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DEVELOPMENTAL EPILEPSIES

Equipe Szepetowski (NICE2: Neonatal, Infantile and Childhood Epilepsies and Encephalopathies)

Human epilepsies represent one of the most frequent neurological disorders worldwide, with a prevalence of 0.5-1%, and cause major socio-economical, societal, welfare, medical and scientific issues. This burden is further emphasized by the frequent neurodevelopmental and comorbid relationships with other brain diseases, such as autism spectrum disorders, depression, migraine, movement disorders, dyslexia, as well as sleep, cognitive, speech and language impairments.

In this neurodevelopmental and pathological context, we aim at studying and at targeting the early events associated with epilepsies and encephalopathies of genetic and nongenetic origins, using multidisciplinary approaches in vitro and in vivo. Particularly we are interested in the early neural and neuroimmune pathological alterations that may occur in the developing brain and that will exert long term influence on brain function.

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Thèmes de Recherche et Principaux Résultats

COMPOSITION OF NICE2 TEAM

as on Sept 18, 2019

Team Leader
Pierre SZEPETOWSKI (DR1 CNRS)

Team Members (in alphabetical order)
Laurent ANIKSZTEJN (DR2 INSERM)
Sylvian BAUER (CR1 CNRS)
Hélène BECQ (IE INSERM)
Najoua BIBA (PhD Student)
Nadine BRUNEAU (CR1 INSERM)
Nail BURNASHEV (DR2 INSERM)
Carla CRESPO QUILES (PhD Student)

 

GENERAL OVERVIEW

OVERALL CONTEXT

Human epilepsies represent one of the most frequent neurological disorders, with an overall prevalence of 0.5-1%. This represents 50 million people worldwide, 6 million in Europe, and 400,000 in France. According to the World Health Organization, the annual cost of the epilepsies in Europe is over €20 billion. One third of the patients do not respond well to current anti-epileptic drugs.

Overall the epilepsies cause major socio-economical, societal, welfare, medical and scientific issues. This burden is further emphasized by the existence of frequent comorbid relationships with other brain diseases, such as autism spectrum disorders, depression, migraine, movement disorders, dyslexia, and sleep, cognitive, speech and language impairments.

 

SCIENTIFIC GOALS & OBJECTIVES

We aim at studying and at targeting the early pathophysiological events associated with epilepsies and encephalopathies of genetic or nongenetic origin, using multidisciplinary approaches in vitro and in vivo.

Particularly we are interested in the pathological alterations that occur early in the developing brain and that may have profound and long-term consequences on brain development and functioning.

Our main objectives are:

• to better understand pediatric epilepsies and epileptic encephalopathies of genetic origin, and to design novel rescue strategies in those contexts;

• to investigate on secondary pathophysiological events, such as neuroimmune alterations (e.g. microglia dysfunctioning), that are likely to impact on the severity, the comorbidity, the outcome and the responses to treatments;

• to decipher how nongenetic factors (e.g. viral infections) impact on brain development and ultimately lead to neurodevelopmental disorders.

 

RECENT FINDINGS

In the recent years we have studied pediatric epilepsies in a genetic and neurodevelopmental perspective.

•• We have made major findings in human epilepsy genetics:

• we have identified mutations in the GRIN2A/GluN2A subunit of glutamate-gated NMDA receptors as the first (and so far major) cause for the sleep-related epilepsy-aphasia spectrum of disorders, which comprises childhood focal epilepsies and epileptic encephalopathies with speech and language dysfunction, and the origin of which had been debated for more than 50 years (Carvill et al. Nature Genetics 2013; Lesca et al. Nature Genetics 2013); since then, we have identified a series of sleep-related anomalies including discharges in the corresponding Grin2a knock-out mouse model, which also displayed transient microstructural anomalies involving the thalamus (Salmi et al. Epilepsia 2018; Salmi et al. Epilepsia 2019).

• we have shown that mutations in the retinoid related nuclear receptor RORB cause epileptic disorders, notably absence seizures, variably associated with behavioral and cognitive impairments (Rudolf et al. European Journal of Human Genetics 2016);

• in the context of an international consortium, we have also identified mutations in the Proline-Rich Repeat Protein PRRT2 as the major genetic cause for the variable comorbid association of infantile convulsions, paroxysmal dyskinesia and hemiplegic migraine, which had been searched for more than 15 years (Lee et al. Cell Reports 2012; Cloarec et al. Neurology 2012).

•• We have made important and original findings on the pathophysiological mechanisms associated with early-onset epileptic encephalopathies (EOEE):

• thanks to collaborations with neuro-pediatricians, geneticists, molecular biologists and biochemists, we showed that Kv7.2 mutations may have opposite effects on M current, and may act on the redistribution of Kv7 channels from the axon initial segment to the somato-dendritic compartment (Abidi et al. Neurobiology of Disease 2015; Devaux et al. Epilepsia 2016);
• we found that STXBP1//Munc18.1 decreased the physical interaction of syntaxine 1A with Kv7 channels and reduced the inhibitory effect of syntaxine 1A on M current, indicating a potential functional link between STXBP1/Munc18.1 and Kv7.2 – the two major proteins involved in EOEE (Devaux et al. Epilepsia 2017).
• we also demonstrated that the degradation of glutamate by glutamine synthase, which is specifically expressed by astrocytes in the brain, is fundamental to ensure proper function of glial glutamate transporters and to prevent glutamate spillover (Trabelsi et al. Glia 2017);

•• We have also made a series of important and original findings regarding the pathophysiological pathways of developmental epilepsies and encephalopathies, and on their possible therapeutic targeting:

• we have demonstrated that a short administration of a tubulin deacetylase inhibitor to pregnant rats was sufficient to prevent the long-term epileptiform consequences of a neuronal migration disorder in the embryos (Salmi et al. Brain 2013);

• in a model of tuberous sclerosis complex (TSC), we have shown that tuberless heterozygote Tsc1+/- mice showed functional upregulation of cortical GluN2C-containing NMDA receptors in an mTOR-dependent manner and exhibited recurrent, unprovoked seizures during early postnatal life. Accordingly, specific GluN2C/D antagonists blocked seizures in Tsc1+/- mice in vivo and in vitro. Likewise, GluN2C expression was upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduced paroxysmal hyperexcitability (Lozovaya et al. Nature Communications 2014); more recently, we showed that a stable analogue of diadenosine-tetraphosphate suppressed spontaneous epileptiform activity in vitro and in vivo in Tsc1+/- mice and in cortical samples from TSC human patients, via enhanced adenosine signaling (Pons-Bennaceur et al. Cereb Cortex 2018).

• in a rat model of cytomegalovirus (CMV) infection of the developing brain in utero, we have detected early neuroimmune alterations including the infection of brain immune cells, the (dys)expression of various chemokines, the infiltration by peripheral cells, and the impairment of microglia phenotype (Cloarec et al. PloS One 2016). The rescue of fetal microglia in utero with pharmacological drugs (clodronate liposomes, tetracyclines) prevented against the future emergence of postnatal neurological phenotypes (Cloarec et al. Front Cell Neurosci 2018).

Projets de recherche

ONGOING PROJECTS & EXPERIMENTAL APPROACHES

Genetic and nongenetic (viruses, drugs…) factors may cause or influence a broad range of neurodevelopmental disorders, including severe epilepsies and encephalopathies, which can be associated with comorbid manifestations (e.g. cognitive or behavioral impairment).

Despite the recent identification of various genes participating in such disorders, the underlying pathogenic mechanisms and rationale for treatment still remain poorly understood. In these conditions, identifying the early events likely altered during brain development and deciphering the underlying pathophysiological processes is mandatory.

Notably, what sustains i/ the variable degree of severity, ii/ the association with different comorbid conditions such as autism manifestations or cognitive and language impairments, iii/ the somehow unpredictable outcome, and iv/ the unsatisfactory response to treatment, that are all frequently seen in such disorders, remains poorly known.

Obviously both genetic factors such as the genetic background or the existence of somatic mutations, and nongenetic factors such as environmental insults or the reaction of the neuroimmune system, might play a role in such a diversity.

We use multidisciplinary approaches and tools that non exhaustively include molecular genetics, cell biology, flow cytometry, protein analysis, electrophysiological recordings in vitro and in vivo, intracerebroventicular electroporation and infection of the embryonic brain in utero, behavioral analyses, rescue strategies in vivo, 2-photon microscopy, etc.

We study four rodent models of different neurodevelopmental disorders where both specific and non-specific determinants are likely involved, albeit at different levels, in the emergence and in the variable evolution of the phenotypes.

•• KCNQ2-related early-onset epileptic encephalopathies: we study the impact of KCNQ2 pathogenic defects on the biophysical properties of Kv7 channels and analyze their consequences on cortical network activities, notably using a mouse model bearing a selective pathogenic Kv7.2 variant.

•• GRIN2A-related disorders: in humans, mutations in the corresponding NMDA receptor subunit GLUN2A cause quite benign to severe disorders of the epilepsy-aphasia spectrum. We study GRIN2A variants in order to investigate for altered functioning of NMDA receptors, and the corresponding Grin2a KO murine model in search of early structural and functional alterations.

•• TSC1-related disorders: in humans, mutations in the hamartin protein (TSC1 gene) cause variably-expressed tuberous sclerosis complex and epilepsy associated with cognitive impairment and autism manifestations. We study the corresponding murine model to decipher the underlying pathophysiological mechanisms of epileptic activity, and to address the possible involvement of early immune events as possible second hits.

•• Cytomegalovirus (CMV)-related disorders: in human, congenital cytomegalovirus (CMV) infections of the brain is a major cause of neurodevelopmental disorders and may have various consequences with highly variable degrees of severity. We have designed a rat model of cytomegalovirus infection into the developing brain in utero. In this model, early neuroimmune alterations (microglia, chemokines) were observed. We study the possible involvement of such early alterations in the pathophysiology and in the emergence of neurological and other postnatal outcome.

Mots-clés

Epilepsy / Encephalopathies /Brain development / NMDA Receptors / GRIN2A / Kv7.2 / Tuberous sclerosis complex /Congenital cytomegalovirus / Microglia / Rodent models

Approches expérimentales

We use multidisciplinary approaches and tools that non exhaustively include molecular genetics, cell biology, flow cytometry, protein analysis, electrophysiological recordings in vitro and in vivo, intracerebroventicular electroporation and infection of the embryonic brain in utero, behavioral analyses, rescue strategies in vivo, 2-photon microscopy, cellular and rodent models, etc.

Collaborations récentes et/ou en cours

Locally, the team has got long-term collaborations with several INMED teams (C Cardoso/A Represa, R Khazipov, J Epsztein) and INMED core facilities (PPGI, PBMC, InMAGIC, animal facility) as well as with pediatric epileptology (M Milh, Marseille University Hospital), CRN2M centre (J Devaux), Marseille Medical Genetics lab (L Villard) and the CIPHE/CIML immunology centre (H Luche, M Malissen). We further integrated within the local epileptology community in the context of the university hospital foundation (FHU) EPINEXT that brings together a large number of teams having well-recognized activity in epileptology, from the clinical aspects to more fundamental views, and located at several research centres in Marseille.

Other collaborations have been established elsewhere in France and abroad: non exhaustively, these include the Rothschild Foundation (O Delalande, Paris), INSERM unit U1141 (P Gressens, Paris), the CERMEP neuroimaging centre (R Bolbos, Lyon), the University of Heidelberg (A Rozov, Germany), University of California San Francisco (LJ Ptacek, USA), Yale University (A Bordey, USA), Washington University (HC Mefford, USA), University of Melbourne (IE Scheffer & SF Berkovic, Australia), Nuremberg-Erlangen University, (T Stamminger, Germany), Oregon University (DN Streblow, USA), Eastern Finland University (R Giniatullin, Finland), Verona University (G Bertini, Italy).

Financements / Labellisations

SUBVENTIONS (as from 2010)

Acronym/Name/Number: CERVIR
Topic: Cytomegalovirus and Brain Development
Funded by: Sud PACA Regional Council
Period: 2011-13

Acronym/Name/Number: EPIPHOT
Topic: Epilepsy
Funded by: UCB-Pharma France
Period: 2012-14

Acronym/Name/Number: EPILAND
Topic: Epilepsy, Brain Development and Comorbidity
Funded by: ANR
Period: 2010-14

Acronym/Name/Number: -
Topic: Tuberous Sclerosis Complex
Funded by: ANR
Period: 2013-15

Acronym/Name/Number: -
Topic: Tuberous Sclerosis Complex
Funded by: Aix-Marseille University (AMIDEX)
Period: 2014-16

Acronym/Name/Number: Early Behavioral Signatures
Topic: Equipement for Behavioral Analyzes
Funded by: FRC
Period: 2015-16

Acronym/Name/Number: -
Topic: Tuberous Sclerosis Complex
Funded by: ANR
Period: 2014-17

Acronym/Name/Number: Behavior impairment in disorders of the epilepsy-aphasia spectrum
Topic: Behavior and Epilepsy
Funded by: FRC
Period: 2015-17

Acronym/Name/Number: EPI’K
Topic: Early Onset Epileptic Encephalopathies
Funded by: ANR
Period: 2015-18

Acronym/Name/Number: DESIRE
Topic: Epilepsy
Funded by: European Community FP7
Period: 2013-18

Acronym/Name/Number: ALTOMIC
Topic: Cytomegalovirus, Brain Development and Microglia
Funded by: NRJ Foundation / Institut de France
Period: 2018-20

Acronym/Name/Number: Alterations and Targeting of Microglia in Congenital Cytomegalovirus Infections
Topic: Cytomegalovirus, Brain Development and Microglia
Funded by: FRC
Period: 2019-21

Stages, Thèses, Post-docs

Applications at various levels are welcome: Engineer schools, Master1, Master2, PhD, post-Doc, permanent researchers. Applications to be sent by email to :pierre.szepetowski@inserm.fr

Nos publications

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, Salmi M, Tsintsadze T, Addis L, Motte J, Wright S, Tsintsadze V, Michel A, Doummar D, Lascelles K, Strug L, Waters P, de Bellescize J, Vrielynck P, de Saint Martin A, Ville D, Ryvlin P, Arzimanoglou A, Hirsch E, Vincent A, Pal D, Burnashev N, Sanlaville D, Szepetowski P

Nature genetics - Sep 2013

Administration of Drugs Targeting Microglia Improves the Neurodevelopmental Outcome Following Cytomegalovirus Infection of the Rat Fetal Brain.

Cloarec R, Bauer S, Teissier N, Schaller F, Luche H, Courtens S, Salmi M, Pauly V, Bois E, Pallesi-Pocachard E, Buhler E, Michel FJ, Gressens P, Malissen M, Stamminger T, Streblow DN, Bruneau N, Szepetowski P

Frontiers in cellular neuroscience - Jan 2018

A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity.

Devaux J, Abidi A, Roubertie A, Molinari F, Becq H, Lacoste C, Villard L, Milh M, Aniksztejn L

Epilepsia - May 2016

Impaired vocal communication, sleep-related discharges, and transient alteration of slow-wave sleep in developing mice lacking the GluN2A subunit of N-methyl-d-aspartate receptors.

Salmi M, Del Gallo F, Minlebaev M, Zakharov A, Pauly V, Perron P, Pons-Bennaceur A, Corby-Pellegrino S, Aniksztejn L, Lenck-Santini PP, Epsztein J, Khazipov R, Burnashev N, Bertini G, Szepetowski P

Epilepsia - Jul 2019

Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model.

Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E, Minlebaev M, Goriounova NA, Buhler E, Watrin F, Shityakov S, Becker AJ, Bordey A, Milh M, Scavarda D, Bulteau C, Dorfmuller G, Delalande O, Represa A, Cardoso C, Dulac O, Ben-Ari Y, Burnashev N

Nature communications - Jan 2014

Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.

Salmi M, Bruneau N, Cillario J, Lozovaya N, Massacrier A, Buhler E, Cloarec R, Tsintsadze T, Watrin F, Tsintsadze V, Zimmer C, Villard C, Lafitte D, Cardoso C, Bao L, Lesca G, Rudolf G, Muscatelli F, Pauly V, Khalilov I, Durbec P, Ben-Ari Y, Burnashev N, Represa A, Szepetowski P

Brain : a journal of neurology - Aug 2013

Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex.

Pons-Bennaceur A, Tsintsadze V, Bui TT, Tsintsadze T, Minlebaev M, Milh M, Scavarda D, Giniatullin R, Giniatullina R, Shityakov S, Wright M, Miller AD, Lozovaya N, Burnashev N

Cerebral cortex (New York, N.Y. : 1991) - Oct 2018

Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a.

Salmi M, Bolbos R, Bauer S, Minlebaev M, Burnashev N, Szepetowski P

Epilepsia - Aug 2018

A possible link between KCNQ2- and STXBP1-related encephalopathies: STXBP1 reduces the inhibitory impact of syntaxin-1A on M current.

Devaux J, Dhifallah S, Maria M, Stuart-Lopez G, Becq H, Milh M, Molinari F, Aniksztejn L

Epilepsia - Oct 2017

Genetics of human epilepsies: Continuing progress.

Szepetowski P

Presse medicale (Paris, France : 1983) - Mar 2018

Functional Properties of Human NMDA Receptors Associated with Epilepsy-Related Mutations of GluN2A Subunit.

Sibarov DA, Bruneau N, Antonov SM, Szepetowski P, Burnashev N, Giniatullin R

Frontiers in cellular neuroscience - Jan 2017

Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations.

Lesca G, Møller RS, Rudolf G, Hirsch E, Hjalgrim H, Szepetowski P

Epileptic disorders : international epilepsy journal with videotape - May 2019

Inhibition of the Mitochondrial Glutamate Carrier SLC25A22 in Astrocytes Leads to Intracellular Glutamate Accumulation.

Goubert E, Mircheva Y, Lasorsa FM, Melon C, Profilo E, Sutera J, Becq H, Palmieri F, Palmieri L, Aniksztejn L, Molinari F

Frontiers in cellular neuroscience - Jan 2017

The conversion of glutamate by glutamine synthase in neocortical astrocytes from juvenile rat is important to limit glutamate spillover and peri/extrasynaptic activation of NMDA receptors.

Trabelsi Y, Amri M, Becq H, Molinari F, Aniksztejn L

Glia - Nov 2016

Cytomegalovirus Infection of the Rat Developing Brain In Utero Prominently Targets Immune Cells and Promotes Early Microglial Activation.

Cloarec R, Bauer S, Luche H, Buhler E, Pallesi-Pocachard E, Salmi M, Courtens S, Massacrier A, Grenot P, Teissier N, Watrin F, Schaller F, Adle-Biassette H, Gressens P, Malissen M, Stamminger T, Streblow DN, Bruneau N, Szepetowski P

PloS one -

Magnetofection™ of NMDA Receptor Subunits GluN1 and GluN2A Expression Vectors in Non-Neuronal Host Cells.

Bruneau N, Szepetowski P

Methods in molecular biology (Clifton, N.J.) - Jan 2017

A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels.

Abidi A, Devaux JJ, Molinari F, Alcaraz G, Michon FX, Sutera-Sardo J, Becq H, Lacoste C, Altuzarra C, Afenjar A, Mignot C, Doummar D, Isidor B, Guyen SN, Colin E, De La Vaissière S, Haye D, Trauffler A, Badens C, Prieur F, Lesca G, Villard L, Milh M, Aniksztejn L

Neurobiology of disease - Aug 2015

Severe phenotypic spectrum of biallelic mutations in PRRT2 gene.

Delcourt M, Riant F, Mancini J, Milh M, Navarro V, Roze E, Humbertclaude V, Korff C, Des Portes V, Szepetowski P, Doummar D, Echenne B, Quintin S, Leboucq N, Singh Amrathlal R, Rochette J, Roubertie A

Journal of neurology, neurosurgery, and psychiatry - Jul 2015

NMDA receptor subunit mutations in neurodevelopmental disorders.

Burnashev N, Szepetowski P

Current opinion in pharmacology - Dec 2014

Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.

Huguet G, Nava C, Lemière N, Patin E, Laval G, Ey E, Brice A, Leboyer M, Szepetowski P, Gillberg C, Depienne C, Delorme R, Bourgeron T

PloS one - Jan 2014

A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2.

Dimassi S, Labalme A, Lesca G, Rudolf G, Bruneau N, Hirsch E, Arzimanoglou A, Motte J, de Saint Martin A, Boutry-Kryza N, Cloarec R, Benitto A, Ameil A, Edery P, Ryvlin P, De Bellescize J, Szepetowski P, Sanlaville D

Epilepsia - Feb 2014

GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

Carvill GL, Regan BM, Yendle SC, O'Roak BJ, Lozovaya N, Bruneau N, Burnashev N, Khan A, Cook J, Geraghty E, Sadleir LG, Turner SJ, Tsai MH, Webster R, Ouvrier R, Damiano JA, Berkovic SF, Shendure J, Hildebrand MS, Szepetowski P, Scheffer IE, Mefford HC

Nature genetics - Sep 2013

PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.

Cloarec R, Bruneau N, Rudolf G, Massacrier A, Salmi M, Bataillard M, Boulay C, Caraballo R, Fejerman N, Genton P, Hirsch E, Hunter A, Lesca G, Motte J, Roubertie A, Sanlaville D, Wong SW, Fu YH, Rochette J, Ptácek LJ, Szepetowski P

Neurology - Nov 2012

Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions.

Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee WL, Lynch DR, Mohammed S, Müller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong BW, Swoboda KJ, Tucker S, Wood N, Hanna M, Bowcock AM, Szepetowski P, Fu YH, Ptáček LJ

Cell reports - Jan 2012

The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system.

Bruneau N, Szepetowski P

Current pharmaceutical design - Jan 2011

Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures.

Jamali S, Salzmann A, Perroud N, Ponsole-Lenfant M, Cillario J, Roll P, Roeckel-Trevisiol N, Crespel A, Balzar J, Schlachter K, Gruber-Sedlmayr U, Pataraia E, Baumgartner C, Zimprich A, Zimprich F, Malafosse A, Szepetowski P

PloS one - Jan 2010

Infantile convulsions with paroxysmal dyskinesia (ICCA syndrome) and copy number variation at human chromosome 16p11.

Roll P, Sanlaville D, Cillario J, Labalme A, Bruneau N, Massacrier A, Délepine M, Dessen P, Lazar V, Robaglia-Schlupp A, Lesca G, Jouve E, Rudolf G, Rochette J, Lathrop GM, Szepetowski P

PloS one - Jan 2010

From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors.

Rudolf G, Valenti MP, Hirsch E, Szepetowski P

Epilepsia - Aug 2009

Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex.

Roll P, Vernes SC, Bruneau N, Cillario J, Ponsole-Lenfant M, Massacrier A, Rudolf G, Khalife M, Hirsch E, Fisher SE, Szepetowski P

Human molecular genetics - Dec 2010

A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene.

Schaller F, Watrin F, Sturny R, Massacrier A, Szepetowski P, Muscatelli F

Human molecular genetics - Dec 2010

Sushi repeat protein X-linked 2, a novel mediator of angiogenesis.

Miljkovic-Licina M, Hammel P, Garrido-Urbani S, Bradfield PF, Szepetowski P, Imhof BA

FASEB journal : official publication of the Federation of American Societies for Experimental Biology - Dec 2009

Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR.

Royer-Zemmour B, Ponsole-Lenfant M, Gara H, Roll P, Lévêque C, Massacrier A, Ferracci G, Cillario J, Robaglia-Schlupp A, Vincentelli R, Cau P, Szepetowski P

Human molecular genetics - Dec 2008

Genetics of infantile seizures with paroxysmal dyskinesia: the infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes.

Rochette J, Roll P, Szepetowski P

Journal of medical genetics - Dec 2008

An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na(+) current.

Lauxmann S, Boutry-Kryza N, Rivier C, Mueller S, Hedrich UB, Maljevic S, Szepetowski P, Lerche H, Lesca G

Epilepsia - Sep 2013

Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.

Lesca G, Boutry-Kryza N, de Toffol B, Milh M, Steschenko D, Lemesle-Martin M, Maillard L, Foletti G, Rudolf G, Nielsen JE, á Rogvi-Hansen B, Erdal J, Mancini J, Thauvin-Robinet C, M'Rrabet A, Ville D, Szepetowski P, Raffo E, Hirsch E, Ryvlin P, Calender A, Genton P

Epilepsia - Sep 2010

Novel familial cases of ICCA (infantile convulsions with paroxysmal choreoathetosis) syndrome.

Rochette J, Roll P, Fu YH, Lemoing AG, Royer B, Roubertie A, Berquin P, Motte J, Wong SW, Hunter A, Robaglia-Schlupp A, Ptacek LJ, Szepetowski P

Epileptic disorders : international epilepsy journal with videotape - Sep 2010

Nuclear localization of a novel human syntaxin 1B isoform.

Pereira S, Massacrier A, Roll P, Vérine A, Etienne-Grimaldi MC, Poitelon Y, Robaglia-Schlupp A, Jamali S, Roeckel-Trevisiol N, Royer B, Pontarotti P, Lévêque C, Seagar M, Lévy N, Cau P, Szepetowski P

Gene - Nov 2008

Epilepsy and mental retardation limited to females: an under-recognized disorder.

Scheffer IE, Turner SJ, Dibbens LM, Bayly MA, Friend K, Hodgson B, Burrows L, Shaw M, Wei C, Ullmann R, Ropers HH, Szepetowski P, Haan E, Mazarib A, Afawi Z, Neufeld MY, Andrews PI, Wallace G, Kivity S, Lev D, Lerman-Sagie T, Derry CP, Korczyn AD, Gecz J, Mulley JC, Berkovic SF

Brain : a journal of neurology - Apr 2008

Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas.

Royer B, Soares DC, Barlow PN, Bontrop RE, Roll P, Robaglia-Schlupp A, Blancher A, Levasseur A, Cau P, Pontarotti P, Szepetowski P

BMC genetics - Oct 2007

SRPX2 mutations in disorders of language cortex and cognition.

Roll P, Rudolf G, Pereira S, Royer B, Scheffer IE, Massacrier A, Valenti MP, Roeckel-Trevisiol N, Jamali S, Beclin C, Seegmuller C, Metz-Lutz MN, Lemainque A, Delepine M, Caloustian C, de Saint Martin A, Bruneau N, Depétris D, Mattéi MG, Flori E, Robaglia-Schlupp A, Lévy N, Neubauer BA, Ravid R, Marescaux C, Berkovic SF, Hirsch E, Lathrop M, Cau P, Szepetowski P

Human molecular genetics - Apr 2006
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