146 results on '"Guerrini, R."'
Search Results
2. DISTRIBUTION OF PROGRESSIVE MYOCLONUS EPILEPSIES IN ITALY; POSITIVELY DIAGNOSED AND UNCLASSIFIED PATIENTS: p827
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Canafoglia, L., Franceschetti, S., Michelucci, R., Magaudda, A., Rubboli, G., Tinuper, P., Striano, P., Striano, S., Gambardella, A., Neve, La A., Francavilla, T., Ferlazzo, E., Italiano, D., Gobbi, G., Villani, F., Nardocci, N., Granata, T., Veggiotti, P., Pareyson, D., Coppola, G., Uziel, G., Belcastro, V., Bisulli, F., Spreafico, R., Guerrini, R., Viri, M., Zucca, C., Capovilla, G., Giovagnoli, A. R., Canevini, M. P., Binelli, S., Casazza, M., Cantisani, A. T., Filla, A., Pezzella, M., Santucci, M., Parmeggiani, A., Posar, A., De Maria, G., Marini, C., Bianchi, A., Ragona, F., Freri, E., Mariotti, C., and Costa, P.
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- 2012
3. IS THE CONCEPT OF ACUTE SYMPTOMATIC SEIZURES VALID?
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Guerrini, R
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- 2010
4. GENOMICS: IMPLICATIONS FOR CLINICAL PRACTICE
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Guerrini, R
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- 2010
5. CHALLENGING THE CONCEPT OF IDIOPATHIC EPILEPSIES CLINICAL EEG (ICTAL - INTERICTAL) EVIDENCE
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Guerrini, R
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- 2010
6. INFANTILE ONSET FOCAL EPILEPSY AND EPILEPTIC ENCEPHALOPATHIES ASSOCIATED WITH PCDH19 GENE MUTATIONS: NEW DE NOVO AND FAMILIAL MUTATIONS: 001
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Marini, C, Mei, D, Parmeggiani, L, Norci, V, Calado, E, Moreira, A, Ferrari, A, Pisano, T, Battaglia, D, and Guerrini, R
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- 2010
7. BRAIN MATURATION AND THE EVOLUTION OF EPILEPSY SYNDROMES
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Guerrini, R.
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- 2006
8. SYMPTOMATIC SYNDROMES IN INFANTS: ETIOLOGY AND ELECTROCLINICAL PATTERNS
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Guerrini, R.
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- 2006
9. Surgical Resection for Intractable Epilepsy in "Double Cortex" Syndrome Yields Inadequate Results
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Bernasconi, A., Martinez, V., Rosa-Neto, P., D'Agostino, D., Bernasconi, N., Berkovic, S., MacKay, M., Harvey, A. Simon, Palmini, A., da Costa, J. Costa, Paglioli, Eliseu, Kim, H. I., Connolly, M., Olivier, A., Dubeau, F., Andermann, E., Guerrini, R., Whisler, W., de Toledo-Morrell, L., Morrell, F., and Andermann, F.
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- 2001
10. The Costs of Childhood Epilepsy in Italy: Comparative Findings from Three Health Care Settings
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Guerrini, R., Battini, R., Ferrari, A. R., Veggiotti, P., Besana, D., Gobbi, G., Pezzani, M., Berta, E., Tetto, A., Beghi, E., Monticelli, M. L., Tediosi, F., Garattini, L., Russo, S., Rasmini, P., Amadi, A., Quarti, P., and Fabrizzi, R.
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- 2001
11. Genetic Predisposition to Severe Myoclonic Epilepsy in Infancy
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Benlounis, A., Nabbout, R., Feingold, J., Parmeggiani, A., Guerrini, R., Kaminska, A., and Dulac, O.
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- 2001
12. Early-Onset Benign Occipital Seizure Susceptibility Syndrome
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Ferrie, C. D., Beaumanoir, A., Guerrini, R., Kivity, S., Vigevano, F., Takaishi, Y., Watanabe, K., Mira, L., Capizzi, G., Costa, P., Valseriati, D., Grioni, D., Lerman, P., Ricci, S., Vigliano, P., Goumas-Kartalas, A., Hashimoto, K., Robinson, R. O., and Panayiotopoulos, C. P.
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- 1997
13. Early Clinical and EEG Features of Infantile Spasms in Down Syndrome
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Silva, M. L., Cieuta, C., Guerrini, R., Plouin, P., Livet, M. O., and Dulac, O.
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- 1996
14. Late-Onset Epileptic Spasms
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Gobbi, Giuseppe, Parmeggiani, A., Guerrini, R., Viani, F., Pini, A., Bertani, G., Romeo, A., Santucci, M., and Rossi, P. Giovanardi
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- 1996
15. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy
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Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH
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Male ,Idiopathic generalized epilepsy ,Neuronal ,Idiopathic Generalized Epilepsy ,1q21 ,1 Microdeletion ,Two-hit Hypothesis ,Nrxn1 ,Neuropsychological Tests ,Immunoglobulin E ,Cell Adhesion Molecules, Neuronal/genetics ,Adult, Age of Onset, Anticonvulsant ,Exon ,1q21.1 microdeletion ,Exons/genetics ,Odds Ratio ,Nerve Tissue Proteins/genetics ,Copy-number variation ,Valproic Acid/therapeutic use ,Age of Onset ,Neural Cell Adhesion Molecules ,genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy ,Genetics ,biology ,Triazines ,Anticonvulsants/therapeutic use ,Electroencephalography ,genetics, Family, Female, Fructose ,Exons ,Middle Aged ,Settore MED/39 - Neuropsichiatria Infantile ,Pedigree ,therapeutic use, Valproic Acid ,Neurology ,Settore MED/26 - Neurologia ,Anticonvulsants ,Epilepsy, Generalized ,Female ,Adult ,Case-Control Studies ,Cell Adhesion Molecules, Neuronal ,DNA Copy Number Variations ,Family ,Fructose ,Gene Deletion ,Genotype ,Humans ,Infant ,Microarray Analysis ,Nerve Tissue Proteins ,Valproic Acid ,analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein ,therapeutic use, Case-Control Studies, Cell Adhesion Molecule ,drug therapy/genetics/psychology, Exon ,genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine ,Lamotrigine ,NRXN1 ,Topiramate ,Epilepsy, Generalized/drug therapy ,medicine ,Allele ,Biology ,Gene ,Generalized ,Point mutation ,Calcium-Binding Proteins ,Odds ratio ,medicine.disease ,Triazines/therapeutic use ,Settore MED/03 - Genetica Medica ,therapeutic use ,biology.protein ,Fructose/analogs & derivatives ,Human medicine ,Neurology (clinical) ,Two-hit hypothesis - Abstract
Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.
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- 2013
16. Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations
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Specchio, N, Marini, C, Terracciano, A, Mei, D, Trivisano, M, Sicca, F, Fusco, L, Cusmai, R, Darra, Francesca, DALLA BERNARDINA, Bernardo, Bertini, E, Guerrini, R, and Vigevano, F.
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Epilepsy ,Mutation, Missense ,Brain ,Infant ,Electroencephalography ,Cadherins ,Protocadherins ,Phenotype ,Seizures ,Child, Preschool ,Humans ,PCDH19 mutation ,Female ,Age of Onset ,Frameshift Mutation - Abstract
To describe clinical and neuropsychological features of six consecutive sporadic girls with protocadherin 19 (PCDH19) mutations.Following recent descriptions of PCDH19 mutation in girls with epilepsy, we sequenced this gene in patients with infantile or early childhood seizures onset, either focal or generalized, without an obvious etiology.Mean age at the time of the study was 13.5 ± 11 years. Mean age at seizure onset was 15.5 ± 11 months (range 9-38). All patients experienced clusters of either focal or generalized seizures, precipitated during febrile illness in five patients. Attacks were very frequent at onset, but they became less numerous during follow-up. Ictal electroencephalography (EEG) showed temporal lobe involvement in five patients. Periictal EEG showed focal or multifocal epileptiform and slow abnormalities. Cognitive impairment became obvious after seizure onset in three patients and was associated with autistic features in two. Genetic analysis revealed five new and one known de novo PCDH19 mutation that were missense in four and frameshift in two. Variants are clustered in the large exon 1, corresponding to the extracellular domain of the PCDH19 protein.Our findings emphasize that de novo PCDH19 mutations are associated with infantile or early childhood onset of febrile or afebrile seizures often occurring in clusters. Cognitive impairment is not constantly present and autistic features are observed in some patients. Most patients have a "stormy" seizure onset, often related to fever; however, seizure severity does not clearly correlate with the degree of cognitive deficit. PCDH19 is likely a major epilepsy gene; phenotypes associated with mutations of this gene range from epileptic encephalopathies to mild epilepsy, yet large series of patients will be necessary to fully delineate phenotypic spectrum.
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- 2011
17. The genetics of Dravet syndrome
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Marini, C., Scheffer, I. E., Nabbout, R., Suls, A., De Jonghe, P., Zara, F., and Guerrini, R.
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Duplication ,Array comparative genome hybridization ,Infant ,Epilepsies, Myoclonic ,Nerve Tissue Proteins ,Syndrome ,Deletion ,Dravet syndrome ,MLPA ,SCN1A ,Humans ,Mutation ,NAV1.1 Voltage-Gated Sodium Channel ,Sodium Channels ,Epilepsies ,Human medicine ,Myoclonic ,Biology - Abstract
Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice-site and missense mutations, most of which fall into the pore-forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur. Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 23% of patients. A small percentage of female patients with a DS-like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.
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- 2011
18. Genetic Predisposition to Severe Myoclonic Epilepsy in Infancy
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Benlounis, A., primary, Nabbout, R., additional, Feingold, J., additional, Parmeggiani, A., additional, Guerrini, R., additional, Kaminska, A., additional, and Dulac, O., additional
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- 2008
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19. Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants
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Renzo Guerrini, Francesco Miceli, Elena Cellini, Mario Nappi, Maurizio Taglialatela, Lucio Parmeggiani, Christina A. Gurnett, Maria Virginia Soldovieri, Davide Mei, Miceli, F., Guerrini, R., Nappi, M., Soldovieri, M. V., Cellini, E., Gurnett, C. A., Parmeggiani, L., Mei, D., and Taglialatela, M.
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Mutant ,Biology ,loss-of-function variants ,developmental encephalopathie ,gain-of-function variant ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,medicine ,Humans ,gain-of-function variants ,Loss function ,030304 developmental biology ,Genetics ,loss-of-function variant ,0303 health sciences ,Sodium channel ,developmental encephalopathies ,epilepsy ,KCNA1 ,potassium channels ,medicine.disease ,Phenotype ,In vitro ,Potassium channel ,Electrophysiology ,Carbamazepine ,Neurology ,Mutation ,Neurology (clinical) ,Kv1.1 Potassium Channel ,030217 neurology & neurosurgery - Abstract
A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored.
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- 2021
20. Autosomal dominant early-onset cortical myoclonus, photic-induced myoclonus, and epilepsy in a large pedigree
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Pasquale Montagna, Francesca Bisulli, Paolo Tinuper, Elio Lugaresi, Carla Marini, Rocco Liguori, Elena Parrini, Renzo Guerrini, Elena Gardella, GARDELLA E., TINUPER P., MARINI C., GUERRINI R., PARRINI E., BISULLI F., LIGUORI R., MONTAGNA P., and LUGARESI E.
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Myoclonus ,Genetic Linkage ,Myoclonic Jerk ,Physiology ,Neurological disorder ,Electroencephalography ,Epilepsy, Reflex ,Epilepsy ,Genetic linkage ,medicine ,Humans ,Age of Onset ,Cerebral Cortex ,Brain Diseases ,medicine.diagnostic_test ,Genetic heterogeneity ,medicine.disease ,Pedigree ,Neurology ,Chromosomes, Human, Pair 2 ,Neurology (clinical) ,Age of onset ,medicine.symptom ,Psychology ,Neuroscience ,Chromosomes, Human, Pair 8 - Abstract
Summary: Purpose: Cortical tremor, a form of rhythmic cortical myoclonus (rhythmic CM), and epilepsy have been described in families with autosomal dominant inheritance. Linkage analyses revealed two putative loci on chromosome 2p and 8q. Clinical photosensitivity was not a prominent feature in such families. We describe a large Italian family with rhythmic CM, photosensitivity, and epilepsy. Methods: Twenty-three individuals of a five-generation family were studied. Linkage analyses for the loci on chromosome 2p11.1 and 8q23.3 were performed. Results: Of the 23 studied family members, 16 were affected. Rhythmic CM of childhood onset was present in all 16 individuals (onset ranging from 3 to 12 years), was associated with photic-induced myoclonic jerks in seven, and with epileptic seizures in six (onset ranging from 23 to 34 years). Five children of the V generation manifested also episodes of arousal with generalized tremor in early infancy (“tremulous arousals”). Jerk-locked back-averaging of rhythmic CM of six affected individuals, documented a premyoclonic EEG correlate. C-reflex at rest was present in two affected adults. Linkage analyses excluded mapping to the 2p11.1 and 8q23.3 loci. Conclusions: Clinical variability and severity of the phenotypes in this family are in line with those of previously described pedigrees with autosomal dominant cortical myoclonus and epilepsy. In this family, a progression of symptoms was found: rhythmic CM and tremulous arousals occurred in childhood, whereas visually induced manifestations and epileptic seizures occurred during adolescence–adulthood. Exclusion of linkage to the two known loci is consistent with genetic heterogeneity of such familial clustering of symptoms.
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- 2006
21. Temporal lobe epilepsy surgery in children and adults: A multicenter study
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Barba, Carmen, Cossu, Massimo, Guerrini, Renzo, Di Gennaro, Giancarlo, Villani, Flavio, De Palma, Luca, Grisotto, Laura, Consales, Alessandro, Battaglia, Domenica, Zamponi, Nelia, d’Orio, Piergiorgio, Revay, Martina, Rizzi, Michele, Casciato, Sara, Esposito, Vincenzo, Quarato, Pier Paolo, Di Giacomo, Roberta, Didato, Giuseppe, Pastori, Chiara, Pavia, Giusy Carfi, Pellacani, Simona, Matta, Giulia, Pacetti, Mattia, Tamburrini, Gianpiero, Cesaroni, Elisabetta, Colicchio, Gabriella, Vatti, Giampaolo, Asioli, Sofia, Caulo, Massimo, Marras, Carlo Efisio, Tassi, Laura, D’Aniello, Alfredo, Morace, Roberta, De Curtis, Marco, Deleo, Francesca, Giordano, Flavio, De Benedictis, Alessandro, Prato, Giulia, Perulli, Marco, Barba C., Cossu M., Guerrini R., Di Gennaro G., Villani F., De Palma L., Grisotto L., Consales A., Battaglia D., Zamponi N., d'Orio P., Revay M., Rizzi M., Casciato S., Esposito V., Quarato P.P., Di Giacomo R., Didato G., Pastori C., Carfi Pavia G., Pellacani S., Matta G., Pacetti M., Tamburrini G., Cesaroni E., Colicchio G., Vatti G., Asioli S., Caulo M., Marras C.E., and Tassi L.
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0301 basic medicine ,Male ,Electroencephalography ,Neuropsychological Tests ,Hippocampus ,Neurosurgical Procedures ,Epilepsy ,0302 clinical medicine ,Postoperative Complications ,Cognition ,Epilepsy surgery ,Child ,seizure outcome ,medicine.diagnostic_test ,Age Factors ,Prognosis ,Temporal Lobe ,Malformations of Cortical Development ,Neurology ,Child, Preschool ,epilepsy surgery ,Anticonvulsants ,Female ,Adult ,medicine.medical_specialty ,Referral ,Adolescent ,Temporal lobe ,03 medical and health sciences ,Young Adult ,Settore MED/39 - NEUROPSICHIATRIA INFANTILE ,children ,Internal medicine ,Early Medical Intervention ,medicine ,Humans ,Preschool ,Retrospective Studies ,Hippocampal sclerosis ,Sclerosis ,business.industry ,Magnetic resonance imaging ,Odds ratio ,cognitive outcome ,medicine.disease ,030104 developmental biology ,Epilepsy, Temporal Lobe ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Objective: To assess seizure and cognitive outcomes and their predictors in children (
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22. Clinical and molecular characterization of patients with YWHAG-related epilepsy.
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Cetica V, Pisano T, Lesca G, Marafi D, Licchetta L, Riccardi F, Mei D, Chung HB, Bayat A, Balasubramanian M, Lowenstein DH, Endzinienė M, Alotaibi M, Villeneuve N, Jacobs J, Isidor B, Solazzi R, den Hollander NS, Marjanovic D, Rougeot-Jung C, Jung J, Lesieur-Sebellin M, Accogli A, Salpietro V, Saadi NW, Panagiotakaki E, Foiadelli T, Redon S, Tsai MH, Bisulli F, Hammer TB, Lupski JR, Parrini E, and Guerrini R
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- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Young Adult, Cohort Studies, Developmental Disabilities genetics, Electroencephalography, Genetic Association Studies, Intellectual Disability genetics, Magnetic Resonance Imaging, Phenotype, Epilepsy diagnostic imaging, Epilepsy genetics, Epilepsy pathology
- Abstract
Objective: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy., Methods: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients., Results: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001)., Significance: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2024
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23. Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies.
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Gallagher D, Pérez-Palma E, Bruenger T, Ghanty I, Brilstra E, Ceulemans B, Chemaly N, de Lange I, Depienne C, Guerrini R, Mei D, Møller RS, Nabbout R, Regan BM, Schneider AL, Scheffer IE, Schoonjans AS, Symonds JD, Weckhuysen S, Zuberi SM, Lal D, and Brunklaus A
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- Humans, Retrospective Studies, NAV1.1 Voltage-Gated Sodium Channel genetics, Phenotype, Genetic Association Studies, Mutation genetics, Epilepsy genetics, Epilepsy diagnosis, Epilepsies, Myoclonic genetics, Seizures, Febrile genetics, Status Epilepticus
- Abstract
Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood., Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype., Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ
2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS., Significance: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)- Published
- 2024
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24. Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.
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Kerestes R, Perry A, Vivash L, O'Brien TJ, Alvim MKM, Arienzo D, Aventurato ÍK, Ballerini A, Baltazar GF, Bargalló N, Bender B, Brioschi R, Bürkle E, Caligiuri ME, Cendes F, de Tisi J, Duncan JS, Engel JP Jr, Foley S, Fortunato F, Gambardella A, Giacomini T, Guerrini R, Hall G, Hamandi K, Ives-Deliperi V, João RB, Keller SS, Kleiser B, Labate A, Lenge M, Marotta C, Martin P, Mascalchi M, Meletti S, Owens-Walton C, Parodi CB, Pascual-Diaz S, Powell D, Rao J, Rebsamen M, Reiter J, Riva A, Rüber T, Rummel C, Scheffler F, Severino M, Silva LS, Staba RJ, Stein DJ, Striano P, Taylor PN, Thomopoulos SI, Thompson PM, Tortora D, Vaudano AE, Weber B, Wiest R, Winston GP, Yasuda CL, Zheng H, McDonald CR, Sisodiya SM, and Harding IH
- Subjects
- Adult, Humans, Phenytoin, Cross-Sectional Studies, Cerebellum diagnostic imaging, Cerebellum pathology, Seizures complications, Magnetic Resonance Imaging methods, Atrophy pathology, Epilepsy, Temporal Lobe complications, Epileptic Syndromes complications
- Abstract
Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group., Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness., Results: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (d
max = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 = .05) and longer epilepsy duration ( η ρ max 2 = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls., Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)- Published
- 2024
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25. Developmental epileptic encephalopathy in DLG4-related synaptopathy.
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Kassabian B, Levy AM, Gardella E, Aledo-Serrano A, Ananth AL, Brea-Fernández AJ, Caumes R, Chatron N, Dainelli A, De Wachter M, Denommé-Pichon AS, Dye TJ, Fazzi E, Felt R, Fernández-Jaén A, Fernández-Prieto M, Gantz E, Gasperowicz P, Gil-Nagel A, Gómez-Andrés D, Greiner HM, Guerrini R, Haanpää MK, Helin M, Hoyer J, Hurst ACE, Kallish S, Karkare SN, Khan A, Kleinendorst L, Koch J, Kothare SV, Koudijs SM, Lagae L, Lakeman P, Leppig KA, Lesca G, Lopergolo D, Lusk L, Mackenzie A, Mei D, Møller RS, Pereira EM, Platzer K, Quelin C, Revah-Politi A, Rheims S, Rodríguez-Palmero A, Rossi A, Santorelli F, Seinfeld S, Sell E, Stephenson D, Szczaluba K, Trinka E, Umair M, Van Esch H, van Haelst MM, Veenma DCM, Weber S, Weckhuysen S, Zacher P, Tümer Z, and Rubboli G
- Subjects
- Humans, Retrospective Studies, Muscle Hypotonia, Seizures complications, Electroencephalography methods, Disks Large Homolog 4 Protein genetics, Epilepsy diagnostic imaging, Epilepsy genetics, Epilepsy complications, Brain Diseases genetics, Epilepsy, Generalized complications, Intellectual Disability genetics, Intellectual Disability complications
- Abstract
Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy., Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician., Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants., Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG., (© 2023 International League Against Epilepsy.)
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- 2024
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26. Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial.
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Sullivan J, Lagae L, Cross JH, Devinsky O, Guerrini R, Knupp KG, Laux L, Nikanorova M, Polster T, Talwar D, Ceulemans B, Nabbout R, Farfel GM, Galer BS, Gammaitoni AR, Lock M, Agarwal A, and Scheffer IE
- Abstract
Objective: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome., Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo., Results: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected., Significance: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Published
- 2023
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27. Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions.
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Corbett MA, Depienne C, Veneziano L, Klein KM, Brancati F, Guerrini R, Zara F, Tsuji S, and Gecz J
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- Humans, Pedigree, Research, Epilepsies, Myoclonic genetics, Epilepsies, Myoclonic pathology
- Abstract
Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade-off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Published
- 2023
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28. Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.
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Knupp KG, Scheffer IE, Ceulemans B, Sullivan J, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Agarwal A, Lock M, Dai D, Farfel GM, Galer BS, Gammaitoni AR, Polega S, Davis R, and Gil-Nagel A
- Subjects
- Adult, Humans, Child, Adolescent, Young Adult, Anticonvulsants therapeutic use, Fenfluramine therapeutic use, Treatment Outcome, Seizures drug therapy, Lennox Gastaut Syndrome drug therapy, COVID-19
- Abstract
Objective: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS)., Methods: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months., Results: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed., Significance: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS., (© 2022 UCB and The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Published
- 2023
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29. The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission.
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Najm I, Lal D, Alonso Vanegas M, Cendes F, Lopes-Cendes I, Palmini A, Paglioli E, Sarnat HB, Walsh CA, Wiebe S, Aronica E, Baulac S, Coras R, Kobow K, Cross JH, Garbelli R, Holthausen H, Rössler K, Thom M, El-Osta A, Lee JH, Miyata H, Guerrini R, Piao YS, Zhou D, and Blümcke I
- Subjects
- Consensus, Humans, Magnetic Resonance Imaging, Neuroimaging, Retrospective Studies, Epilepsy diagnosis, Epilepsy pathology, Malformations of Cortical Development diagnostic imaging, Malformations of Cortical Development genetics, Malformations of Cortical Development, Group I diagnosis
- Abstract
Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico-pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular-genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro-clinical-imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico-pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and "no definite FCD on histopathology" as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi-layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Published
- 2022
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30. Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.
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Lopez SM, Aksman LM, Oxtoby NP, Vos SB, Rao J, Kaestner E, Alhusaini S, Alvim M, Bender B, Bernasconi A, Bernasconi N, Bernhardt B, Bonilha L, Caciagli L, Caldairou B, Caligiuri ME, Calvet A, Cendes F, Concha L, Conde-Blanco E, Davoodi-Bojd E, de Bézenac C, Delanty N, Desmond PM, Devinsky O, Domin M, Duncan JS, Focke NK, Foley S, Fortunato F, Galovic M, Gambardella A, Gleichgerrcht E, Guerrini R, Hamandi K, Ives-Deliperi V, Jackson GD, Jahanshad N, Keller SS, Kochunov P, Kotikalapudi R, Kreilkamp BAK, Labate A, Larivière S, Lenge M, Lui E, Malpas C, Martin P, Mascalchi M, Medland SE, Meletti S, Morita-Sherman ME, Owen TW, Richardson M, Riva A, Rüber T, Sinclair B, Soltanian-Zadeh H, Stein DJ, Striano P, Taylor PN, Thomopoulos SI, Thompson PM, Tondelli M, Vaudano AE, Vivash L, Wang Y, Weber B, Whelan CD, Wiest R, Winston GP, Yasuda CL, McDonald CR, Alexander DC, Sisodiya SM, and Altmann A
- Subjects
- Atrophy pathology, Biomarkers, Cross-Sectional Studies, Hippocampus diagnostic imaging, Hippocampus pathology, Humans, Magnetic Resonance Imaging methods, Sclerosis complications, Epilepsy complications, Epilepsy, Temporal Lobe pathology
- Abstract
Objective: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features., Methods: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance., Results: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10
-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI., Significance: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)- Published
- 2022
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31. Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants.
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Miceli F, Guerrini R, Nappi M, Soldovieri MV, Cellini E, Gurnett CA, Parmeggiani L, Mei D, and Taglialatela M
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- Carbamazepine therapeutic use, Humans, Kv1.1 Potassium Channel genetics, Mutation genetics, Phenotype, Epilepsy drug therapy, Epilepsy genetics
- Abstract
A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Published
- 2022
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32. Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study.
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Wagstyl K, Whitaker K, Raznahan A, Seidlitz J, Vértes PE, Foldes S, Humphreys Z, Hu W, Mo J, Likeman M, Davies S, Lenge M, Cohen NT, Tang Y, Wang S, Ripart M, Chari A, Tisdall M, Bargallo N, Conde-Blanco E, Pariente JC, Pascual-Diaz S, Delgado-Martínez I, Pérez-Enríquez C, Lagorio I, Abela E, Mullatti N, O'Muircheartaigh J, Vecchiato K, Liu Y, Caligiuri M, Sinclair B, Vivash L, Willard A, Kandasamy J, McLellan A, Sokol D, Semmelroch M, Kloster A, Opheim G, Yasuda C, Zhang K, Hamandi K, Barba C, Guerrini R, Gaillard WD, You X, Wang I, González-Ortiz S, Severino M, Striano P, Tortora D, Kalviainen R, Gambardella A, Labate A, Desmond P, Lui E, O'Brien T, Shetty J, Jackson G, Duncan JS, Winston GP, Pinborg L, Cendes F, Cross JH, Baldeweg T, and Adler S
- Subjects
- Child, Freedom, Humans, Magnetic Resonance Imaging, Retrospective Studies, Seizures diagnostic imaging, Seizures etiology, Seizures surgery, Treatment Outcome, Drug Resistant Epilepsy complications, Drug Resistant Epilepsy diagnostic imaging, Drug Resistant Epilepsy surgery, Epilepsy diagnostic imaging, Epilepsy etiology, Epilepsy surgery, Malformations of Cortical Development complications, Malformations of Cortical Development diagnostic imaging, Malformations of Cortical Development surgery
- Abstract
Objective: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome., Methods: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom., Results: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%., Significance: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Published
- 2022
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33. Temporal lobe epilepsy surgery in children and adults: A multicenter study.
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Barba C, Cossu M, Guerrini R, Di Gennaro G, Villani F, De Palma L, Grisotto L, Consales A, Battaglia D, Zamponi N, d'Orio P, Revay M, Rizzi M, Casciato S, Esposito V, Quarato PP, Di Giacomo R, Didato G, Pastori C, Pavia GC, Pellacani S, Matta G, Pacetti M, Tamburrini G, Cesaroni E, Colicchio G, Vatti G, Asioli S, Caulo M, Marras CE, and Tassi L
- Subjects
- Adolescent, Adult, Age Factors, Anticonvulsants therapeutic use, Child, Child, Preschool, Early Medical Intervention, Electroencephalography, Epilepsy, Temporal Lobe drug therapy, Epilepsy, Temporal Lobe physiopathology, Epilepsy, Temporal Lobe psychology, Female, Hippocampus pathology, Humans, Male, Malformations of Cortical Development pathology, Neuropsychological Tests, Postoperative Complications epidemiology, Prognosis, Retrospective Studies, Sclerosis, Young Adult, Cognition, Epilepsy, Temporal Lobe surgery, Neurosurgical Procedures
- Abstract
Objective: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers., Methods: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons., Results: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group., Significance: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome., (© 2020 International League Against Epilepsy.)
- Published
- 2021
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34. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.
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Bar C, Kuchenbuch M, Barcia G, Schneider A, Jennesson M, Le Guyader G, Lesca G, Mignot C, Montomoli M, Parrini E, Isnard H, Rolland A, Keren B, Afenjar A, Dorison N, Sadleir LG, Breuillard D, Levy R, Rio M, Dupont S, Negrin S, Danieli A, Scalais E, De Saint Martin A, El Chehadeh S, Chelly J, Poisson A, Lebre AS, Nica A, Odent S, Sekhara T, Brankovic V, Goldenberg A, Vrielynck P, Lederer D, Maurey H, Terrone G, Besmond C, Hubert L, Berquin P, Billette de Villemeur T, Isidor B, Freeman JL, Mefford HC, Myers CT, Howell KB, Rodríguez-Sacristán Cascajo A, Meyer P, Genevieve D, Guët A, Doummar D, Durigneux J, van Dooren MF, de Wit MCY, Gerard M, Marey I, Munnich A, Guerrini R, Scheffer IE, Kabashi E, and Nabbout R
- Subjects
- Adolescent, Adult, Brain Diseases physiopathology, Child, Child, Preschool, Cohort Studies, Electroencephalography trends, Epilepsy physiopathology, Female, Humans, Infant, Male, Retrospective Studies, Time Factors, Treatment Outcome, Young Adult, Brain Diseases diagnostic imaging, Brain Diseases genetics, Epilepsy diagnostic imaging, Epilepsy genetics, Genetic Variation genetics, Shab Potassium Channels genetics
- Abstract
Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy., Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature., Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants., Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis., (© 2020 International League Against Epilepsy.)
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- 2020
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35. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.
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Specchio N, Pietrafusa N, Doccini V, Trivisano M, Darra F, Ragona F, Cossu A, Spolverato S, Battaglia D, Quintiliani M, Luigia Gambardella M, Rosati A, Mei D, Granata T, Dalla Bernardina B, Vigevano F, and Guerrini R
- Subjects
- Adolescent, Adult, Anorexia chemically induced, Anticonvulsants administration & dosage, Anticonvulsants adverse effects, Child, Child, Preschool, Epilepsies, Myoclonic diagnostic imaging, Epilepsies, Myoclonic physiopathology, Female, Fenfluramine adverse effects, Follow-Up Studies, Humans, Male, Prospective Studies, Seizures diagnostic imaging, Seizures physiopathology, Selective Serotonin Reuptake Inhibitors adverse effects, Treatment Outcome, Young Adult, Epilepsies, Myoclonic drug therapy, Fenfluramine administration & dosage, Seizures drug therapy, Selective Serotonin Reuptake Inhibitors administration & dosage
- Abstract
Objective: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS., Methods: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months., Results: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA., Significance: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated., (© 2020 International League Against Epilepsy.)
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- 2020
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36. Lessons learned from 40 novel PIGA patients and a review of the literature.
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Bayat A, Knaus A, Pendziwiat M, Afenjar A, Barakat TS, Bosch F, Callewaert B, Calvas P, Ceulemans B, Chassaing N, Depienne C, Endziniene M, Ferreira CR, Moura de Souza CF, Freihuber C, Ganesan S, Gataullina S, Guerrini R, Guerrot AM, Hansen L, Jezela-Stanek A, Karsenty C, Kievit A, Kooy FR, Korff CM, Kragh Hansen J, Larsen M, Layet V, Lesca G, McBride KL, Meuwissen M, Mignot C, Montomoli M, Moore H, Naudion S, Nava C, Nougues MC, Parrini E, Pastore M, Schelhaas JH, Skinner S, Szczałuba K, Thomas A, Thomassen M, Tranebjaerg L, van Slegtenhorst M, Wolfe LA, Lal D, Gardella E, Bomme Ousager L, Brünger T, Helbig I, Krawitz P, and Møller RS
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- Adult, Amino Acid Sequence, Child, Cohort Studies, Electroencephalography methods, Facies, Hernia, Diaphragmatic physiopathology, Humans, Infant, Newborn, Limb Deformities, Congenital physiopathology, Magnetic Resonance Imaging methods, Male, Genetic Variation genetics, Hernia, Diaphragmatic diagnostic imaging, Hernia, Diaphragmatic genetics, Limb Deformities, Congenital diagnostic imaging, Limb Deformities, Congenital genetics, Membrane Proteins genetics
- Abstract
Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations., Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches., Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein., Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA., (© 2020 International League Against Epilepsy.)
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- 2020
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37. Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures.
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Tang S, Addis L, Smith A, Topp SD, Pendziwiat M, Mei D, Parker A, Agrawal S, Hughes E, Lascelles K, Williams RE, Fallon P, Robinson R, Cross HJ, Hedderly T, Eltze C, Kerr T, Desurkar A, Hussain N, Kinali M, Bagnasco I, Vassallo G, Whitehouse W, Goyal S, Absoud M, Møller RS, Helbig I, Weber YG, Marini C, Guerrini R, Simpson MA, and Pal DK
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- Age of Onset, Attention Deficit Disorder with Hyperactivity complications, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity pathology, Autism Spectrum Disorder complications, Autism Spectrum Disorder genetics, Autism Spectrum Disorder pathology, Child, Child, Preschool, Electroencephalography, Epilepsies, Myoclonic complications, Epilepsies, Myoclonic genetics, Epilepsy, Generalized complications, Epilepsy, Generalized genetics, Female, Humans, Infant, Intellectual Disability complications, Intellectual Disability genetics, Intellectual Disability pathology, Male, Neuroimaging, Phenotype, Seizures genetics, Exome Sequencing, Epilepsies, Myoclonic pathology, Epilepsy, Generalized pathology, Seizures pathology
- Abstract
Objective: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE)., Methods: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies., Results: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each., Significance: MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2020
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38. Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.
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Barba C, Cross JH, Braun K, Cossu M, Klotz KA, De Masi S, Perez Jiménez MA, Gaily E, Specchio N, Cabral P, Toulouse J, Dimova P, Battaglia D, Freri E, Consales A, Cesaroni E, Tarta-Arsene O, Gil-Nagel A, Mindruta I, Di Gennaro G, Giulioni M, Tisdall MM, Eltze C, Tahir MZ, Jansen F, van Rijen P, Sanders M, Tassi L, Francione S, Lo Russo G, Jacobs J, Bast T, Matta G, Budke M, Fournier Del Castillo C, Metsahonkala EL, Karppinen A, Ferreira JC, Minkin K, Marras CE, Arzimanoglou A, and Guerrini R
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- Adolescent, Age Factors, Child, Child, Preschool, Electroencephalography, Epilepsy epidemiology, Epilepsy pathology, Europe epidemiology, Female, Humans, Magnetic Resonance Imaging, Male, Neurosurgery statistics & numerical data, Neurosurgical Procedures statistics & numerical data, Retrospective Studies, Seizures epidemiology, Temporal Lobe diagnostic imaging, Temporal Lobe surgery, Treatment Outcome, Epilepsy surgery, Neurosurgery trends, Neurosurgical Procedures trends
- Abstract
Objective: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015., Methods: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries., Results: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015., Significance: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2020
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39. Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies.
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Mei D, Cetica V, Marini C, and Guerrini R
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- Brain Diseases genetics, Humans, Seizures, Febrile genetics, Epilepsies, Myoclonic genetics, Epilepsy genetics, Epileptic Syndromes genetics, NAV1.1 Voltage-Gated Sodium Channel genetics
- Abstract
Dravet syndrome is the most studied form of genetic epilepsy. It has now been clarified that the clinical spectrum of the syndrome does not have firmly established boundaries. The core phenotype is characterized by intractable, mainly clonic, seizures precipitated by increased body temperature with onset in the first year of life and subsequent appearance of multiple seizures types still precipitated by, but not confined to, hyperthermia. Cognitive impairment is invariably present when the full syndrome is manifested. This complex of symptoms is related to mutations in the SCN1A gene, which are often de novo and constitutional but can also be inherited from a parent with less severe clinical manifestations or be present as somatic mosaicism. Inheritance from less severely affected individuals, at times only having experienced a few febrile seizures, and differences in severity, even within the same family, with a subset of patients only showing fragments of the syndrome, testify to a remarkable phenotypic heterogeneity as far as severity, but less so clinical phenomenology, are concerned. This characteristic, together with underascertainment of SCN1A mutations due to human errors or technical limitations in uncovering alternative pathogenic molecular mechanisms, such as genomic rearrangements or poison exons, has contributed to making clinicians and geneticists suspicious that Dravet syndrome may be caused by more than one gene. This opinion has been further amplified by the description of other genetic disorders, such as PCDH19- or CHD2-related epilepsy, whose phenotypes have included fragments of the Dravet phenotypic spectrum, and by the suboptimal characterization of phenotypes associated with mutations in SCN1B, HCN1, KCN2A, GABRA1, GABRG2, and STXBP1. The SCN1A gene-Dravet syndrome association is in our opinion highly specific. However, because the syndrome spectrum is wide, fragments of it can at times also be manifested in other genetic epilepsy syndromes, thereby leading to overdiagnosis of Dravet syndrome beyond SCN1A. Dravet syndrome is in turn a severe SCN1A phenotype within a continuum of SCN1A-related clinical phenomenology., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2019
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40. Dravet syndrome: Treatment options and management of prolonged seizures.
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Cross JH, Caraballo RH, Nabbout R, Vigevano F, Guerrini R, and Lagae L
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- Diet, Ketogenic methods, Humans, Valproic Acid therapeutic use, Anticonvulsants therapeutic use, Dioxolanes pharmacology, Epilepsies, Myoclonic drug therapy, Seizures drug therapy
- Abstract
Over time, with careful delineation of Dravet syndrome, we have gained experience in treatments most likely to lead to improvement in seizures, as well as those that should be avoided. Sodium valproate, clobazam, stiripentol, and topiramate are all medications that may lead to benefit, as well as the ketogenic diet. Bromides may be utilized in resistant cases. However, equally important are outlining prompt rescue treatment for prolonged seizures and avoidance of precipitants. Newer agents including cannabidiol and fenfluramine have been demonstrated to be of benefit in clinical trials. We propose an algorithm for management, but appreciate that the positioning of newer agents is yet to be established., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2019
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41. Dravet syndrome and other sodium channel-related encephalopathies.
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Guerrini R, Cross H, Nabbout R, and Dalla Bernardina B
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- Epilepsies, Myoclonic diagnosis, Humans, Mutation genetics, Brain Diseases genetics, Epilepsies, Myoclonic genetics, Epilepsy therapy, Sodium Channels genetics
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- 2019
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42. Long-term efficacy of add-on stiripentol treatment in children, adolescents, and young adults with refractory epilepsies: A single center prospective observational study.
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Rosati A, Boncristiano A, Doccini V, Pugi A, Pisano T, Lenge M, De Masi S, and Guerrini R
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Drug Therapy, Combination, Female, Humans, Infant, Male, Prospective Studies, Retrospective Studies, Time Factors, Treatment Outcome, Young Adult, Anticonvulsants administration & dosage, Dioxolanes administration & dosage, Drug Resistant Epilepsy diagnosis, Drug Resistant Epilepsy drug therapy
- Abstract
Objective: To assess the long-term efficacy and tolerability of stiripentol (STP) as an adjunctive treatment in different forms of refractory epilepsies., Methods: The medical records of all individuals consecutively treated with STP as add-on therapy for refractory epilepsies, irrespective of their being focal, generalized, or both, and followed at Meyer Children's Hospital between January 2007 and May 2018, were reviewed. The drug scheme administration consisted of a starting dose of STP of 10-15 mg/kg/d with increments every week, up to a maximum of 50 mg/kg/d, based on both age and weight. Etiology of epilepsy was codified as structural, genetic, infectious, immune, metabolic, and unknown. Responders were defined as patients who achieved a seizure frequency reduction of ≥50%. Retention rate was defined as the probability of continuing STP without additional therapy. Tolerability was assessed by reporting adverse events., Results: A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with Dravet syndrome (DS). The median follow-up was 14.8 months (range = 4 months-18 years, interquartile range = 25.72). Twenty-nine individuals (22%) received more than two antiepileptic drugs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals., Significance: This study confirms the long-term efficacy of add-on STP treatment in patients with different types of refractory epilepsies, including focal onset epilepsy without bilateral tonic-clonic seizures. Further confirmations based on prospectively designed studies are required to confirm STP efficacy in focal epilepsy., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2019
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43. Advancing research toward faster diagnosis, better treatment, and end of stigma in epilepsy.
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Pitkänen A, Henshall DC, Cross JH, Guerrini R, Jozwiak S, Kokaia M, Simonato M, Sisodiya S, and Mifsud J
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- Epilepsy therapy, European Union, Humans, Biomedical Research, Epilepsy diagnosis, Social Stigma
- Abstract
Seven large European Union (EU)-funded epilepsy-related research projects joined forces in May 2018 in Brussels, Belgium, in a unique community building event-the epiXchange conference. During this conference, 170 investigators from the projects DESIRE, EpimiRNA, EPISTOP, EpiTarget, EpiXchange, and EpiPGX as well as the European Reference Network EpiCARE, met up with key stakeholders including representatives of the European Commission, patient organizations, commercial partners, and other European and International groups. The epiXchange conference focused on sharing and reviewing the advances made by each project in the previous 5 years; describing the infrastructures generated; and discussing the innovations and commercial applications across five thematic areas: biomarkers, genetics, therapeutics, comorbidities, and biobanks and resources. These projects have, in fact, generated major breakthroughs including the discovery of biofluid-based molecules for diagnosis, elucidating new genetic causes of epilepsy, creating advanced new models of epilepsy, and the pre-clinical development of novel compounds. Workshop-style discussions focused on how to overcome scientific and clinical challenges for accelerating translation of research outcomes and how to increase synergies between the projects and stakeholders at a European level. The resulting advances would lead toward a measurable impact of epilepsy research through better diagnostics, treatments, and quality-of-life for persons with epilepsy. In addition, epiXchange provided a unique forum for examining how the different projects could build momentum for future novel groundbreaking epilepsy research in Europe and beyond. This report includes the main recommendations that resulted from these discussions., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2019
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44. Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia.
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Kobow K, Ziemann M, Kaipananickal H, Khurana I, Mühlebner A, Feucht M, Hainfellner JA, Czech T, Aronica E, Pieper T, Holthausen H, Kudernatsch M, Hamer H, Kasper BS, Rössler K, Conti V, Guerrini R, Coras R, Blümcke I, El-Osta A, and Kaspi A
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- Adolescent, Adult, Child, Child, Preschool, Cluster Analysis, DNA genetics, Epilepsies, Partial classification, Epilepsies, Partial genetics, Female, Gene Expression Profiling, Genome, Human, Humans, Infant, Male, Malformations of Cortical Development classification, Malformations of Cortical Development diagnostic imaging, Middle Aged, RNA, Messenger genetics, TOR Serine-Threonine Kinases genetics, Tissue Banks, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed, Transcriptome, Young Adult, DNA Methylation genetics, Malformations of Cortical Development genetics
- Abstract
Objectives: Focal cortical dysplasia (FCD) is a major cause of drug-resistant focal epilepsy in children, and the clinicopathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation-based classification of human brain tumors we examined whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtypes., Methods: DNA methylomes and transcriptomes were generated from massive parallel sequencing in 15 surgical FCD specimens, matched with 5 epilepsy and 6 nonepilepsy controls., Results: Differential hierarchical cluster analysis of DNA methylation distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNA methylation or gene expression was observed in mechanistic target of rapamycin (mTOR) pathway-related genes., Significance: Our studies extend the evidence for disease-specific methylation signatures toward focal epilepsies in favor of an integrated clinicopathologic and molecular classification system of FCD subtypes incorporating genomic methylation., (© 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)
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- 2019
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45. The spectrum of intermediate SCN8A-related epilepsy.
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Johannesen KM, Gardella E, Encinas AC, Lehesjoki AE, Linnankivi T, Petersen MB, Lund ICB, Blichfeldt S, Miranda MJ, Pal DK, Lascelles K, Procopis P, Orsini A, Bonuccelli A, Giacomini T, Helbig I, Fenger CD, Sisodiya SM, Hernandez-Hernandez L, Krithika S, Rumple M, Masnada S, Valente M, Cereda C, Giordano L, Accorsi P, Bürki SE, Mancardi M, Korff C, Guerrini R, von Spiczak S, Hoffman-Zacharska D, Mazurczak T, Coppola A, Buono S, Vecchi M, Hammer MF, Varesio C, Veggiotti P, Lal D, Brünger T, Zara F, Striano P, Rubboli G, and Møller RS
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- Anticonvulsants therapeutic use, Ataxia genetics, Child, Child, Preschool, Cognitive Dysfunction genetics, Electroencephalography, Epilepsy drug therapy, Epilepsy physiopathology, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Infant, Intellectual Disability genetics, Language Development Disorders genetics, Movement Disorders genetics, Muscle Hypotonia genetics, Pedigree, Severity of Illness Index, Epilepsy genetics, Mutation, Missense, NAV1.6 Voltage-Gated Sodium Channel genetics
- Abstract
Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies., Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study., Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser., Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2019
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46. No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy.
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Schulz H, Ruppert AK, Zara F, Madia F, Iacomino M, S Vari M, Balagura G, Minetti C, Striano P, Bianchi A, Marini C, Guerrini R, Weber YG, Becker F, Lerche H, Kapser C, Schankin CJ, Kunz WS, Møller RS, Oliver KL, Bellows ST, Mullen SA, Berkovic SF, Scheffer IE, Caglayan H, Ozbek U, Hoffmann P, Schramm S, Tsortouktzidis D, Becker AJ, and Sander T
- Subjects
- Epilepsy, Absence epidemiology, Epilepsy, Absence genetics, Europe, Female, Humans, Leukocytes chemistry, Male, Myoclonic Epilepsy, Juvenile blood, Myoclonic Epilepsy, Juvenile epidemiology, Polymorphism, Single Nucleotide, CpG Islands genetics, DNA Methylation, Myoclonic Epilepsy, Juvenile genetics, Promoter Regions, Genetic genetics, Transcription Factors genetics
- Abstract
Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76-CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2019
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47. Diagnostic implications of genetic copy number variation in epilepsy plus.
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Coppola A, Cellini E, Stamberger H, Saarentaus E, Cetica V, Lal D, Djémié T, Bartnik-Glaska M, Ceulemans B, Helen Cross J, Deconinck T, Masi S, Dorn T, Guerrini R, Hoffman-Zacharska D, Kooy F, Lagae L, Lench N, Lemke JR, Lucenteforte E, Madia F, Mefford HC, Morrogh D, Nuernberg P, Palotie A, Schoonjans AS, Striano P, Szczepanik E, Tostevin A, Vermeesch JR, Van Esch H, Van Paesschen W, Waters JJ, Weckhuysen S, Zara F, De Jonghe P, Sisodiya SM, and Marini C
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- Comorbidity, DNA Copy Number Variations, Epilepsy complications, Genetic Predisposition to Disease, Genotype, Humans, Phenotype, Epilepsy genetics
- Abstract
Objective: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available., Methods: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy., Results: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10
-9 ). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs., Significance: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes., (© 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)- Published
- 2019
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48. Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.
- Author
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Trivisano M, Pietrafusa N, Terracciano A, Marini C, Mei D, Darra F, Accorsi P, Battaglia D, Caffi L, Canevini MP, Cappelletti S, Cesaroni E, de Palma L, Costa P, Cusmai R, Giordano L, Ferrari A, Freri E, Fusco L, Granata T, Martino T, Mastrangelo M, Bova SM, Parmeggiani L, Ragona F, Sicca F, Striano P, Specchio LM, Tondo I, Zambrelli E, Zamponi N, Zanus C, Boniver C, Vecchi M, Avolio C, Dalla Bernardina B, Bertini E, Guerrini R, Vigevano F, and Specchio N
- Subjects
- Adolescent, Adult, Age of Onset, Autistic Disorder complications, Autistic Disorder psychology, Child, Child, Preschool, Cohort Studies, Electroencephalography, Female, Humans, Infant, Intellectual Disability complications, Intellectual Disability psychology, Male, Phenotype, Protocadherins, Retrospective Studies, Seizures, Treatment Outcome, Young Adult, Cadherins genetics, Epileptic Syndromes genetics, Epileptic Syndromes therapy
- Abstract
Objective: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors., Methods: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency., Results: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124)., Significance: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)
- Published
- 2018
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49. Long-term efficacy of add-on lacosamide treatment in children and adolescents with refractory epilepsies: A single-center observational study.
- Author
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Rosati A, Ilvento L, Rizzi R, Doccini V, Leo MC, Pugi A, De Masi S, and Guerrini R
- Subjects
- Adolescent, Child, Child, Preschool, Drug Therapy, Combination methods, Female, Humans, Infant, Kaplan-Meier Estimate, Male, Progression-Free Survival, Retrospective Studies, Anticonvulsants therapeutic use, Drug Resistant Epilepsy drug therapy, Lacosamide therapeutic use
- Abstract
Objective: To assess long-term efficacy and tolerability of lacosamide (LCM) as adjunctive treatment through a retrospective study in children and adolescents with refractory epilepsies., Methods: All patients consecutively treated with LCM as add-on for refractory focal and generalized epilepsy and followed at the Neuroscience Center of Excellence of the Meyer Children's Hospital of Florence between January 2011 and September 2015 were included in the study. Responder rate, relapse-free survival, and retention rate were calculated. Tolerability was assessed by reporting adverse events., Results: A total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add-on LCM treatment for refractory epilepsy. Thirty-four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure-free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow-up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add-on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11)., Significance: This study documents a real-world progressive and significant loss of LCM efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of LCM efficacy over time., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)
- Published
- 2018
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50. Comparative efficacy of antiepileptic drugs in children and adolescents: A network meta-analysis.
- Author
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Rosati A, Ilvento L, Lucenteforte E, Pugi A, Crescioli G, McGreevy KS, Virgili G, Mugelli A, De Masi S, and Guerrini R
- Subjects
- Adolescent, Adrenal Cortex Hormones therapeutic use, Adrenocorticotropic Hormone therapeutic use, Carbamazepine therapeutic use, Child, Child, Preschool, Drug Resistant Epilepsy drug therapy, Epilepsies, Partial drug therapy, Epilepsy, Absence drug therapy, Ethosuximide therapeutic use, Hormones therapeutic use, Humans, Infant, Lamotrigine, Levetiracetam, Network Meta-Analysis, Nitriles, Odds Ratio, Piracetam analogs & derivatives, Piracetam therapeutic use, Pyridones therapeutic use, Spasms, Infantile drug therapy, Treatment Outcome, Triazines therapeutic use, Valproic Acid therapeutic use, Anticonvulsants therapeutic use, Epilepsy drug therapy
- Abstract
Objective: To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years)., Methods: Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction., Results: We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies., Significance: This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)
- Published
- 2018
- Full Text
- View/download PDF
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