy (SUDEP): a postmortem study

Author: Patodia, S, Tachrount, M, Somani, A, Scheffer, I, Yousry, T, Golay, X, Sisodiya, SM, Thom, M, Patodia, S, Tachrount, M, Somani, A, Scheffer, I, Yousry, T, Golay, X, Sisodiya, SM, and Thom, M
Abstract: AIMS: Sudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions. METHODS: Forty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI. RESULTS: Lower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P < 0.05). No differences between groups for T1, T2, T2* and MTR values in any region was seen but a positive correlation between T1 values and MAP2 labelling index in RtZ (P < 0.05). Significantly lower MAP2 LI were noted in the rostral medulla RtZ in epilepsy cases (P < 0.05). CONCLUSIONS: Rostro-caudal alterations of medullary volume in SUDEP localize with regions containing respiratory regulatory nuclei. They may represent seizure-related alterations, relevant to the pathophysiology of SUDEP.
Published: 2020

26. Cardiac phenotype in ATP1A3-related syndromes A multicenter cohort study

Author: Balestrini, S, Mikati, MA, Alvarez-Garcia-Roves, R, Carboni, M, Hunanyan, AS, Kherallah, B, McLean, M, Prange, L, De Grandis, E, Gagliardi, A, Pisciotta, L, Stagnaro, M, Veneselli, E, Campistol, J, Fons, C, Pias-Peleteiro, L, Brashear, A, Miller, C, Samoes, R, Brankovic, V, Padiath, QS, Potic, A, Pilch, J, Vezyroglou, A, Bye, AME, Davis, AM, Ryan, MM, Semsarian, C, Hollingsworth, G, Scheffer, IE, Granata, T, Nardocci, N, Ragona, F, Arzimanoglou, A, Panagiotakaki, E, Carrilho, I, Zucca, C, Novy, J, Parowicz, M, Weckhuysen, S, Pons, R, Groppa, S, Sinden, DS, Pitt, GS, Tinker, A, Ashworth, M, Michalak, Z, Thom, M, Cross, JH, Vavassori, R, Kaski, JP, Sisodiya, SM, Dzieiyc, K, Mazurkiewicz-Beldzinska, M, Balestrini, S, Mikati, MA, Alvarez-Garcia-Roves, R, Carboni, M, Hunanyan, AS, Kherallah, B, McLean, M, Prange, L, De Grandis, E, Gagliardi, A, Pisciotta, L, Stagnaro, M, Veneselli, E, Campistol, J, Fons, C, Pias-Peleteiro, L, Brashear, A, Miller, C, Samoes, R, Brankovic, V, Padiath, QS, Potic, A, Pilch, J, Vezyroglou, A, Bye, AME, Davis, AM, Ryan, MM, Semsarian, C, Hollingsworth, G, Scheffer, IE, Granata, T, Nardocci, N, Ragona, F, Arzimanoglou, A, Panagiotakaki, E, Carrilho, I, Zucca, C, Novy, J, Parowicz, M, Weckhuysen, S, Pons, R, Groppa, S, Sinden, DS, Pitt, GS, Tinker, A, Ashworth, M, Michalak, Z, Thom, M, Cross, JH, Vavassori, R, Kaski, JP, Sisodiya, SM, Dzieiyc, K, and Mazurkiewicz-Beldzinska, M
Abstract: OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
Published: 2020

27. The ENIGMA-Epilepsy working group: Mapping disease from large data sets

Author: Sisodiya, SM, Whelan, CD, Hatton, SN, Huynh, K, Altmann, A, Ryten, M, Vezzani, A, Caligiuri, ME, Labate, A, Gambardella, A, Ives-Deliperi, V, Meletti, S, Munsell, BC, Bonilha, L, Tondelli, M, Rebsamen, M, Rummel, C, Vaudano, AE, Wiest, R, Balachandra, AR, Bargallo, N, Bartolini, E, Bernasconi, A, Bernasconi, N, Bernhardt, B, Caldairou, B, Carr, SJA, Cavalleri, GL, Cendes, F, Concha, L, Desmond, PM, Domin, M, Duncan, JS, Focke, NK, Guerrini, R, Hamandi, K, Jackson, GD, Jahanshad, N, Kalviainen, R, Keller, SS, Kochunov, P, Kowalczyk, MA, Kreilkamp, BAK, Kwan, P, Lariviere, S, Lenge, M, Lopez, SM, Martin, P, Mascalchi, M, Moreira, JCV, Morita-Sherman, ME, Pardoe, HR, Pariente, JC, Raviteja, K, Rocha, CS, Rodriguez-Cruces, R, Seeck, M, Semmelroch, MKHG, Sinclair, B, Soltanian-Zadeh, H, Stein, DJ, Striano, P, Taylor, PN, Thomas, RH, Thomopoulos, SI, Velakoulis, D, Vivash, L, Weber, B, Yasuda, CL, Zhang, J, Thompson, PM, McDonald, CR, Sisodiya, SM, Whelan, CD, Hatton, SN, Huynh, K, Altmann, A, Ryten, M, Vezzani, A, Caligiuri, ME, Labate, A, Gambardella, A, Ives-Deliperi, V, Meletti, S, Munsell, BC, Bonilha, L, Tondelli, M, Rebsamen, M, Rummel, C, Vaudano, AE, Wiest, R, Balachandra, AR, Bargallo, N, Bartolini, E, Bernasconi, A, Bernasconi, N, Bernhardt, B, Caldairou, B, Carr, SJA, Cavalleri, GL, Cendes, F, Concha, L, Desmond, PM, Domin, M, Duncan, JS, Focke, NK, Guerrini, R, Hamandi, K, Jackson, GD, Jahanshad, N, Kalviainen, R, Keller, SS, Kochunov, P, Kowalczyk, MA, Kreilkamp, BAK, Kwan, P, Lariviere, S, Lenge, M, Lopez, SM, Martin, P, Mascalchi, M, Moreira, JCV, Morita-Sherman, ME, Pardoe, HR, Pariente, JC, Raviteja, K, Rocha, CS, Rodriguez-Cruces, R, Seeck, M, Semmelroch, MKHG, Sinclair, B, Soltanian-Zadeh, H, Stein, DJ, Striano, P, Taylor, PN, Thomas, RH, Thomopoulos, SI, Velakoulis, D, Vivash, L, Weber, B, Yasuda, CL, Zhang, J, Thompson, PM, and McDonald, CR
Abstract: Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.
Published: 2020

28. Clinical spectrum of STX1B-related epileptic disorders

Author: Wolking, S, May, P, Mei, D, Møller, RS, Balestrini, S, Helbig, KL, Altuzarra, CD, Chatron, N, Kaiwar, C, Stöhr, K, Widdess-Walsh, P, Mendelsohn, BA, Numis, A, Cilio, MR, Van Paesschen, W, Svendsen, LL, Oates, S, Hughes, E, Goyal, S, Brown, K, Saenz, M, Dorn, T, Muhle, H, Pagnamenta, AT, Vavoulis, DV, Knight, SJL, Taylor, JC, Canevini, MP, Darra, F, Gavrilova, RH, Powis, Z, Tang, S, Marquetand, J, Armstrong, M, McHale, D, Klee, EW, Kluger, GJ, Lowenstein, DH, Weckhuysen, S, Pal, DK, Helbig, I, Guerrini, R, Thomas, RH, Rees, MI, Lesca, G, Sisodiya, SM, Weber, YG, Lal, D, Marini, C, Lerche, H, and Schubert, J
Subjects: Male, Drug Resistant Epilepsy, Adolescent, Developmental Disabilities, Mutation, Missense, Clinical Neurology, FEBRILE SEIZURES PLUS, GENERALIZED EPILEPSY, Syntaxin 1, PROTEIN, Article, Seizures, Febrile, Young Adult, Loss of Function Mutation, Humans, HETEROGENEITY, SCN1A, Child, Epilepstic disorders, Science & Technology, Learning Disabilities, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, GENETIC-VARIATION, Electroencephalography, Sequence Analysis, DNA, SODIUM-CHANNEL, Epilepstic disorders, STX1B, Phenotype, DE-NOVO MUTATIONS, Child, Preschool, ONSET, STXBP1, STX1B, Anticonvulsants, Female, Human medicine, Epilepsies, Partial, Neurosciences & Neurology, Epileptic Syndromes, Life Sciences & Biomedicine
Abstract: OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies. ispartof: NEUROLOGY vol:92 issue:11 pages:E1238-E1249 ispartof: location:United States status: published
Published: 2019

29. Epilepsy: management

Author: Sisodiya, SM and Sander, JW
Published: 2004
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30. Epilepsy: epidemiology, clinical assessment, investigation and natural history

Author: Sisodiya, SM and Duncan, John
Published: 2004
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31. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author: Steward, CA, Roovers, J, Suner, M-M, Gonzalez, JM, Uszczynska-Ratajczak, B, Pervouchine, D, Fitzgerald, S, Viola, M, Stamberger, H, Hamdan, FF, Ceulemans, B, Leroy, P, Nava, C, Lepine, A, Tapanari, E, Keiller, D, Abbs, S, Sanchis-Juan, A, Grozeva, D, Rogers, AS, Diekhans, M, Guigo, R, Petryszak, R, Minassian, BA, Cavalleri, G, Vitsios, D, Petrovski, S, Harrow, J, Flicek, P, Raymond, FL, Lench, NJ, De Jonghe, P, Mudge, JM, Weckhuysen, S, Sisodiya, SM, Frankish, A, Steward, CA, Roovers, J, Suner, M-M, Gonzalez, JM, Uszczynska-Ratajczak, B, Pervouchine, D, Fitzgerald, S, Viola, M, Stamberger, H, Hamdan, FF, Ceulemans, B, Leroy, P, Nava, C, Lepine, A, Tapanari, E, Keiller, D, Abbs, S, Sanchis-Juan, A, Grozeva, D, Rogers, AS, Diekhans, M, Guigo, R, Petryszak, R, Minassian, BA, Cavalleri, G, Vitsios, D, Petrovski, S, Harrow, J, Flicek, P, Raymond, FL, Lench, NJ, De Jonghe, P, Mudge, JM, Weckhuysen, S, Sisodiya, SM, and Frankish, A
Abstract: The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.
Published: 2019

32. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Author: Corbett, MA, Kroes, T, Veneziano, L, Bennett, MF, Florian, R, Schneider, AL, Coppola, A, Licchetta, L, Franceschetti, S, Suppa, A, Wenger, A, Mei, D, Pendziwiat, M, Kaya, S, Delledonne, M, Straussberg, R, Xumerle, L, Regan, B, Crompton, D, van Rootselaar, A-F, Correll, A, Catford, R, Bisulli, F, Chakraborty, S, Baldassari, S, Tinuper, P, Barton, K, Carswell, S, Smith, M, Berardelli, A, Carroll, R, Gardner, A, Friend, KL, Blatt, I, Iacomino, M, Di Bonaventura, C, Striano, S, Buratti, J, Keren, B, Nava, C, Forlani, S, Rudolf, G, Hirsch, E, Leguern, E, Labauge, P, Balestrini, S, Sander, JW, Afawi, Z, Helbig, I, Ishiura, H, Tsuji, S, Sisodiya, SM, Casari, G, Sadleir, LG, van Coller, R, Tijssen, MAJ, Klein, KM, van den Maagdenberg, AMJM, Zara, F, Guerrini, R, Berkovic, SF, Pippucci, T, Canafoglia, L, Bahlo, M, Striano, P, Scheffer, IE, Brancati, F, Depienne, C, Gecz, J, Corbett, MA, Kroes, T, Veneziano, L, Bennett, MF, Florian, R, Schneider, AL, Coppola, A, Licchetta, L, Franceschetti, S, Suppa, A, Wenger, A, Mei, D, Pendziwiat, M, Kaya, S, Delledonne, M, Straussberg, R, Xumerle, L, Regan, B, Crompton, D, van Rootselaar, A-F, Correll, A, Catford, R, Bisulli, F, Chakraborty, S, Baldassari, S, Tinuper, P, Barton, K, Carswell, S, Smith, M, Berardelli, A, Carroll, R, Gardner, A, Friend, KL, Blatt, I, Iacomino, M, Di Bonaventura, C, Striano, S, Buratti, J, Keren, B, Nava, C, Forlani, S, Rudolf, G, Hirsch, E, Leguern, E, Labauge, P, Balestrini, S, Sander, JW, Afawi, Z, Helbig, I, Ishiura, H, Tsuji, S, Sisodiya, SM, Casari, G, Sadleir, LG, van Coller, R, Tijssen, MAJ, Klein, KM, van den Maagdenberg, AMJM, Zara, F, Guerrini, R, Berkovic, SF, Pippucci, T, Canafoglia, L, Bahlo, M, Striano, P, Scheffer, IE, Brancati, F, Depienne, C, and Gecz, J
Abstract: 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.
Published: 2019

33. Polygenic burden in focal and generalized epilepsies

Author: Leu, C, Stevelink, R, Smith, AW, Goleva, SB, Kanai, M, Ferguson, L, Campbell, C, Kamatani, Y, Okada, Y, Sisodiya, SM, Cavalleri, GL, Koeleman, BPC, Lerche, H, Jehi, L, Davis, LK, Najm, IM, Palotie, A, Daly, MJ, Busch, RM, Lal, D, Leu, C, Stevelink, R, Smith, AW, Goleva, SB, Kanai, M, Ferguson, L, Campbell, C, Kamatani, Y, Okada, Y, Sisodiya, SM, Cavalleri, GL, Koeleman, BPC, Lerche, H, Jehi, L, Davis, LK, Najm, IM, Palotie, A, Daly, MJ, Busch, RM, and Lal, D
Abstract: Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.3
Published: 2019

34. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Author: Berghuis, B, Stapleton, C, Sonsma, ACM, Hulst, J, de Haan, G-J, Lindhout, D, Demurtas, R, Consortium, E, Krause, R, Depondt, C, Kunz, WS, Zara, F, Striano, P, Craig, J, Auce, P, Marson, AG, Stefansson, H, O'Brien, TJ, Johnson, MR, Sills, GJ, Wolking, S, Lerche, H, Sisodiya, SM, Sander, JW, Cavalleri, GL, Koeleman, BPC, McCormack, M, Berghuis, B, Stapleton, C, Sonsma, ACM, Hulst, J, de Haan, G-J, Lindhout, D, Demurtas, R, Consortium, E, Krause, R, Depondt, C, Kunz, WS, Zara, F, Striano, P, Craig, J, Auce, P, Marson, AG, Stefansson, H, O'Brien, TJ, Johnson, MR, Sills, GJ, Wolking, S, Lerche, H, Sisodiya, SM, Sander, JW, Cavalleri, GL, Koeleman, BPC, and McCormack, M
Abstract: OBJECTIVE: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. METHODS: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. RESULTS: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. SIGNIFICANCE: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.
Published: 2019

35. Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Author: Silvennoinen, K, de Lange, N, Zagaglia, S, Balestrini, S, Androsova, G, Wassenaar, M, Auce, P, Avbersek, A, Becker, F, Berghuis, B, Campbell, E, Coppola, A, Francis, B, Wolking, S, Cavalleri, GL, Craig, J, Delanty, N, Johnson, MR, Koeleman, BPC, Kunz, WS, Lerche, H, Marson, AG, O'Brien, TJ, Sander, JW, Sills, GJ, Striano, P, Zara, F, van der Palen, J, Krause, R, Depondt, C, Sisodiya, SM, Silvennoinen, K, de Lange, N, Zagaglia, S, Balestrini, S, Androsova, G, Wassenaar, M, Auce, P, Avbersek, A, Becker, F, Berghuis, B, Campbell, E, Coppola, A, Francis, B, Wolking, S, Cavalleri, GL, Craig, J, Delanty, N, Johnson, MR, Koeleman, BPC, Kunz, WS, Lerche, H, Marson, AG, O'Brien, TJ, Sander, JW, Sills, GJ, Striano, P, Zara, F, van der Palen, J, Krause, R, Depondt, C, and Sisodiya, SM
Abstract: OBJECTIVE: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). METHODS: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. RESULTS: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). SIGNIFICANCE: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate
Published: 2019

36. Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study

Author: Whelan, Cd, Altmann, A, Botía, Ja, Jahanshad, N, Hibar, Dp, Absil, J, Alhusaini, S, Alvim, Mkm, Auvinen, P, Bartolini, E, Bergo, Fpg, Bernardes, T, Blackmon, K, Braga, B, Caligiuri, Me, Calvo, A, Carr, Sj, Chen, J, Chen, S, Cherubini, A, David, P, Domin, M, Foley, S, França, W, Haaker, G, Isaev, D, Keller, Ss, Kotikalapudi, R, Kowalczyk, Ma, Kuzniecky, R, Langner, S, Lenge, M, Leyden, Km, Liu, M, Loi, Rq, Martin, P, Mascalchi, M, Morita, Me, Pariente, Jc, Rodríguez-Cruces, R, Rummel, C, Saavalainen, T, Semmelroch, Mk, Severino, M, Thomas, Rh, Tondelli, M, Tortora, D, Vaudano, AE39, Vivash, L40, von Podewils F42, Wagner, J43, Weber, B43, Yao, Y46, Yasuda, CL7, Zhang, G47, Bargalló, N15, Bender, B26, Bernasconi, N, Bernasconi, A, Bernhardt, Bc, Blümcke, I, Carlson, C, Cavalleri, Gl, Cendes, F, Concha, L, Delanty, N, Depondt, C, Devinsky, O, Doherty, CP51, Focke, Nk, Gambardella, A, Guerrini, R, Hamandi, K, Jackson, Gd, Kälviäinen, R, Kochunov, P, Kwan, P, Labate, A, McDonald, Cr, Meletti, S, O'Brien, Tj, Ourselin, S, Richardson MP Striano, P, Thesen, T, Wiest, R, Zhang, J, Vezzani, A, Ryten, M, Thompson, Pm, and Sisodiya, Sm.
Subjects: MRI, epilepsy, precentral gyrus, thalamus
Published: 2018

37. Whole genome sequencing identifies putative associations between genomic polymorphisms and clinical response to the antiepileptic drug levetiracetam

Author: Vavoulis, DV, primary, Pagnamenta, AT, additional, Knight, SJL, additional, Pentony, MM, additional, Armstrong, M, additional, Galizia, EC, additional, Balestrini, S, additional, Sisodiya, SM, additional, and Taylor, JC, additional
Published: 2019
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38. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author: Abou-Khalil, B, Auce, P, Avbersek, A, Bahlo, M, Balding, DJ, Bast, T, Baum, L, Becker, AJ, Becker, F, Berghuis, B, Berkovic, SF, Boysen, KE, Bradfield, JP, Brody, LC, Buono, RJ, Campbell, E, Cascino, GD, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Coppola, A, Cossette, P, Craig, JJ, de Haan, G-J, De Jonghe, P, de Kovel, CGF, Delanty, N, Depondt, C, Devinsky, O, Dlugos, DJ, Doherty, CP, Elger, CE, Eriksson, JG, Ferraro, TN, Feucht, M, Francis, B, Franke, A, French, JA, Freytag, S, Gaus, V, Geller, EB, Gieger, C, Glauser, T, Glynn, S, Goldstein, DB, Gui, H, Guo, Y, Haas, KF, Hakonarson, H, Hallmann, K, Haut, S, Heinzen, EL, Helbig, I, Hengsbach, C, Hjalgrim, H, Iacomino, M, Ingason, A, Jamnadas-Khoda, J, Johnson, MR, Kalviainen, R, Kantanen, A-M, Kasperaviciute, D, Trenite, DK-N, Kirsch, HE, Knowlton, RC, Koeleman, BPC, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Kwan, P, Lal, D, Lau, Y-L, Lehesjoki, A-E, Lerche, H, Leu, C, Lieb, W, Lindhout, D, Lo, WD, Lopes-Cendes, I, Lowenstein, DH, Malovini, A, Marson, AG, Mayer, T, McCormack, M, Mills, JL, Mirza, N, Moerzinger, M, Moller, RS, Molloy, AM, Muhle, H, Newton, M, Ng, P-W, Noethen, MM, Nuernberg, P, O'Brien, TJ, Oliver, KL, Palotie, A, Pangilinan, F, Peter, S, Petrovski, S, Poduri, A, Privitera, M, Radtke, R, Rau, S, Reif, PS, Reinthaler, EM, Rosenow, F, Sander, JW, Sander, T, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Sham, PC, Shih, JJ, Sills, GJ, Sisodiya, SM, Slattery, L, Smith, A, Smith, DF, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Steinhoff, BJ, Stephani, U, Stevelink, R, Strauch, K, Striano, P, Stroink, H, Surges, R, Tan, KM, Thio, LL, Thomas, GN, Todaro, M, Tozzi, R, Vari, MS, Vining, EPG, Visscher, F, von Spiczak, S, Walley, NM, Weber, YG, Wei, Z, Weisenberg, J, Whelan, CD, Widdess-Walsh, P, Wolff, M, Wolking, S, Yang, W, Zara, F, Zimprich, F, Abou-Khalil, B, Auce, P, Avbersek, A, Bahlo, M, Balding, DJ, Bast, T, Baum, L, Becker, AJ, Becker, F, Berghuis, B, Berkovic, SF, Boysen, KE, Bradfield, JP, Brody, LC, Buono, RJ, Campbell, E, Cascino, GD, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Coppola, A, Cossette, P, Craig, JJ, de Haan, G-J, De Jonghe, P, de Kovel, CGF, Delanty, N, Depondt, C, Devinsky, O, Dlugos, DJ, Doherty, CP, Elger, CE, Eriksson, JG, Ferraro, TN, Feucht, M, Francis, B, Franke, A, French, JA, Freytag, S, Gaus, V, Geller, EB, Gieger, C, Glauser, T, Glynn, S, Goldstein, DB, Gui, H, Guo, Y, Haas, KF, Hakonarson, H, Hallmann, K, Haut, S, Heinzen, EL, Helbig, I, Hengsbach, C, Hjalgrim, H, Iacomino, M, Ingason, A, Jamnadas-Khoda, J, Johnson, MR, Kalviainen, R, Kantanen, A-M, Kasperaviciute, D, Trenite, DK-N, Kirsch, HE, Knowlton, RC, Koeleman, BPC, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Kwan, P, Lal, D, Lau, Y-L, Lehesjoki, A-E, Lerche, H, Leu, C, Lieb, W, Lindhout, D, Lo, WD, Lopes-Cendes, I, Lowenstein, DH, Malovini, A, Marson, AG, Mayer, T, McCormack, M, Mills, JL, Mirza, N, Moerzinger, M, Moller, RS, Molloy, AM, Muhle, H, Newton, M, Ng, P-W, Noethen, MM, Nuernberg, P, O'Brien, TJ, Oliver, KL, Palotie, A, Pangilinan, F, Peter, S, Petrovski, S, Poduri, A, Privitera, M, Radtke, R, Rau, S, Reif, PS, Reinthaler, EM, Rosenow, F, Sander, JW, Sander, T, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Sham, PC, Shih, JJ, Sills, GJ, Sisodiya, SM, Slattery, L, Smith, A, Smith, DF, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Steinhoff, BJ, Stephani, U, Stevelink, R, Strauch, K, Striano, P, Stroink, H, Surges, R, Tan, KM, Thio, LL, Thomas, GN, Todaro, M, Tozzi, R, Vari, MS, Vining, EPG, Visscher, F, von Spiczak, S, Walley, NM, Weber, YG, Wei, Z, Weisenberg, J, Whelan, CD, Widdess-Walsh, P, Wolff, M, Wolking, S, Yang, W, Zara, F, and Zimprich, F
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Published: 2018

39. The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy

Author: Patodia, S, Somani, A, O'Hare, M, Venkateswaran, R, Liu, J, Michalak, Z, Ellis, M, Scheffer, IE, Diehl, B, Sisodiya, SM, Thom, M, Patodia, S, Somani, A, O'Hare, M, Venkateswaran, R, Liu, J, Michalak, Z, Ellis, M, Scheffer, IE, Diehl, B, Sisodiya, SM, and Thom, M
Abstract: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in patients with epilepsy. One hypothesis proposes that sudden death is mediated by post-ictal central respiratory depression, which could relate to underlying pathology in key respiratory nuclei and/or their neuromodulators. Our aim was to investigate neuronal populations in the ventrolateral medulla (which includes the putative human pre-Bötzinger complex) and the medullary raphe. Forty brainstems were studied comprising four groups: 14 SUDEP, six epilepsy controls, seven Dravet syndrome cases and 13 non-epilepsy controls. Serial sections through the medulla (from obex 1 to 10 mm) were stained for Nissl, somatostatin, neurokinin 1 receptor (for pre-Bötzinger complex neurons) and galanin, tryptophan hydroxylase and serotonin transporter (neuromodulatory systems). Using stereology total neuronal number and densities, with respect to obex level, were measured. Whole slide scanning image analysis was used to quantify immunolabelling indices as well as co-localization between markers. Significant findings included reduction in somatostatin neurons and neurokinin 1 receptor labelling in the ventrolateral medulla in sudden death in epilepsy compared to controls (P < 0.05). Galanin and tryptophan hydroxylase labelling was also reduced in sudden death cases and more significantly in the ventrolateral medulla region than the raphe (P < 0.005 and P < 0.05). With serotonin transporter, reduction in labelling in cases of sudden death in epilepsy was noted only in the raphe (P ≤ 0.01); however, co-localization with tryptophan hydroxylase was significantly reduced in the ventrolateral medulla. Epilepsy controls and cases with Dravet syndrome showed less significant alterations with differences from non-epilepsy controls noted only for somatostatin in the ventrolateral medulla (P < 0.05). Variations in labelling with respect to obex level were noted of potential relevance to the rostro-caudal organi
Published: 2018

40. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Author: McCormack, M, Gui, H, Ingason, A, Speed, D, Wright, GEB, Zhang, EJ, Secolin, R, Yasuda, C, Kwok, M, Wolking, S, Becker, F, Rau, S, Avbersek, A, Heggeli, K, Leu, C, Depondt, C, Sills, GJ, Marson, AG, Auce, P, Brodie, MJ, Francis, B, Johnson, MR, Koeleman, BPC, Striano, P, Coppola, A, Zara, F, Kunz, WS, Sander, JW, Lerche, H, Klein, KM, Weckhuysen, S, Krenn, M, Gudmundsson, LJ, Stefansson, K, Krause, R, Shear, N, Ross, CJD, Delanty, N, Pirmohamed, M, Carleton, BC, Cendes, F, Lopes-Cendes, I, Liao, W-P, O'Brien, TJ, Sisodiya, SM, Cherny, S, Kwan, P, Baum, L, Cavalleri, GL, McCormack, M, Gui, H, Ingason, A, Speed, D, Wright, GEB, Zhang, EJ, Secolin, R, Yasuda, C, Kwok, M, Wolking, S, Becker, F, Rau, S, Avbersek, A, Heggeli, K, Leu, C, Depondt, C, Sills, GJ, Marson, AG, Auce, P, Brodie, MJ, Francis, B, Johnson, MR, Koeleman, BPC, Striano, P, Coppola, A, Zara, F, Kunz, WS, Sander, JW, Lerche, H, Klein, KM, Weckhuysen, S, Krenn, M, Gudmundsson, LJ, Stefansson, K, Krause, R, Shear, N, Ross, CJD, Delanty, N, Pirmohamed, M, Carleton, BC, Cendes, F, Lopes-Cendes, I, Liao, W-P, O'Brien, TJ, Sisodiya, SM, Cherny, S, Kwan, P, Baum, L, and Cavalleri, GL
Abstract: OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. CONCLUSIONS: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.
Published: 2018

41. Familial childhood-onset progressive cerebellar syndrome associated with the ATP1A3 mutation

Author: Jaffer, F, Fawcett, K, Sims, D, Heger, A, Houlden, H, Hanna, MG, Kingston, H, and Sisodiya, SM
Subjects: Clinical/Scientific Notes
Abstract: The allelic disorders rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS/CAOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural deafness) are caused by ATP1A3 mutations.1,–,3 Intermediate RDP-AHC phenotypes are emerging. Positional mutations 274, 583, 867, and 923 lead to both RDP and AHC, suggesting different pathomechanisms.4,5 The E818K mutation underlies all reported cases of CAPOS/CAOS, including an AHC-CAPOS overlap syndrome.6 We report a family with features of all 3 ATP1A3-spectrum disorders.
Published: 2017

42. DNM1 encephalopathy

Author: Von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenço, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Møller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, Helbig, I, Von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenço, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Møller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, and Helbig, I
Abstract: Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. Results: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. Conclusions: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
Published: 2017

43. DNM1 encephalopathy A new disease of vesicle fission

Author: von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenco, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Moller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, Helbig, I, von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenco, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Moller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, and Helbig, I
Abstract: OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
Published: 2017

44. Novel genetic loci associated with hippocampal volume

Author: Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, Ikram, MA, Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, and Ikram, MA
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017

45. ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

Author: Thompson, PM, Andreassen, OA, Arias-Vasquez, A, Bearden, CE, Boedhoe, PS, Brouwer, RM, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cannon, DM, Cohen, RA, Conrod, PJ, Dale, AM, Deary, IJ, Dennis, EL, de Reus, MA, Desrivieres, S, Dima, D, Donohoe, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Ganjgahi, H, Garavan, H, Glahn, DC, Grabe, HJ, Guadalupe, T, Gutman, BA, Hashimoto, R, Hibar, DP, Holland, D, Hoogman, M, Pol, HEH, Hosten, N, Jahanshad, N, Kelly, S, Kochunov, P, Kremen, WS, Lee, PH, Mackey, S, Martin, NG, Mazoyer, B, McDonald, C, Medland, SE, Morey, RA, Nichols, TE, Paus, T, Pausova, Z, Schmaal, L, Schumann, G, Shen, L, Sisodiya, SM, Smit, DJA, Smoller, JW, Stein, DJ, Stein, JL, Toro, R, Turner, JA, van den Heuvel, MP, van den Heuvel, OL, van Erp, TGM, van Rooij, D, Veltman, DJ, Walter, H, Wang, Y, Wardlaw, JM, Whelan, CD, Wright, MJ, Ye, J, Thompson, PM, Andreassen, OA, Arias-Vasquez, A, Bearden, CE, Boedhoe, PS, Brouwer, RM, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cannon, DM, Cohen, RA, Conrod, PJ, Dale, AM, Deary, IJ, Dennis, EL, de Reus, MA, Desrivieres, S, Dima, D, Donohoe, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Ganjgahi, H, Garavan, H, Glahn, DC, Grabe, HJ, Guadalupe, T, Gutman, BA, Hashimoto, R, Hibar, DP, Holland, D, Hoogman, M, Pol, HEH, Hosten, N, Jahanshad, N, Kelly, S, Kochunov, P, Kremen, WS, Lee, PH, Mackey, S, Martin, NG, Mazoyer, B, McDonald, C, Medland, SE, Morey, RA, Nichols, TE, Paus, T, Pausova, Z, Schmaal, L, Schumann, G, Shen, L, Sisodiya, SM, Smit, DJA, Smoller, JW, Stein, DJ, Stein, JL, Toro, R, Turner, JA, van den Heuvel, MP, van den Heuvel, OL, van Erp, TGM, van Rooij, D, Veltman, DJ, Walter, H, Wang, Y, Wardlaw, JM, Whelan, CD, Wright, MJ, and Ye, J
Abstract: In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.
Published: 2017

46. Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Author: Androsova, G, Krause, R, Borghei, M, Wassenaar, M, Auce, P, Avbersek, A, Becker, F, Berghuis, B, Campbell, E, Coppola, A, Francis, B, Wolking, S, Cavalleri, GL, Craig, J, Delanty, N, Koeleman, BPC, Kunz, WS, Lerche, H, Marson, AG, Sander, JW, Sills, GJ, Striano, P, Zara, F, Sisodiya, SM, Depondt, C, Androsova, G, Krause, R, Borghei, M, Wassenaar, M, Auce, P, Avbersek, A, Becker, F, Berghuis, B, Campbell, E, Coppola, A, Francis, B, Wolking, S, Cavalleri, GL, Craig, J, Delanty, N, Koeleman, BPC, Kunz, WS, Lerche, H, Marson, AG, Sander, JW, Sills, GJ, Striano, P, Zara, F, Sisodiya, SM, and Depondt, C
Abstract: OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. METHODS: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. RESULTS: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. SIGNIFICANCE: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS.
Published: 2017

47. Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Author: Jaffer F, Avbersek A, Vavassori R, Fons-Estupina C, Campistol-Plana J, Stagnaro M, De Grandis E, Veneselli E, Rosewich H, Gianotta M, Zucca C, Ragona F, Granata T, Nardocci N, Mikati M, Helseth AR, Boelman C, Minassian BA, Johns S, Garry SI, Scheffer IE, Gourfinkel-An I, Carrilho I, Aylett SE, Parton M, Hanna MG, Houlden H, Neville B, Kurian MA, Novy J, Sander JW, Lambiase PD, Behr ER, Schyns T, Arzimanoglou A, Cross JH, Kaski JP, and Sisodiya SM
Subjects: Adult, Male, SUDEP, Adolescent, Heart Diseases, Heart Ventricles, International Cooperation, Hemiplegia, alternating hemiplegia of childhood, ATP1A3, Na+ /K + -ATPase, electrocardiogram, Na+/K+-ATPase, Age Factors, Autonomic Nervous System Diseases, Child, Child, Preschool, Cohort Studies, Electrocardiography, Female, Heart Rate, Humans, Infant, Infant, Newborn, Mutation, Sodium-Potassium-Exchanging ATPase, Young Adult, Medicine (all), Arts and Humanities (miscellaneous), Neurology (clinical), Preschool, Original Articles, Newborn, cardiovascular system
Abstract: Alternating hemiplegia of childhood is rare and usually results from mutations in cardiac- and brain-expressed ATP1A3. In an ECG study of 52 cases, Jaffer et al. reveal dynamic cardiac repolarisation or conduction abnormalities in over 50%. Abnormalities are more common in those ≥16 years, and suggest impaired cardiac repolarisation reserve., Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term ‘alternating hemiplegia’. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those
Published: 2015

48. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Author: Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, Tiziano FD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E, European Alternating Hemiplegia of Childhood Genetics Consortium, Neri G, Koelewijn S, Kamphorst J, Geilenkirchen M, Pelzer N, Laan L, Haan J, Ferrari M, van den Maagdenberg A, Biobanca e. Registro Clinico per l'Emiplegia Alternante Consortium, Zucca C, Bassi MT, Franchini F, Vavassori R, Giannotta M, Gobbi G, Granata T, Nardocci N, De Grandis E, Veneselli E, Stagnaro M, Vigevano F, European Network for Research on Alternating Hemiplegia for Small, Medium sized Enterpriese Consortium, Oechsler C, Arzimanoglou A, Ninan M, Neville B, Ebinger F, Fons C, Campistol J, Kemlink D, Nevsimalova S, Peeters Scholte C, Casaer P, Sange G, Spiel G, Martinelli Boneschi F, Schyns T, Crawley F, Poncelin D, Fiori S, Abiusi E, Di Pietro L, Sweney MT, Newcomb TM, Viollet L, Huff C, Jorde LB, Reyna SP, Murphy KJ, Shianna KV, Gumbs CE, Little L, Silver K, Ptáček LJ, Ferrari MD, Bye AM, Herkes GK, Whitelaw CM, Webb D, Lynch BJ, Uldall P, King MD, Scheffer IE, van den Maagdenberg AM, Sisodiya SM, Mikati MA, Goldstein D.B., CASARI , GIORGIO NEVIO, Heinzen, El, Swoboda, Kj, Hitomi, Y, Gurrieri, F, Nicole, S, de Vries, B, Tiziano, Fd, Fontaine, B, Walley, Nm, Heavin, S, Panagiotakaki, E, European Alternating Hemiplegia of Childhood Genetics, Consortium, Neri, G, Koelewijn, S, Kamphorst, J, Geilenkirchen, M, Pelzer, N, Laan, L, Haan, J, Ferrari, M, van den Maagdenberg, A, Biobanca e., Registro Clinico per l'Emiplegia Alternante Consortium, Zucca, C, Bassi, Mt, Franchini, F, Vavassori, R, Giannotta, M, Gobbi, G, Granata, T, Nardocci, N, De Grandis, E, Veneselli, E, Stagnaro, M, Vigevano, F, European Network for Research on Alternating Hemiplegia for, Small, Medium sized Enterpriese, Consortium, Oechsler, C, Arzimanoglou, A, Ninan, M, Neville, B, Ebinger, F, Fons, C, Campistol, J, Kemlink, D, Nevsimalova, S, Peeters Scholte, C, Casaer, P, Casari, GIORGIO NEVIO, Sange, G, Spiel, G, Martinelli Boneschi, F, Schyns, T, Crawley, F, Poncelin, D, Fiori, S, Abiusi, E, Di Pietro, L, Sweney, Mt, Newcomb, Tm, Viollet, L, Huff, C, Jorde, Lb, Reyna, Sp, Murphy, Kj, Shianna, Kv, Gumbs, Ce, Little, L, Silver, K, Ptáček, Lj, Ferrari, Md, Bye, Am, Herkes, Gk, Whitelaw, Cm, Webb, D, Lynch, Bj, Uldall, P, King, Md, Scheffer, Ie, van den Maagdenberg, Am, Sisodiya, Sm, Mikati, Ma, and Goldstein, D. B.
Subjects: Nonsynonymous substitution, Genetics, 0303 health sciences, Mutation, Alternating hemiplegia of childhood, Neurological disorder, Biology, Settore MED/03 - GENETICA MEDICA, medicine.disease, medicine.disease_cause, Alternating Hemiplegia, Article, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, ATP1A3, medicine, Etiology, 030217 neurology & neurosurgery, Alternating hemiplegia, Exome sequencing, 030304 developmental biology
Abstract: Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.
Published: 2012

49. Pitfalls in genetic testing: the story of missed SCN1A mutations

Author: Djemie, T, Weckhuysen, S, von Spiczak, S, Carvill, GL, Jaehn, J, Anttonen, A-K, Brilstra, E, Caglayan, HS, de Kovel, CG, Depienne, C, Gaily, E, Hamalainen, E, Giraldez, BG, Gormley, P, Guerrero-Lopez, R, Guerrini, R, Hartmann, C, Hernandez-Hernandez, L, Hjalgrim, H, Koeleman, BPC, Leguern, E, Lehesjoki, A-E, Lemke, JR, Leu, C, Marini, C, McMahon, JM, Mei, D, Moller, RS, Muhle, H, Myers, CT, Nava, C, Serratosa, JM, Sisodiya, SM, Stephani, U, Striano, P, van Kempen, MJA, Verbeek, NE, Usluer, S, Zara, F, Palotie, A, Mefford, HC, Scheffer, IE, De Jonghe, P, Helbig, I, Suls, A, Djemie, T, Weckhuysen, S, von Spiczak, S, Carvill, GL, Jaehn, J, Anttonen, A-K, Brilstra, E, Caglayan, HS, de Kovel, CG, Depienne, C, Gaily, E, Hamalainen, E, Giraldez, BG, Gormley, P, Guerrero-Lopez, R, Guerrini, R, Hartmann, C, Hernandez-Hernandez, L, Hjalgrim, H, Koeleman, BPC, Leguern, E, Lehesjoki, A-E, Lemke, JR, Leu, C, Marini, C, McMahon, JM, Mei, D, Moller, RS, Muhle, H, Myers, CT, Nava, C, Serratosa, JM, Sisodiya, SM, Stephani, U, Striano, P, van Kempen, MJA, Verbeek, NE, Usluer, S, Zara, F, Palotie, A, Mefford, HC, Scheffer, IE, De Jonghe, P, Helbig, I, and Suls, A
Abstract: BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing. RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.
Published: 2016

50. TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features

Author: Balestrini, S, Milh, M, Castiglioni, C, Luethy, K, Finelli, MJ, Verstreken, P, Cardon, A, Strazisar, BG, Holder, JL, Lesca, G, Mancardi, MM, Poulat, AL, Repetto, GM, Banka, S, Bilo, L, Birkeland, LE, Bosch, F, Brockmann, K, Cross, JH, Doummar, D, Felix, TM, Giuliano, F, Hori, M, Huening, I, Kayserili, H, Kini, U, Lees, MM, Meenakshi, G, Mewasingh, L, Pagnamenta, AT, Peluso, S, Mey, A, Rice, GM, Rosenfeld, JA, Taylor, JC, Troester, MM, Stanley, CM, Ville, D, Walkiewicz, M, Falace, A, Fassio, A, Lemke, JR, Biskup, S, Tardif, J, Ajeawung, NF, Tolun, A, Corbett, M, Gecz, J, Afawi, Z, Howell, KB, Oliver, KL, Berkovic, SF, Scheffer, IE, de Falco, FA, Oliver, PL, Striano, P, Zara, F, Campeau, PM, Sisodiya, SM, Balestrini, S, Milh, M, Castiglioni, C, Luethy, K, Finelli, MJ, Verstreken, P, Cardon, A, Strazisar, BG, Holder, JL, Lesca, G, Mancardi, MM, Poulat, AL, Repetto, GM, Banka, S, Bilo, L, Birkeland, LE, Bosch, F, Brockmann, K, Cross, JH, Doummar, D, Felix, TM, Giuliano, F, Hori, M, Huening, I, Kayserili, H, Kini, U, Lees, MM, Meenakshi, G, Mewasingh, L, Pagnamenta, AT, Peluso, S, Mey, A, Rice, GM, Rosenfeld, JA, Taylor, JC, Troester, MM, Stanley, CM, Ville, D, Walkiewicz, M, Falace, A, Fassio, A, Lemke, JR, Biskup, S, Tardif, J, Ajeawung, NF, Tolun, A, Corbett, M, Gecz, J, Afawi, Z, Howell, KB, Oliver, KL, Berkovic, SF, Scheffer, IE, de Falco, FA, Oliver, PL, Striano, P, Zara, F, Campeau, PM, and Sisodiya, SM
Abstract: OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.
Published: 2016

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