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3. Adolescent gender dysphoria management: position paper from the Italian Academy of Pediatrics, the Italian Society of Pediatrics, the Italian Society for Pediatric Endocrinology and Diabetes, the Italian Society of Adolescent Medicine and the Italian Society of Child and Adolescent Neuropsychiatry

Author

Calcaterra, Valeria, Tornese, Gianluca, Zuccotti, Gianvincenzo, Staiano, Annamaria, Cherubini, Valentino, Gaudino, Rossella, Fazzi, Elisa Maria, Barbi, Egidio, Chiarelli, Francesco, Corsello, Giovanni, Esposito, Susanna Maria Roberta, Ferrara, Pietro, Iughetti, Lorenzo, Laforgia, Nicola, Maghnie, Mohamad, Marseglia, Gianluigi, Perilongo, Giorgio, Pettoello-Mantovani, Massimo, Ruggieri, Martino, Russo, Giovanna, Salerno, Mariacarolina, Striano, Pasquale, Valerio, Giuliana, and Wasniewska, Malgorzata

Published
2024
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4. SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.

Author

Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine, Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander, Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan, Hajianpour, M, Pal, Deb, Engelen, Marc, Hagebeuk, Eveline, Shinawi, Marwan, Heidlebaugh, Alexis, Oetjens, Kathryn, Hoffman, Trevor, Striano, Pasquale, Freed, Amanda, Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nouri, Maryam, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine, Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes, Tiller, Jacob, Freed, Amber, Kang, Jing-Qiong, Wuster, Arthur, Møller, Rikke, and Lal, Dennis

Subjects
SLC6A1, autism, epilepsy, genetics, neurodevelopmental disorder, Humans, GABA Plasma Membrane Transport Proteins, Genetic Association Studies, Mutation, Missense, Phenotype
Abstract

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).

Published
2023

5. Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies

Author

Accogli, Andrea, Zaki, Maha S, Al-Owain, Mohammed, Otaif, Mansour Y, Jackson, Adam, Argilli, Emanuela, Chandler, Kate E, De Goede, Christian GEL, Cora, Tülün, Alvi, Javeria Raza, Eslahi, Atieh, Asl Mohajeri, Mahsa Sadat, Ashtiani, Setareh, Au, PY Billie, Scocchia, Alicia, Alakurtti, Kirsi, Pagnamenta, Alistair T, Toosi, Mehran Beiraghi, Ghayoor Karimiani, Ehsan, Mojarrad, Majid, Arab, Fatemeh, Duymuş, Fahrettin, Scantlebury, Morris H, Yeşil, Gözde, Rosenfeld, Jill Anne, Türkyılmaz, Ayberk, Sağer, Safiye Güneş, Sultan, Tipu, Ashrafzadeh, Farah, Zahra, Tatheer, Rahman, Fatima, Maqbool, Shazia, Abdel-Hamid, Mohamed S, Issa, Mahmoud, Efthymiou, Stephanie, Bauer, Peter, Zifarelli, Giovanni, Salpietro, Vincenzo, Al-Hassnan, Zuhair, Banka, Siddharth, Sherr, Elliot H, Gleeson, Joseph G, Striano, Pasquale, Houlden, Henry, Severino, Mariasavina, and Maroofian, Reza

Subjects
Pediatric, Neurosciences, Genetics, Neurodegenerative, Clinical Research, Congenital Structural Anomalies, Brain Disorders, Rare Diseases, Human Genome, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Clinical sciences, Biological psychology
Abstract

Abstract: LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy, and non-specific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in eleven families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified twelve distinct homozygous loss-of-function variants in sixteen individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor (“ear-of-the-lynx” sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain, and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the “ear of the lynx” sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

Published
2023

6. BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.

Author

Engel, Camille, Valence, Stéphanie, Delplancq, Geoffroy, Maroofian, Reza, Accogli, Andrea, Agolini, Emanuele, Alkuraya, Fowzan, Baglioni, Valentina, Bagnasco, Irene, Becmeur-Lefebvre, Mathilde, Bertini, Enrico, Borggraefe, Ingo, Brischoux-Boucher, Elise, Bruel, Ange-Line, Brusco, Alfredo, Bubshait, Dalal, Cabrol, Christelle, Cilio, Maria, Cornet, Marie-Coralie, Coubes, Christine, Danhaive, Olivier, Delague, Valérie, Denommé-Pichon, Anne-Sophie, Di Giacomo, Marilena, Doco-Fenzy, Martine, Engels, Hartmut, Cremer, Kirsten, Gérard, Marion, Gleeson, Joseph, Heron, Delphine, Goffeney, Joanna, Guimier, Anne, Harms, Frederike, Houlden, Henry, Iacomino, Michele, Kaiyrzhanov, Rauan, Kamien, Benjamin, Karimiani, Ehsan, Kraus, Dror, Kuentz, Paul, Kutsche, Kerstin, Lederer, Damien, Massingham, Lauren, Mignot, Cyril, Morris-Rosendahl, Déborah, Nagarajan, Lakshmi, Odent, Sylvie, Ormières, Clothilde, Partlow, Jennifer, Pasquier, Laurent, Penney, Lynette, Philippe, Christophe, Piccolo, Gianluca, Poulton, Cathryn, Putoux, Audrey, Rio, Marlène, Rougeot, Christelle, Salpietro, Vincenzo, Scheffer, Ingrid, Schneider, Amy, Srivastava, Siddharth, Straussberg, Rachel, Striano, Pasquale, Valente, Enza, Venot, Perrine, Villard, Laurent, Vitobello, Antonio, Wagner, Johanna, Wagner, Matias, Zaki, Maha, Zara, Federizo, Lesca, Gaetan, Yassaee, Vahid, Miryounesi, Mohammad, Hashemi-Gorji, Farzad, Beiraghi, Mehran, Ashrafzadeh, Farah, Galehdari, Hamid, Walsh, Christopher, Novelli, Antonio, Tacke, Moritz, Sadykova, Dinara, Maidyrov, Yerdan, Koneev, Kairgali, Shashkin, Chingiz, Capra, Valeria, Zamani, Mina, Van Maldergem, Lionel, Burglen, Lydie, and Piard, Juliette

Subjects
Humans, Nuclear Proteins, Epilepsy, Phenotype, Genotype, Genetic Association Studies, Neurodegenerative Diseases, Atrophy
Abstract

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Published
2023

7. Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

Author

Carapancea, Evelina, Cornet, Marie-Coralie, Milh, Mathieu, De Cosmo, Lucrezia, Huang, Eric J, Granata, Tiziana, Striano, Pasquale, Ceulemans, Berten, Stein, Anja, Morris-Rosendahl, Deborah, Conti, Greta, Mitra, Nipa, Raymond, F Lucy, Rowitch, David H, Solazzi, Roberta, Vercellino, Fabiana, De Liso, Paola, D'Onofrio, Gianluca, Boniver, Clementina, Danhaive, Olivier, Carkeek, Katherine, Salpietro, Vincenzo, Weckhuysen, Sarah, Fedrigo, Marny, Angelini, Annalisa, Castellotti, Barbara, Lederer, Damien, Benoit, Valerie, Raviglione, Federico, Guerrini, Renzo, Dilena, Robertino, and Cilio, Maria Roberta

Subjects
Paediatrics, Biomedical and Clinical Sciences, Neurosciences, Perinatal Period - Conditions Originating in Perinatal Period, Pediatric, Clinical Research, Brain Disorders, Neurodegenerative, Infant Mortality, Neurological, Humans, Myoclonus, Apnea, Hyperekplexia, Bradycardia, Brain Diseases, Seizures, Phenotype, Muscle Hypertonia, Nuclear Proteins, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and objectivesBRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.DiscussionBRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Published
2023

8. De novo KCNA6 variants with attenuated KV1.6 channel deactivation in patients with epilepsy

Author

Salpietro, Vincenzo, Deforie, Valentina Galassi, Efthymiou, Stephanie, O'Connor, Emer, Marcé‐Grau, Anna, Maroofian, Reza, Striano, Pasquale, Zara, Federico, Morrow, Michelle M, Group, SYNAPS Study, Reich, Adi, Blevins, Amy, Sala‐Coromina, Júlia, Accogli, Andrea, Fortuna, Sara, Alesandrini, Marie, Au, PY Billie, Singhal, Nilika Shah, Cogne, Benjamin, Isidor, Bertrand, Hanna, Michael G, Macaya, Alfons, Kullmann, Dimitri M, Houlden, Henry, and Männikkö, Roope

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Pediatric, Neurodegenerative, Genetics, Biotechnology, Brain Disorders, Epilepsy, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Mutation, Neurodevelopmental Disorders, Seizures, Kv1.6 Potassium Channel, K(V)1 Shaker channel family, neurodevelopmental disorder, voltage-gated potassium channels, whole exome sequencing, SYNAPS Study Group, KV1 Shaker channel family, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveMutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.MethodsFollowing clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp.ResultsWe identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of KV 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV 1.6 or KV 1.1 subunits.SignificanceThis is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Published
2023

9. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.

Author

Scala, Marcello, Nishikawa, Masashi, Ito, Hidenori, Tabata, Hidenori, Khan, Tayyaba, Accogli, Andrea, Davids, Laura, Ruiz, Anna, Chiurazzi, Pietro, Cericola, Gabriella, Schulte, Björn, Monaghan, Kristin G, Begtrup, Amber, Torella, Annalaura, Pinelli, Michele, Denommé-Pichon, Anne Sophie, Vitobello, Antonio, Racine, Caroline, Mancardi, Maria Margherita, Kiss, Courtney, Guerin, Andrea, Wu, Wendy, Gabau Vila, Elisabeth, Mak, Bryan C, Martinez-Agosto, Julian A, Gorin, Michael B, Duz, Bugrahan, Bayram, Yavuz, Carvalho, Claudia MB, Vengoechea, Jaime E, Chitayat, David, Tan, Tiong Yang, Callewaert, Bert, Kruse, Bernd, Bird, Lynne M, Faivre, Laurence, Zollino, Marcella, Biskup, Saskia, Undiagnosed Diseases Network, Telethon Undiagnosed Diseases Program, Striano, Pasquale, Nigro, Vincenzo, Severino, Mariasavina, Capra, Valeria, Costain, Gregory, and Nagata, Koh Ichi

Subjects
Undiagnosed Diseases Network, Telethon Undiagnosed Diseases Program, Neurons, Animals, Humans, Mice, rac GTP-Binding Proteins, Phenotype, p21-Activated Kinases, Neurodevelopmental Disorders, RAC3, axon guidance, brain development, neuronal migration, small GTPase, Neurosciences, Pediatric, Congenital Structural Anomalies, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, RAC3, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.

Published
2022

10. Event‐based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross‐sectional data

Author

Lopez, Seymour M, Aksman, Leon M, Oxtoby, Neil P, Vos, Sjoerd B, Rao, Jun, Kaestner, Erik, Alhusaini, Saud, Alvim, Marina, Bender, Benjamin, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Bonilha, Leonardo, Caciagli, Lorenzo, Caldairou, Benoit, Caligiuri, Maria Eugenia, Calvet, Angels, Cendes, Fernando, Concha, Luis, Conde‐Blanco, Estefania, Davoodi‐Bojd, Esmaeil, de Bézenac, Christophe, Delanty, Norman, Desmond, Patricia M, Devinsky, Orrin, Domin, Martin, Duncan, John S, Focke, Niels K, Foley, Sonya, Fortunato, Francesco, Galovic, Marian, Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ives‐Deliperi, Victoria, Jackson, Graeme D, Jahanshad, Neda, Keller, Simon S, Kochunov, Peter, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Labate, Angelo, Larivière, Sara, Lenge, Matteo, Lui, Elaine, Malpas, Charles, Martin, Pascal, Mascalchi, Mario, Medland, Sarah E, Meletti, Stefano, Morita‐Sherman, Marcia E, Owen, Thomas W, Richardson, Mark, Riva, Antonella, Rüber, Theodor, Sinclair, Ben, Soltanian‐Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomopoulos, Sophia I, Thompson, Paul M, Tondelli, Manuela, Vaudano, Anna Elisabetta, Vivash, Lucy, Wang, Yujiang, Weber, Bernd, Whelan, Christopher D, Wiest, Roland, Winston, Gavin P, Yasuda, Clarissa Lin, McDonald, Carrie R, Alexander, Daniel C, Sisodiya, Sanjay M, Altmann, Andre, Bargalló, Núria, Bartolini, Emanuele, O’Brien, Terence J, and Thomas, Rhys H

Subjects
Brain Disorders, Epilepsy, Neurodegenerative, Neurosciences, Clinical Research, Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Atrophy, Biomarkers, Cross-Sectional Studies, Epilepsy, Temporal Lobe, Hippocampus, Humans, Magnetic Resonance Imaging, Sclerosis, disease progression, duration of illness, event-based model, MTLE, patient staging, ENIGMA-Epilepsy Working Group, Clinical Sciences, Neurology & Neurosurgery
Abstract

ObjectiveRecent 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.MethodsWe 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.ResultsIn 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.SignificanceFrom 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.

Published
2022

11. mTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion.

Author

Calhoun, Jeffrey, Aziz, Miriam, Happ, Hannah, Gunti, Jonathan, Gleason, Colleen, Mohamed, Najma, Zeng, Kristy, Hiller, Meredith, Bryant, Emily, Mithal, Divakar, Bellinski, Irena, Kinsley, Lisa, Grimmel, Mona, Schwaibold, Eva, Smith-Hicks, Constance, Chassevent, Anna, Scala, Marcello, Accogli, Andrea, Torella, Annalaura, Striano, Pasquale, Capra, Valeria, Ben-Sahra, Issam, Ekhilevich, Nina, Hershkovitz, Tova, Weiss, Karin, Millichap, John, Gerard, Elizabeth, Carvill, Gemma, and Bird, Lynne

Subjects
SZT2, epilepsy, genetics, mTOR, variant, Epilepsies, Partial, Epilepsy, Humans, Mechanistic Target of Rapamycin Complex 1, Megalencephaly, Nerve Tissue Proteins, Tumor Suppressor Proteins
Abstract

Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions, but these variants are increasingly detected and reported by clinical genetic testing in individuals with epilepsy. To exemplify this latter point, here we describe a cohort of 12 individuals with biallelic SZT2 variants and phenotypic overlap with SZT2-related neurodevelopmental disorders. However, the majority of individuals carried one or more SZT2 variants of uncertain significance (VUS), highlighting the need for functional characterization to determine, which, if any, of these VUS were pathogenic. Thus, we developed a novel individualized platform to identify SZT2 loss-of-function variants in the context of mTORC1 signalling and reclassify VUS. Using this platform, we identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis revealed that this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Moreover, this approach allowed us to tentatively reclassify all of the VUS in our cohort of 12 individuals, identifying five individuals with biallelic pathogenic or likely pathogenic variants. Clinical features of these five individuals consisted of early-onset seizures (median 24 months), focal seizures, developmental delay and macrocephaly similar to previous reports. However, we also show a widening of the phenotypic spectrum, as none of the five individuals had corpus callosum abnormalities, in contrast to previous reports. Overall, we present a rapid assay to resolve VUS in SZT2, identify a founder variant in individuals of Ashkenazi Jewish ancestry, and demonstrate that corpus callosum abnormalities is not a hallmark feature of this condition. Our approach is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

Published
2022

13. Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity

Author

Kalm, Tassja, Schob, Claudia, Völler, Hanna, Gardeitchik, Thatjana, Gilissen, Christian, Pfundt, Rolph, Klöckner, Chiara, Platzer, Konrad, Klabunde-Cherwon, Annick, Ries, Markus, Syrbe, Steffen, Beccaria, Francesca, Madia, Francesca, Scala, Marcello, Zara, Federico, Hofstede, Floris, Simon, Marleen E.H., van Jaarsveld, Richard H., Oegema, Renske, van Gassen, Koen L.I., Holwerda, Sjoerd J.B., Barakat, Tahsin Stefan, Bouman, Arjan, van Slegtenhorst, Marjon, Álvarez, Sara, Fernández-Jaén, Alberto, Porta, Javier, Accogli, Andrea, Mancardi, Margherita Maria, Striano, Pasquale, Iacomino, Michele, Chae, Jong-Hee, Jang, SeSong, Kim, Soo Y., Chitayat, David, Mercimek-Andrews, Saadet, Depienne, Christel, Kampmeier, Antje, Kuechler, Alma, Surowy, Harald, Bertini, Enrico Silvio, Radio, Francesca Clementina, Mancini, Cecilia, Pizzi, Simone, Tartaglia, Marco, Gauthier, Lucas, Genevieve, David, Tharreau, Mylène, Azoulay, Noy, Zaks-Hoffer, Gal, Gilad, Nesia K., Orenstein, Naama, Bernard, Geneviève, Thiffault, Isabelle, Denecke, Jonas, Herget, Theresia, Kortüm, Fanny, Kubisch, Christian, Bähring, Robert, and Kindler, Stefan

Published
2024
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14. Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy

Author

Park, Bo-yong, Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Tavakol, Shahin, Wang, Yezhou, Caciagli, Lorenzo, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Alvim, Marina KM, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Kreilkamp, Barbara AK, Domin, Martin, von Podewils, Felix, Langner, Soenke, Rummel, Christian, Rebsamen, Michael, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, Bender, Benjamin, O’Brien, Terence J, Law, Meng, Sinclair, Benjamin, Vivash, Lucy, Kwan, Patrick, Desmond, Patricia M, Malpas, Charles B, Lui, Elaine, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Parodi, Costanza, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Galovic, Marian, Whelan, Christopher D, Bargalló, Núria, Pariente, Jose, Conde-Blanco, Estefania, Vaudano, Anna Elisabetta, Tondelli, Manuela, Meletti, Stefano, Kong, Xiang‐Zhen, Francks, Clyde, Fisher, Simon E, Caldairou, Benoit, Ryten, Mina, Labate, Angelo, Sisodiya, Sanjay M, Thompson, Paul M, McDonald, Carrie R, Bernasconi, Andrea, Bernasconi, Neda, and Bernhardt, Boris C

Subjects
Epilepsy, Neurodegenerative, Clinical Research, Brain Disorders, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Atrophy, Connectome, Epilepsy, Temporal Lobe, Hippocampus, Humans, Magnetic Resonance Imaging, temporal lobe epilepsy, asymmetry, cortical thickness, multi-site, gradients, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

Published
2022

15. The ENIGMA‐Epilepsy working group: Mapping disease from large data sets

Author

Sisodiya, Sanjay M, Whelan, Christopher D, Hatton, Sean N, Huynh, Khoa, Altmann, Andre, Ryten, Mina, Vezzani, Annamaria, Caligiuri, Maria Eugenia, Labate, Angelo, Gambardella, Antonio, Ives‐Deliperi, Victoria, Meletti, Stefano, Munsell, Brent C, Bonilha, Leonardo, Tondelli, Manuela, Rebsamen, Michael, Rummel, Christian, Vaudano, Anna Elisabetta, Wiest, Roland, Balachandra, Akshara R, Bargalló, Núria, Bartolini, Emanuele, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Caldairou, Benoit, Carr, Sarah JA, Cavalleri, Gianpiero L, Cendes, Fernando, Concha, Luis, Desmond, Patricia M, Domin, Martin, Duncan, John S, Focke, Niels K, Guerrini, Renzo, Hamandi, Khalid, Jackson, Graeme D, Jahanshad, Neda, Kälviäinen, Reetta, Keller, Simon S, Kochunov, Peter, Kowalczyk, Magdalena A, Kreilkamp, Barbara AK, Kwan, Patrick, Lariviere, Sara, Lenge, Matteo, Lopez, Seymour M, Martin, Pascal, Mascalchi, Mario, Moreira, José CV, Morita‐Sherman, Marcia E, Pardoe, Heath R, Pariente, Jose C, Raviteja, Kotikalapudi, Rocha, Cristiane S, Rodríguez‐Cruces, Raúl, Seeck, Margitta, Semmelroch, Mira KHG, Sinclair, Benjamin, Soltanian‐Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Thomopoulos, Sophia I, Velakoulis, Dennis, Vivash, Lucy, Weber, Bernd, Yasuda, Clarissa Lin, Zhang, Junsong, Thompson, Paul M, McDonald, Carrie R, Abela, Eugenio, Absil, Julie, Adams, Sophia, Alhusaini, Saud, Alvim, Marina, Balestrini, Simona, Bender, Benjamin, Bergo, Felipe, Bernardes, Tauana, Calvo, Anna, Carreno, Mar, Cherubini, Andrea, David, Philippe, Davoodi‐Bojd, Esmaeil, Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Doherty, Colin, França, Wendy Caroline, Franceschet, Leticia, Hibar, Derrek P, Ishikawa, Akari, Kaestner, Erik, Langner, Soenke, Liu, Min, Mirandola, Laura, Naylor, Jillian, and Nazem‐Zadeh, Mohammad‐reza

Subjects
Brain Disorders, Biomedical Imaging, Neurosciences, Epilepsy, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, covariance, deep learning, DTI, event-based modeling, gene expression, genetics, imaging, MRI, quantitative, rsfMRI, ENIGMA Consortium Epilepsy Working Group, Cognitive Sciences, Experimental Psychology
Abstract

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

Published
2022

16. Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

Author

Leitão, Elsa, Schröder, Christopher, Parenti, Ilaria, Dalle, Carine, Rastetter, Agnès, Kühnel, Theresa, Kuechler, Alma, Kaya, Sabine, Gérard, Bénédicte, Schaefer, Elise, Nava, Caroline, Drouot, Nathalie, Engel, Camille, Piard, Juliette, Duban-Bedu, Bénédicte, Villard, Laurent, Stegmann, Alexander PA, Vanhoutte, Els K, Verdonschot, Job AJ, Kaiser, Frank J, Tran Mau-Them, Frédéric, Scala, Marcello, Striano, Pasquale, Frints, Suzanna GM, Argilli, Emanuela, Sherr, Elliott H, Elder, Fikret, Buratti, Julien, Keren, Boris, Mignot, Cyril, Héron, Delphine, Mandel, Jean-Louis, Gecz, Jozef, Kalscheuer, Vera M, Horsthemke, Bernhard, Piton, Amélie, and Depienne, Christel

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Mental Health, Intellectual and Developmental Disabilities (IDD), Biotechnology, Autism, Human Genome, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Mental health, Humans, Chromosomes, Human, X, Genes, X-Linked, Intellectual Disability, Autism Spectrum Disorder, Databases, Genetic
Abstract

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

Published
2022

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

Author

Larivière, Sara, Royer, Jessica, Rodríguez-Cruces, Raúl, Paquola, Casey, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa L, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O’Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Lui, Elaine, Vaudano, Anna Elisabetta, Meletti, Stefano, Tondelli, Manuela, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Winston, Gavin P, Griffin, Aoife, Singh, Aditi, Tiwari, Vijay K, Kreilkamp, Barbara AK, Lenge, Matteo, Guerrini, Renzo, Hamandi, Khalid, Foley, Sonya, Rüber, Theodor, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Kaestner, Erik, Hatton, Sean N, Vos, Sjoerd B, Caciagli, Lorenzo, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C

Subjects
Neurodegenerative, Genetics, Neurosciences, Brain Disorders, Epilepsy, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Connectome, Epilepsy, Generalized, Epilepsy, Temporal Lobe, Gene Expression, Humans, Immunoglobulin E, Magnetic Resonance Imaging, Nerve Net
Abstract

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.

Published
2022

18. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia

Author

Yap, Zheng Yie, Efthymiou, Stephanie, Seiffert, Simone, Parra, Karen Vargas, Lee, Sukyeong, Nasca, Alessia, Maroofian, Reza, Schrauwen, Isabelle, Pendziwiat, Manuela, Jung, Sunhee, Bhoj, Elizabeth, Striano, Pasquale, Mankad, Kshitij, Vona, Barbara, Cuddapah, Sanmati, Wagner, Anja, Alvi, Javeria Raza, Davoudi-Dehaghani, Elham, Fallah, Mohammad-Sadegh, Gannavarapu, Srinitya, Lamperti, Costanza, Legati, Andrea, Murtaza, Bibi Nazia, Nadeem, Muhammad Shahid, Rehman, Mujaddad Ur, Saeidi, Kolsoum, Salpietro, Vincenzo, von Spiczak, Sarah, Sandoval, Abigail, Zeinali, Sirous, Zeviani, Massimo, Reich, Adi, Group, SYNaPS Study, Genomics, University of Washington Center for Mendelian, Jang, Cholsoon, Helbig, Ingo, Barakat, Tahsin Stefan, Ghezzi, Daniele, Leal, Suzanne M, Weber, Yvonne, Houlden, Henry, and Yoon, Wan Hee

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Clinical Research, Brain Disorders, Neurosciences, Neurodegenerative, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alleles, Animals, Ataxia, Cells, Cultured, Child, Cohort Studies, DNA Mutational Analysis, Drosophila melanogaster, Epilepsy, Family Health, Female, Fibroblasts, Hearing Loss, Humans, Ketoglutarate Dehydrogenase Complex, Male, Mutation, Neurodevelopmental Disorders, RNA Splicing, Vision Disorders, SYNaPS Study Group, University of Washington Center for Mendelian Genomics, CRISPR-Cas9 gene editing, DEE, Drosophila, OGDHL, bi-allelic, developmental and epileptic encephalopathy, exome sequencing, mitochondria, neurodevelopmental disease, α-ketoglutarate, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.

Published
2021

21. De novo variants in DENND5B cause a neurodevelopmental disorder

Author

Acosta, Maria T., Adams, David R., Alvarez, Raquel L., Alvey, Justin, Allworth, Aimee, Andrews, Ashley, Ashley, Euan A., Afzali, Ben, Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennett, Jimmy, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Briere, Lauren C., Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, HsiaoTuan, Chinn, Ivan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cope, Heidi, Corona, Rosario, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Delgado, Margaret, Dell'Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Falk, Marni, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fu, Jiayu, Gahl, William A., Glass, Ian, Goddard, Page C., Godfrey, Rena A., Grajewski, Alana, Gropman, Andrea, Halley, Meghan C., Hamid, Rizwan, Hanchard, Neal, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yan, Hutchison, Sarah, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Kaitryn, Emerald, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korrick, Susan, Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, AudreyStephannie, Mahoney, Rachel, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Might, Matthew, Miller, Danny, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo, Morimoto, Marie, Mulvihill, John J., Nakano-Okuno, Mariko, Nelson, Stanley F., Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Papp, Jeanette C., Parker, Neil H., Petcharet, Leoyklang, Phillips, John A., III, Posey, Jennifer E., Potocki, Lorraine, Swerdzewski, Barbara N. Pusey, Quinlan, Aaron, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenthal, Elizabeth, Rossignol, Francis, Ruzhnikov, Maura, Sabaii, Marla, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Seto, Elaine, Sharma, Prashant, Shashi, Vandana, Shelkowitz, Emily, Sheppeard, Sam, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stergachis, Andrew, Stoler, Joan M., Sullivan, Kathleen, Sullivan, Jennifer A., Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L.M., Tarakad, Arjun, Taylor, Herman, Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Weisz Hubshman, Monika, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Yamamoto, Shinya, Zhang, Zhe, Zuchner, Stephan, Scala, Marcello, Tomati, Valeria, Ferla, Matteo, Lena, Mariateresa, Cohen, Julie S., Fatemi, Ali, Brokamp, Elly, Koziura, Mary E., Nicouleau, Michael, Rio, Marlene, Siquier, Karine, Boddaert, Nathalie, Musante, Ilaria, Tamburro, Serena, Baldassari, Simona, Iacomino, Michele, Scudieri, Paolo, Bellus, Gary, Reed, Sara, Al Saif, Hind, Russo, Rossana Sanchez, Walsh, Matthew B., Cantagrel, Vincent, Crunk, Amy, Gustincich, Stefano, Ruggiero, Sarah M., Fitzgerald, Mark P., Helbig, Ingo, Striano, Pasquale, Severino, Mariasavina, Salpietro, Vincenzo, Pedemonte, Nicoletta, and Zara, Federico

Published
2024
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23. The wide world of technological telerehabilitation for pediatric neurologic and neurodevelopmental disorders – a systematic review

Author

Benedetta Del Lucchese, Stefano Parravicini, Silvia Filogna, Gloria Mangani, Elena Beani, Maria Chiara Di Lieto, Alessandra Bardoni, Marta Bertamino, Marta Papini, Chiara Tacchino, Francesca Fedeli, Giovanni Cioni, Giuseppina Sgandurra, the Italian Neuroscience and Neurorehabilitation Network, Arnoldi Maria Teresa, Baglio Francesca, Barzacchi Veronica, Bassi Maria Teresa, Berardinelli Angela, Bombonato Clara, Borgatti Renato, Calabrò Rocco Salvatore, Cardillo Ilaria, Castelli Enrico, Cavallini Anna, Ceragioli Beatrice, Cersosimo Antonella, Condoluci Claudia, Corti Claudia, Di Girolamo Gabriella, Di Giusto Valentina, Elia Maurizio, Favetta Martina, Ferrante Carolina, Ferri Raffaele, Ghione Valeria, Goffredo Michela, Lugari Patrizia, Manzia Carlotta Maria, Martini Giada, Matteucci Elisa, Menici Valentina, Moretti Paolo, Pagliano Emanuela, Perinelli Martina Giorgia, Petrarca Maurizio, Poggi Geraldina, Pulvirenti Francesca, Rizzo Marta, Sgherri Giada, Strazzer Sandra, Striano Pasquale, Tassorelli Cristina, Vannetti Federica, and Viganò Marta

Subjects
technologies, telerehabilitation, pediatric, neurodevelopmental disorders, neurological disorders, children, Public aspects of medicine, RA1-1270
Abstract

IntroductionThe use of Information and Communication Technology (ICT) for assessing and treating cognitive and motor disorders is promoting home-based telerehabilitation. This approach involves ongoing monitoring within a motivating context to help patients generalize their skills. It can also reduce healthcare costs and geographic barriers by minimizing hospitalization. This systematic review focuses on investigating key aspects of telerehabilitation protocols for children with neurodevelopmental or neurological disorders, including technology used, outcomes, caregiver involvement, and dosage, to guide clinical practice and future research.MethodThis systematic review adhered to PRISMA guidelines and was registered in PROSPERO. The PICO framework was followed to define the search strategy for technology-based telerehabilitation interventions targeting the pediatric population (aged 0–18) with neurological or neurodevelopmental disorders. The search encompassed Medline/PubMed, EMBASE, and Web of Science databases. Independent reviewers were responsible for selecting relevant papers and extracting data, while data harmonization and analysis were conducted centrally.ResultsA heterogeneous and evolving situation emerged from our data. Our findings reported that most of the technologies adopted for telerehabilitation are commercial devices; however, research prototypes and clinical software were also employed with a high potential for personalization and treatment efficacy. The efficacy of these protocols on health or health-related domains was also explored by categorizing the outcome measures according to the International Classification of Functioning, Disability, and Health (ICF). Most studies targeted motor and neuropsychological functions, while only a minority of papers explored language or multi-domain protocols. Finally, although caregivers were rarely the direct target of intervention, their role was diffusely highlighted as a critical element of the home-based rehabilitation setting.DiscussionThis systematic review offers insights into the integration of technological devices into telerehabilitation programs for pediatric neurologic and neurodevelopmental disorders. It highlights factors contributing to the effectiveness of these interventions and suggests the need for further development, particularly in creating dynamic and multi-domain rehabilitation protocols. Additionally, it emphasizes the importance of promoting home-based and family-centered care, which could involve caregivers more actively in the treatment, potentially leading to improved clinical outcomes for children with neurological or neurodevelopmental conditions.Systematic review registrationPROSPERO (CRD42020210663).

Published
2024
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24. SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy

Author

Roshandel, Delnaz, Sanders, Eric J., Shakeshaft, Amy, Panjwani, Naim, Lin, Fan, Collingwood, Amber, Hall, Anna, Keenan, Katherine, Deneubourg, Celine, Mirabella, Filippo, Topp, Simon, Zarubova, Jana, Thomas, Rhys H., Talvik, Inga, Syvertsen, Marte, Striano, Pasquale, Smith, Anna B., Selmer, Kaja K., Rubboli, Guido, Orsini, Alessandro, Ng, Ching Ching, Møller, Rikke S., Lim, Kheng Seang, Hamandi, Khalid, Greenberg, David A., Gesche, Joanna, Gardella, Elena, Fong, Choong Yi, Beier, Christoph P., Andrade, Danielle M., Jungbluth, Heinz, Richardson, Mark P., Pastore, Annalisa, Fanto, Manolis, Pal, Deb K., and Strug, Lisa J.

Published
2023
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25. GLUT1-DS Italian registry: past, present, and future: a useful tool for rare disorders

Author

Varesio, Costanza, De Giorgis, Valentina, Veggiotti, Pierangelo, Nardocci, Nardo, Granata, Tiziana, Ragona, Francesca, Pasca, Ludovica, Mensi, Martina Maria, Borgatti, Renato, Olivotto, Sara, Previtali, Roberto, Riva, Antonella, Mancardi, Maria Margherita, Striano, Pasquale, Cavallin, Mara, Guerrini, Renzo, Operto, Francesca Felicia, Pizzolato, Alice, Di Maulo, Ruggero, Martino, Fabiola, Lodi, Andrea, and Marini, Carla

Published
2023
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27. Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

Author

Cali, Elisa, Quirin, Tania, Rocca, Clarissa, Efthymiou, Stephanie, Riva, Antonella, Marafi, Dana, Zaki, Maha S., Suri, Mohnish, Dominguez, Roberto, Elbendary, Hasnaa M., Alavi, Shahryar, Abdel-Hamid, Mohamed S., Morsy, Heba, Mau-Them, Frederic Tran, Nizon, Mathilde, Tesner, Pavel, Ryba, Lukáš, Zafar, Faisal, Rana, Nuzhat, Saadi, Nebal W., Firoozfar, Zahra, Gencpinar, Pinar, Unay, Bulent, Ustun, Canan, Bruel, Ange-Line, Coubes, Christine, Stefanich, Jennifer, Sezer, Ozlem, Agolini, Emanuele, Novelli, Antonio, Vasco, Gessica, Lettori, Donatella, Milh, Mathieu, Villard, Laurent, Zeidler, Shimriet, Opperman, Henry, Strehlow, Vincent, Issa, Mahmoud Y., El Khassab, Hebatallah, Chand, Prem, Ibrahim, Shahnaz, Nejad-Rashidi, Ali, Miryounesi, Mohammad, Larki, Pegah, Morrison, Jennifer, Cristian, Ingrid, Thiffault, Isabelle, Bertsch, Nicole L., Noh, Grace J., Pappas, John, Moran, Ellen, Marinakis, Nikolaos M., Traeger-Synodinos, Joanne, Hosseini, Susan, Abbaszadegan, Mohammad Reza, Caumes, Roseline, Vissers, Lisenka E.L.M., Neshatdoust, Maedeh, Montazer, Mostafa Zohour, El Fahime, Elmostafa, Canavati, Christin, Kamal, Lara, Kanaan, Moien, Askander, Omar, Voinova, Victoria, Levchenko, Olga, Haider, Shahzhad, Halbach, Sara S., Maia, Elias Rayana, Mansoor, Salehi, Vivek, Jain, Tawde, Sanjukta, Challa, Viveka Santhosh R., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Victor, Lucas Alves, Pinero-Banos, Benito, Hague, Jennifer, Ei-Awady, Heba Ahmed, Maria de Miranda Henriques-Souza, Adelia, Cheema, Huma Arshad, Anjum, Muhammad Nadeem, Idkaidak, Sara, Alqarajeh, Firas, Atawneh, Osama, Mor-Shaked, Hagar, Harel, Tamar, Zifarelli, Giovanni, Bauer, Peter, Kok, Fernando, Kitajima, Joao Paulo, Monteiro, Fabiola, Josahkian, Juliana, Lesca, Gaetan, Chatron, Nicolas, Ville, Dorothe, Murphy, David, Neul, Jeffrey L., Mullegama, Sureni V., Begtrup, Amber, Herman, Isabella, Mitani, Tadahiro, Posey, Jennifer E., Tay, Chee Geap, Javed, Iram, Carr, Lucinda, Kanani, Farah, Beecroft, Fiona, Hane, Lee, Abdelkreem, Elsayed, Macek, Milan, Bispo, Luciana, Elmaksoud, Marwa Abd, Hashemi-Gorji, Farzad, Pehlivan, Davut, Amor, David J., Jamra, Rami Abou, Chung, Wendy K., Ghayoor, Eshan Karimiani, Campeau, Philippe, Alkuraya, Fowzan S., Pagnamenta, Alistair T., Gleeson, Joseph, Lupski, James R., Striano, Pasquale, Moreno-De-Luca, Andres, Lafontaine, Denis L.J., Houlden, Henry, and Maroofian, Reza

Published
2024
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28. Dual operative radar for vehicle to vehicle and vehicle to infrastructure communication

Author

Striano, Pasquale and Clemente, Carmine

Abstract

The research presented in this Thesis deals with the concepts of joint radar and communication system for automotive application. The novel systems developed include a joint radar and communication system based on the fractional Fourier transform (FrFT) and two interference mitigation frameworks. In the joint radar and communication system the FrFT is used to embed the data information into a radar waveform in order to obtain a signal sharing Linear Frequency Modulation (LFM) characteristics while allowing data transmission. Furthermore, in the proposed system multi user operations are allowed by assigning a specific order of the FrFT to each user. In this way, a fractional order division multiplexing can be implemented allowing the allocation of more than one user in the same frequency band with the advantage that the range resolution does not depend on the number of the users that share the same frequency band but only from the assigned of the FrFT. Remarkably, the predicted simulated radar performance of the proposed joint radar and communication system when using Binary Frequency Shift Keying (BFSK) encoding is not significantly affected by the transmitted data. In order to fully describe the proposed waveform design, the signal model when the bits of information are modulated using either BFSK or Binary Phase Shift Keying (BPSK) encoding is derived. This signal model will result also useful in the interference mitigation frameworks. In multi user scenarios to prevent mutual radar interference caused by users that share the same frequency band at the same time, each user has to transmit waveforms that are uncorrelated with those of other users. However, due to spectrum limitations, the uncorrelated property cannot always be satisfied even by using fractional order division multiplexing, thus interference is unavoidable. In order to mitigate the interference, two frameworks are introduced. In a joint radar communication system, the radar also has access to the communication data. With a near-precision reconstruction of the communication signal, this interference can be subtracted. In these two frameworks the interfering signal can be reconstructed using the derived mathematical model of the proposed FrFT waveform. In the first framework the subtraction between the received and reconstructed interference signals is carried out in a coherent manner, where the amplitude and phase of the two signals are taken into account. The performance of this framework is highly depend on the correct estimation of the Doppler frequency of the interfering user. A small error on the Doppler frequency can lead to a lack of synchronization between the received and reconstructed signal. Consequently, the subtraction will not be performed in a correct way and further interference components can be introduced. In order to solve the problem of the lack of the synchronization an alternative framework is developed where the subtraction is carried out in non-coherent manner. In the proposed framework, the subtraction is carried out after that the received radar signal and the reconstructed interference are processed, respectively. The performance is tested on simulated and real signals. The simulated and experimental results show that this framework is capable of mitigating the interference from other users successfully.

Published
2021
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29. Climate change and epilepsy: Insights from clinical and basic science studies

Author

Gulcebi, Medine I, Bartolini, Emanuele, Lee, Omay, Lisgaras, Christos Panagiotis, Onat, Filiz, Mifsud, Janet, Striano, Pasquale, Vezzani, Annamaria, Hildebrand, Michael S, Jimenez-Jimenez, Diego, Junck, Larry, Lewis-Smith, David, Scheffer, Ingrid E, Thijs, Roland D, Zuberi, Sameer M, Blenkinsop, Stephen, Fowler, Hayley J, Foley, Aideen, Sisodiya, Sanjay M, Consortium, on behalf of the EpilepsyClimateChange, Balestrini, Simona, Berkovic, Samuel, Cavalleri, Gianpiero, Correa, Daniel José, Custodio, Helena Martins, Galovic, Marian, Guerrini, Renzo, Henshall, David, Howard, Olga, Hughes, Kelvin, Katsarou, Anna, Koeleman, Bobby PC, Krause, Roland, Lowenstein, Daniel, Mandelenaki, Despoina, Marini, Carla, O'Brien, Terence J, Pace, Adrian, De Palma, Luca, Perucca, Piero, Pitkänen, Asla, Quinn, Finola, Selmer, Kaja Kristine, Steward, Charles A, Swanborough, Nicola, Thijs, Roland, Tittensor, Phil, Trivisano, Marina, Weckhuysen, Sarah, and Zara, Federico

Subjects
Biomedical and Clinical Sciences, Neurosciences, Epilepsy, Climate-Related Exposures and Conditions, Global Warming Climate Change, Brain Disorders, Climate Change, Sleep Research, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Climate Action, Animals, COVID-19, Death, Sudden, Global Health, Hot Temperature, Humans, Humidity, Public Health, Sleep Deprivation, Weather, Global warming, Emergency, Seizure, Temperature, Extreme weather events, Public health, Epilepsy Climate Change Consortium, Clinical Sciences, Neurology & Neurosurgery, Biological psychology, Clinical and health psychology
Abstract

Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.

Published
2021

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

Author

Gleichgerrcht, Ezequiel, Munsell, Brent C, Alhusaini, Saud, Alvim, Marina KM, Bargalló, Núria, Bender, Benjamin, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Blackmon, Karen, Caligiuri, Maria Eugenia, Cendes, Fernando, Concha, Luis, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Gambardella, Antonio, Gong, Bo, Guerrini, Renzo, Hatton, Sean N, Kälviäinen, Reetta, Keller, Simon S, Kochunov, Peter, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Labate, Angelo, Langner, Soenke, Larivière, Sara, Lenge, Matteo, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Meletti, Stefano, O'Brien, Terence J, Pardoe, Heath R, Pariente, Jose C, Rao, Jun Xian, Richardson, Mark P, Rodríguez-Cruces, Raúl, Rüber, Theodor, Sinclair, Ben, Soltanian-Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Vaudano, Anna Elisabetta, Vivash, Lucy, von Podewills, Felix, Vos, Sjoerd B, Weber, Bernd, Yao, Yi, Yasuda, Clarissa Lin, Zhang, Junsong, Thompson, Paul M, Sisodiya, Sanjay M, McDonald, Carrie R, Bonilha, Leonardo, Group, ENIGMA-Epilepsy Working, Altmann, Andre, Depondt, Chantal, Galovic, Marian, Thomopoulos, Sophia I, and Wiest, Roland

Subjects
Biomedical Imaging, Neurodegenerative, Neurosciences, Brain Disorders, Prevention, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Neurological, Artificial Intelligence, Brain, Epilepsy, Temporal Lobe, Hippocampus, Humans, Magnetic Resonance Imaging, Sclerosis, Support Vector Machine, Temporal lobe epilepsy, Machine learning, Artificial inteligence, ENIGMA-Epilepsy Working Group
Abstract

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.

Published
2021

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

Author

Larivière, Sara, Rodríguez-Cruces, Raúl, Royer, Jessica, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O’Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C

Subjects
Mental Health, Brain Disorders, Epilepsy, Clinical Research, Neurosciences, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological
Abstract

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.

Published
2020

33. White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study

Author

Hatton, Sean N, Huynh, Khoa H, Bonilha, Leonardo, Abela, Eugenio, Alhusaini, Saud, Altmann, Andre, Alvim, Marina KM, Balachandra, Akshara R, Bartolini, Emanuele, Bender, Benjamin, Bernasconi, Neda, Bernasconi, Andrea, Bernhardt, Boris, Bargallo, Núria, Caldairou, Benoit, Caligiuri, Maria E, Carr, Sarah JA, Cavalleri, Gianpiero L, Cendes, Fernando, Concha, Luis, Davoodi-bojd, Esmaeil, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Foley, Sonya F, Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ishikawa, Akari, Keller, Simon S, Kochunov, Peter V, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Kwan, Patrick, Labate, Angelo, Langner, Soenke, Lenge, Matteo, Liu, Min, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Moreira, José CV, Morita-Sherman, Marcia E, O’Brien, Terence J, Pardoe, Heath R, Pariente, José C, Ribeiro, Letícia F, Richardson, Mark P, Rocha, Cristiane S, Rodríguez-Cruces, Raúl, Rosenow, Felix, Severino, Mariasavina, Sinclair, Benjamin, Soltanian-Zadeh, Hamid, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Tortora, Domenico, Velakoulis, Dennis, Vezzani, Annamaria, Vivash, Lucy, von Podewils, Felix, Vos, Sjoerd B, Weber, Bernd, Winston, Gavin P, Yasuda, Clarissa L, Zhu, Alyssa H, Thompson, Paul M, Whelan, Christopher D, Jahanshad, Neda, Sisodiya, Sanjay M, and McDonald, Carrie R

Subjects
Genetics, Neurodegenerative, Epilepsy, Clinical Research, Brain Disorders, Neurosciences, Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Brain, Diffusion Magnetic Resonance Imaging, Epileptic Syndromes, Female, Humans, Image Interpretation, Computer-Assisted, Male, Middle Aged, White Matter, epilepsy, diffusion tensor imaging, multisite analysis, white matter, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P

Published
2020

34. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Abbott, Kristin M., Banka, Siddharth, de Boer, Elke, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Gilissen, Christian, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Martín, Estrella López, Macek, Milan, Jr., Matalonga, Leslie, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Riess, Olaf, Rooryck, Caroline, Ryba, Lukas, Agathe, Jean-Madeleine de Sainte, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Trimouille, Aurélien, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Zguro, Kristina, Boer, Elke de, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B.A.W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, ‘t Hoen, Peter A.C., Vissers, Lisenka E.L.M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Başak, Ayşe Nazlı, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A.L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Radio, Francesca Clementina, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Jean-Marçais, Nolwenn, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Safraou, Hana, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, de Vries, Bert B.A., Willemsen, Marjolein H., and Philippe, Christophe

Published
2023
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35. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author

Collaborative, Epi25, Feng, Yen-Chen Anne, Howrigan, Daniel P, Abbott, Liam E, Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L, Dhindsa, Ryan S, Stanley, Kate E, Cavalleri, Gianpiero L, Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M, Cossette, Patrick, Cotsapas, Chris, De Jonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G, Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J, Scheffer, Ingrid E, Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M, Bellows, Susannah T, Leu, Costin, Bennett, Caitlin A, Johns, Esther MC, Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J, Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M, Sadoway, Tara R, Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S, Kousiappa, Ioanna, Tanteles, George A, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S, Knake, Susanne, Kunz, Wolfram S, Zsurka, Gábor, Elger, Christian E, Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D, Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R, Krey, Ilona, Weber, Yvonne G, Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F, Steinhoff, Bernhard J, Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, and Schreiber, Herbert

Subjects
Clinical Research, Human Genome, Neurosciences, Epilepsy, Biotechnology, Genetics, Neurodegenerative, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Case-Control Studies, DNA Mutational Analysis, Exome, Genetic Markers, Genetic Predisposition to Disease, Genetic Variation, Humans, Phenotype, Exome Sequencing, Epi25 Collaborative. Electronic address: s.berkovic@unimelb.edu.au, Epi25 Collaborative, burden analysis, epilepsy, epileptic encephalopathy, exome, seizures, sequencing, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Published
2019

36. SLC35A2‐CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Author

Ng, Bobby G, Sosicka, Paulina, Agadi, Satish, Almannai, Mohammed, Bacino, Carlos A, Barone, Rita, Botto, Lorenzo D, Burton, Jennifer E, Carlston, Colleen, Chung, Brian Hon‐Yin, Cohen, Julie S, Coman, David, Dipple, Katrina M, Dorrani, Naghmeh, Dobyns, William B, Elias, Abdallah F, Epstein, Leon, Gahl, William A, Garozzo, Domenico, Hammer, Trine Bjørg, Haven, Jaclyn, Héron, Delphine, Herzog, Matthew, Hoganson, George E, Hunter, Jesse M, Jain, Mahim, Juusola, Jane, Lakhani, Shenela, Lee, Hane, Lee, Joy, Lewis, Katherine, Longo, Nicola, Lourenço, Charles Marques, Mak, Christopher CY, McKnight, Dianalee, Mendelsohn, Bryce A, Mignot, Cyril, Mirzaa, Ghayda, Mitchell, Wendy, Muhle, Hiltrud, Nelson, Stanley F, Olczak, Mariusz, Palmer, Christina GS, Partikian, Arthur, Patterson, Marc C, Pierson, Tyler M, Quinonez, Shane C, Regan, Brigid M, Ross, M Elizabeth, Sacoto, Maria J Guillen, Scaglia, Fernando, Scheffer, Ingrid E, Segal, Devorah, Singhal, Nilika Shah, Striano, Pasquale, Sturiale, Luisa, Symonds, Joseph D, Tang, Sha, Vilain, Eric, Willis, Mary, Wolfe, Lynne A, Yang, Hui, Yano, Shoji, Powis, Zöe, Suchy, Sharon F, Rosenfeld, Jill A, Edmondson, Andrew C, Grunewald, Stephanie, and Freeze, Hudson H

Subjects
Clinical Research, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, Animals, Biopsy, CHO Cells, Cells, Cultured, Congenital Disorders of Glycosylation, Cricetulus, Female, Humans, Male, Monosaccharide Transport Proteins, Mutation, Uridine Diphosphate Galactose, congenital disorders of glycosylation, glycoside, nucleotide sugar transporter, UDP-galactose, Clinical Sciences, Genetics & Heredity
Abstract

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Published
2019

37. Hydranencephaly in CENPJ-related Seckel syndrome

Author

Cuccurullo, Claudia, Miele, Giuseppina, Piccolo, Gianluca, Bilo, Leonilda, Accogli, Andrea, D'Amico, Alessandra, Fratta, Mario, Guerrisi, Sara, Iacomino, Michele, Salpietro, Vincenzo, Ugga, Lorenzo, Striano, Pasquale, and Coppola, Antonietta

Published
2022
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40. Brivaracetam add-on treatment in pediatric patients with severe drug-resistant epilepsy: Italian real-world evidence

Author

Russo, Angelo, Pruccoli, Jacopo, Cesaroni, Carlo Alberto, Belotti, Laura Maria Beatrice, Zenesini, Corrado, Bonanni, Paolo, Boni, Antonella, Cesaroni, Elisabetta, Coppola, Giangennaro, Cordelli, Duccio Maria, Danieli, Alberto, Mancardi, Maria Margherita, Marchese, Francesca, Matricardi, Sara, Messana, Tullio, Nocera, Giovanna Martina, Operto, Francesca Felicia, Pellino, Giuditta, Reina, Federica, Vanadia, Francesca, Verrotti, Alberto, and Striano, Pasquale

Published
2022
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41. An Italian consensus on the management of Lennox-Gastaut syndrome

Author

Aguglia, Umberto, Bagnasco, Irene, Bartolini, Emanuele, Battaglia, Domenica, Beccaria, Francesca, Belcastro, Vincenzo, Bernardo, Pia, Bonanni, Paolo, Boniver, Clementina, Bonuccelli, Alice, Briatore, Eleonora, Brigo, Francesco, Cesaroni, Elisabetta, Coa, Roberta, Costa, Cinzia, D'Aniello, Alfredo, De Giorgis, Valentina, Gennaro, Giancarlo Di, Ferrari, Anna Rita, Marchese, Francesca, Matricardi, Sara, Messana, Tullio, Morano, Alessandra, Operto, Francesca Felicia, Orsini, Alessandro, Parmeggiani, Lucio, Peruzzi, Cinzia, Pruna, Dario, Puligheddu, Monica, Pulitano, Patrizia, Ragona, Francesca, Romigi, Andrea, Rosati, Anna, Rosati, Eleonora, Russo, Angelo, Sartori, Stefano, Spagnoli, Carlotta, Spanò, Maria, Trabacca, Antonio, Troisi, Serena, Viri, Maurizio, Zucca, Claudio, Riva, Antonella, Coppola, Antonietta, Bonaventura, Carlo Di, Elia, Maurizio, Ferlazzo, Edoardo, Gobbi, Giuseppe, Marini, Carla, Meletti, Stefano, Romeo, Antonino, Santoro, Katia, Verrotti, Alberto, Capovilla, Giuseppe, and Striano, Pasquale

Published
2022
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42. ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model

Author

Vitobello, Antonio, Mazel, Benoit, Lelianova, Vera G., Zangrandi, Alice, Petitto, Evelina, Suckling, Jason, Salpietro, Vincenzo, Meyer, Robert, Elbracht, Miriam, Kurth, Ingo, Eggermann, Thomas, Benlaouer, Ouafa, Lall, Gurprit, Tonevitsky, Alexander G., Scott, Daryl A., Chan, Katie M., Rosenfeld, Jill A., Nambot, Sophie, Safraou, Hana, Bruel, Ange-Line, Denommé-Pichon, Anne-Sophie, Tran Mau-Them, Frédéric, Philippe, Christophe, Duffourd, Yannis, Guo, Hui, Petersen, Andrea K., Granger, Leslie, Crunk, Amy, Bayat, Allan, Striano, Pasquale, Zara, Federico, Scala, Marcello, Thomas, Quentin, Delahaye, Andrée, de Sainte Agathe, Jean-Madeleine, Buratti, Julien, Kozlov, Serguei V., Faivre, Laurence, Thauvin-Robinet, Christel, and Ushkaryov, Yuri

Published
2022
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45. The Interplay Between Gut Microbiota, Adipose Tissue, and Migraine: A Narrative Review.

Author

Biagioli, Valentina, Mela, Federica, Ferraro, Paola, Villano, Gianmichele, Orsini, Alessandro, Diana, Maria Cristina, Striano, Pasquale, and Santangelo, Andrea

Abstract

Background: Migraine, a prevalent neurovascular disorder, affects millions globally and is associated with significant morbidity. Emerging evidence suggests a crucial role of the gut microbiota and adipose tissue in the modulation of migraine pathophysiology, particularly through mechanisms involving neuroinflammation and metabolic regulation. Material and Methods: A narrative review of the literature from 2000 to 2024 was conducted using the PubMed database. Studies addressing the relationships between microbiota, adipose tissue, and migraine—including dietary interventions and their impact—were analyzed. Results: The findings highlight a bidirectional gut–brain axis, with gut microbiota influencing neuroinflammation via metabolites such as short-chain fatty acids (SCFAs). Obesity exacerbates migraine severity through chronic inflammation and the dysregulation of adipocytokines like leptin and adiponectin. Dietary patterns, such as low glycemic index diets and Mediterranean diets, and the use of prebiotics, probiotics, and postbiotics show potential in migraine management. Conclusions: This review underscores the need for integrative approaches targeting the microbiota–gut–brain axis and adipose tissue in migraine therapy. Future studies should explore longitudinal effects and personalized interventions to optimize outcomes. [ABSTRACT FROM AUTHOR]

Published
2025
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46. A VAMS‐based LC–MS/MS method for precise cenobamate quantification in epilepsy (patients).

Author

Pigliasco, Federica, Cafaro, Alessia, Barco, Sebastiano, Biondi, Margherita, Stella, Manuela, Mattioli, Francesca, Riva, Antonella, de Grazia, Ugo, Molteni, Linda, Micalizzi, Elisa, Villani, Flavio, Striano, Pasquale, Bandettini, Roberto, and Cangemi, Giuliana

Subjects
DRUG monitoring, PEOPLE with epilepsy, DRUG interactions, DRUG toxicity, ANTICONVULSANTS
Abstract

Objective: Cenobamate (CNB), a recently approved antiseizure medication by the European Medicines Agency (EMA), serves as an adjunctive therapy for focal‐onset seizures in adult patients unresponsive to at least two other treatments. Administered in polytherapy, CNB can potentially interact with co‐administered drugs in epilepsy patients, necessitating dose adjustments and the need for effective therapeutic drug monitoring (TDM). Methods: In this study, we introduce a novel LC–MS/MS method for precise CNB quantification using Volumetric Absorptive Microsampling (VAMS), following validation according to ICH guidelines M10. VAMS samples are efficiently extracted with 200 μL of methanol, with chromatographic separation achieved using an Acquity UPLC HSS PFP column. The method's efficacy was confirmed through its application to real samples from adult CNB‐treated patients. Results: Our results demonstrate that the method exhibits linearity within the range of 0.05–30 mg/L, with intra‐ and inter‐run precision ranging from 1% to 8% and accuracy from 1% to 10% based on 30 μL of sample. Furthermore, CNB stability in VAMS is confirmed for up to 15 days at 25°C and −20°C. Importantly, no significant difference was observed between CNB concentrations in VAMS samples and those in plasma obtained from venous blood. Significance: This VAMS‐based LC–MS/MS method presents a robust alternative for TDM in CNB‐treated patients. Future investigations should explore CNB concentrations in capillary blood and assess their correlation with plasma levels to further enhance its clinical utility. Plain Language Summary: Cenobamate is an antiepileptic drug and used for treatment of focal‐onset seizures in adult patients (≥18 age). TDM can prevent drug interactions and minimize drug toxicity. The aim of this work is to evaluate volumetric absorptive microsampling (VAMS) from capillary blood as an alternative strategy for TDM in patients treated with the newly antiepileptic drug. Our method is suitable for TDM, and this study suggests that VAMS allows monitoring of cenobamate concentration and can offer valuable support for personalized therapy in refractory epilepsy. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Role of Human Milk Microbiota in Infant Neurodevelopment: Mechanisms and Clinical Implications.

Author

Biagioli, Valentina, Sortino, Vincenzo, Falsaperla, Raffaele, and Striano, Pasquale

Subjects
ASTHMA-related mortality, MORTALITY risk factors, NEUROPROTECTIVE agents, RISK assessment, BREASTFEEDING, RESPIRATORY infections, CROHN'S disease, MALNUTRITION, NEURAL development, BRAIN, BREAST milk, HUMAN microbiota, ULCERATIVE colitis, PROBIOTICS, DIABETES, DISEASE risk factors, CHILDREN
Abstract

Background: Human milk (HM) is recognized as an ideal source of nutrition for newborns; as a result, its multiple bioactive molecules can support the growth of healthy newborns and reduce the risk of mortality and diseases such as asthma, respiratory infections, diabetes (type 1 and 2), and gastrointestinal disorders such as ulcerative colitis and Crohn's disease. Furthermore, it can reduce the severity of necrotizing enterocolitis (NEC) in preterm infants. Moreover, human milk oligosaccharides (HMOs) present in breast milk show an immunomodulatory, prebiotic, and neurodevelopmental effect that supports the microbiota–gut–brain axis. Material and methods: This study examined the state-of-the-art research, using keywords such as "breastfeeding", "human milk oligosaccharides", "microbiota–gut–brain axis", "infants", and "malnutrition". The literature review was conducted by selecting articles between 2013 and 2024, as the most recent ones. The databases used were Web Science, PubMed, and Scopus. Results: We found multiple studies examining the composition of HM and infant formula (IF). However, further longitudinal studies and randomized control trials (RCTs) are needed to better understand the clinical outcomes that bioactive components exert on healthy and hospitalized children and how, in conditions of malnutrition, it is necessary to support the growth of the newborn. Conclusions: In this review, we affirm the importance of human milk and, through it, the modulation of the microbiota and the neuroprotective role in newborns, determining the health of the following years of life. [ABSTRACT FROM AUTHOR]

Published
2024
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49. Structural mapping of GABRB3 variants reveals genotype–phenotype correlations

Author

Johannesen, Katrine M., Iqbal, Sumaiya, Guazzi, Milena, Mohammadi, Nazanin A., Pérez-Palma, Eduardo, Schaefer, Elise, De Saint Martin, Anne, Abiwarde, Marie Therese, McTague, Amy, Pons, Roser, Piton, Amelie, Kurian, Manju A., Ambegaonkar, Gautam, Firth, Helen, Sanchis-Juan, Alba, Deprez, Marie, Jansen, Katrien, De Waele, Liesbeth, Briltra, Eva H., Verbeek, Nienke E., van Kempen, Marjan, Fazeli, Walid, Striano, Pasquale, Zara, Federico, Visser, Gerhard, Braakman, Hilde M.H., Haeusler, Martin, Elbracht, Miriam, Vaher, Ulvi, Smol, Thomas, Lemke, Johannes R., Platzer, Konrad, Kennedy, Joanna, Klein, Karl Martin, Au, Ping Yee Billie, Smyth, Kimberly, Kaplan, Julie, Thomas, Morgan, Dewenter, Malin K., Dinopoulos, Argirios, Campbell, Arthur J., Lal, Dennis, Lederer, Damien, Liao, Vivian W.Y., Ahring, Philip K., Møller, Rikke S., and Gardella, Elena

Published
2022
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50. Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome

Author

Ghosh, Shereen G, Becker, Kerstin, Huang, He, Dixon-Salazar, Tracy, Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K, Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M, Efthymiou, Stephanie, Hanna, Michael G, Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmüller, Janine, Weixler, Lisa, Nürnberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B, Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M, Wolf, Nicole I, Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, and Gleeson, Joseph G

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Epilepsy, Pediatric, Brain Disorders, Neurosciences, Rare Diseases, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, ADP-ribosylation, ADPRHL2, ARH3, SUDEP, ataxia, epilepsy, neurodegeneration, neuropathy, oxidative stress, poly-ADP ribose, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.

Published
2018

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