For many years, our work has been focused on intellectual deficiency (ID) caused by genetic defects in children. Our work can be separated into three main topics: the study of the genetic bases of ID, the study of Rett syndrome (RTT), and the study of early onset epileptic encephalopathy (EOEE). Our goals are threefold:
1- to contribute to the growth of knowledge in the field of neurological diseases causing ID in children;
2- to improve diagnosis and genetic counselling for these diseases;
3- to propose new therapeutic approaches.

The permanent staff making up this team has complementary skills in the field of clinical genetics, molecular genetics, neurophysiology and paediatric neurology. Several physicians are team members and actively participate in the projects in the field of intellectual disability and epilepsy. We have established and maintain strong links with the local, national and international hospital environments.

We developed original projects for early onset epileptic encephalopathies while constituting the largest European cohort of patients (1100 patients as of december 2019). We have identified several "candidate" genes for EOEE using comparative genomic hybridization (CGH) or exome sequencing. We redefined the clinical and electroclinical characteristics of EOEE caused by mutations in several genes and identified mutations in two new epilepsy genes. In parallel, we have developed models for electrophysiology and pre-clinical research (new KI mice and human neurons derived from induced pluripotent stem cells (iPS) ). Recently, we have discovered a new mechanism explaining the severe epilepsies caused by KCNQ2 gene mutations.
In parallel, a researcher of the team (L. Villard) is responsible for the molecular diagnosis of genetic epilepsies in the Department of Medical Genetics (La Timone Children's Hospital). In 2015, this activity led to the creation of a national network under the umbrella of the ANPGM (association of professionals in charge of molecular genetics testing), using high-throughput sequencing technologies: the EPIGENE network.

For our activities in the field of Rett syndrome, we discovered and documented bioaminergic abnormalities in several brain structures involved in autonomic function and the development of motor strategies in an animal model of the disease. We have demonstrated the interest of desipramine to treat autonomic dysfunction in an animal model of RTT and obtained an orphan drug designation from the European Medicine Agency (EMA). We also discovered an axonal transport defect in the animal model of RTT (patented). The results with desipramine and on axonal transport have led to the establishment of two clinical trials for Rett syndrome patients (one of which has been licenced to a US industrial). We also validated the use of adeno-associated viruses (AAV) for gene therapy in Rett syndrome using a mouse model of RTT (with the support of the French muscular dystrophy associated, AFM). Finally, we have structured a European network of professionals in collaboration with the European Federation of RTT associations (RSE) and developed a European database now containing 2,000 files.
For the next few years, our keywords will be high throughput genotyping and pre-clinical research. For the project on EOEE, we now have unique models handy (patient neurons and knock-in mice), which will allow us to better comprehend the neuronal abnormalities induced by mutations in the most frequent disease-causing genes. For Rett syndrome, we place great hope in the partnerships that have been forged with physicists and with a company specializing in the development of molecules crossing the blood brain barrier to enable us to significantly improve the penetration of virus particles or candidates molecules in the brain of mouse models. Furthermore, we will invest into alternative (out of the mainstream) projects to study neuroinflammation, the glial secretome and lipidomics, allowing us to be less exposed to the fierce international competition that exists in the field of Rett syndrome.

The overall strategy of the team is to build perfectly phenotyped and genotyped large cohorts as a first line, in order to better understand the clinical and genetic landscape of the studied diseases. We will implement research projects to study pathophysiology using several models (mostly animal models). We already master the cellular studies and the phenotyping of rodents, and we will develop the study of zebrafish as a new and promising model. Equipped with original findings on pathophysiology, we hope to offer new treatments after in vivo testing of our original models, in collaboration with industrial partners when appropriate.
The recent history of our team shows that we successfully travelled twice the virtuous circle going from basic research to clinical trials in patients, and we hope that our future work will provide other examples during the next term.



Frullanti, E.  et al. 2019

Analysis of the Phenotypes in the Rett Networked Database

Rett spectrum disorder is a progressive neurological disease and the most common genetic cause of intellectual disability in females. MECP2 is the major causative gene. In addition, CDKL5 and FOXG1...
Int J Genomics - issue: - volume: 2019 - pages: 6956934.

Mignot, C.  et al. 2019

IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We...
Genet. Med. - issue: 4 - volume: 21 - pages: 837-849.

Valence, S.  et al. 2019

Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies

PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify...
Genet. Med. - issue: 3 - volume: 21 - pages: 553-563.

O'Donnell-Luria, AH.  et al. 2019

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker...
Am. J. Hum. Genet. - issue: 6 - volume: 104 - pages: 1210-1222.

Piard, J.  et al. 2019

The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

PURPOSE: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We...
Genet. Med. - issue: 6 - volume: 21 - pages: 1308-1318.

Denis, J.  et al. 2019

Clinical study of 19 patients with SCN8A-related epilepsy: Two modes of onset regarding EEG and seizures

OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed...
Epilepsia - issue: 5 - volume: 60 - pages: 845-856.

Mignon-Ravix, C.  et al. 2018

Abnormal function of the UBA5 protein in a case of early developmental and epileptic encephalopathy with suppression-burst

Early myoclonic epilepsy (EME) or Aicardi syndrome is one of the most severe epileptic syndromes affecting neonates. We performed whole exome sequencing in a sporadic case affected by EME and his...
Hum. Mutat. - issue: 7 - volume: 39 - pages: 934-938.

Ehinger, Y.  et al. 2018

Rett syndrome from bench to bedside: recent advances

Rett Syndrome is a severe neurological disorder mainly due to de novo mutations in the methyl-CpG-binding protein 2 gene ( MECP2). Mecp2 is known to play a role in chromatin organization and...
F1000Res - issue: - volume: 7 - pages: 398.

Mancini, J.  et al. 2018

Effect of desipramine on patients with breathing disorders in RETT syndrome

Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced...
Ann Clin Transl Neurol - issue: 2 - volume: 5 - pages: 118-127.

Mortreux, J.  et al. 2018

The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability

INTRODUCTION: A large number of genes involved in autosomal recessive forms of intellectual disability (ID) were identified over the past few years through whole-exome sequencing (WES) or whole-genome...
Eur. J. Hum. Genet. - issue: 1 - volume: 26 - pages: 143-148.

Marzin, P.  et al. 2018

Early-onset encephalopathy with paroxysmal movement disorders and epileptic seizures without hemiplegic attacks: About three children with novel ATP1A3 mutations

OBJECTIVE: Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset...
Brain Dev. - issue: 9 - volume: 40 - pages: 768-774.

Bramswig, NC.  et al. 2018

Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the...
Hum. Genet. - issue: 9 - volume: 137 - pages: 753-768.

Villeneuve, N.  et al. 2017

Heterogeneity of FHF1 related phenotype: Novel case with early onset severe attacks of apnea, partial mitochondrial respiratory chain complex II deficiency, neonatal onset seizures without neurodegeneration

INTRODUCTION/OBJECTIVES: We report the case of a child prospectively followed in our institution for a severe, neonatal onset epilepsy presenting with severe attacks of apnea that were not initially...
Eur. J. Paediatr. Neurol. - issue: 5 - volume: 21 - pages: 783-786.

Wolff, M.  et al. 2017

Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71...
Brain - issue: 5 - volume: 140 - pages: 1316-1336.

Matagne, V.  et al. 2017

A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). RTT is the second most prevalent cause of...
Neurobiol. Dis. - issue: - volume: 99 - pages: 1-11.

Goldenberg, A.  et al. 2016

Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11

KBG syndrome, due to ANKRD11 alteration is characterized by developmental delay, short stature, dysmorphic facial features, and skeletal anomalies. We report a clinical and molecular study of 39...
Am. J. Med. Genet. A - issue: 11 - volume: 170 - pages: 2847-2859.

Devaux, J.  et al. 2016

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

Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or...
Epilepsia - issue: 5 - volume: 57 - pages: e87-93.

Lemke, JR.  et al. 2016

Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected...
Neurology - issue: 23 - volume: 86 - pages: 2171-2178.

Lefebvre, M.  et al. 2016

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates...
Clin. Genet. - issue: 5 - volume: 89 - pages: 630-635.

Zillhardt, JL.  et al. 2016

Mosaic parental germline mutations causing recurrent forms of malformations of cortical development

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of...
Eur. J. Hum. Genet. - issue: 4 - volume: 24 - pages: 611-614.

Abidi, A.  et al. 2016

Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient

Variants in the WD repeat 45 (WDR45) gene in human Xp11.23 have recently been identified in patients suffering from neurodegeneration with brain iron accumulation, a genetically and phenotypically...
Eur. J. Hum. Genet. - issue: 4 - volume: 24 - pages: 615-618.

Abidi, A.  et al. 2016

Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient

Variants in the WD repeat 45 (WDR45) gene in human Xp11.23 have recently been identified in patients suffering from neurodegeneration with brain iron accumulation, a genetically and phenotypically...
Eur. J. Hum. Genet. - issue: 4 - volume: 24 - pages: 615-618.

Lacoste, C.  et al. 2016

Coverage Analysis of Lists of Genes involved in Heterogeneous Genetic Diseases following Benchtop Exome Sequencing using the Ion Proton

J. Genet. - issue: 1 - volume: 95 - pages: 203-208.

Abidi, A.  et al. 2015

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

Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit cause either benign epilepsy or early onset epileptic encephalopathy (EOEE). It has been proposed that the...
Neurobiol. Dis. - issue: - volume: 80 - pages: 80-92.

Niceta, M.  et al. 2015

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis,...
Am. J. Hum. Genet. - issue: 5 - volume: 96 - pages: 816-825.

Nissenkorn, A.  et al. 2015

Epilepsy in Rett syndrome-Lessons from the Rett networked database

ObjectiveRett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and...
Epilepsia - issue: 4 - volume: 56 - pages: 569-576.

Poulat, A.  et al. 2015

Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability

Mutations in the TBC1D24 gene were first reported in an Italian family with a unique epileptic phenotype consisting of drug-responsive, early-onset idiopathic myoclonic seizures. Patients presented...
Epilepsy Res. - issue: - volume: 111 - pages: 72-77.

Bauer, M.  et al. 2015

Infectious and Immunologic Phenotype of MECP2 Duplication Syndrome

MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We...
J. Clin. Immunol. - issue: 2 - volume: 35 - pages: 168-181.

Herbaux, C.  et al. 2014

Incidence of Atrx Mutations in Myelodysplastic Syndromes (MDS)

Blood - issue: 21 - volume: 124 - pages: .

Lacoste, C.  et al. 2014

Mutations of codon 2085 in the helicase domain of ATRX are recurrent and cause ATRX syndrome

Clin. Genet. - issue: 5 - volume: 86 - pages: 502-503.

Gorincour, G.  et al. 2014

Fetal skeletal computed tomography: When? How? Why?

Purpose: To study the additional role of fetal skeletal computed tomography in suspected prenatal bone abnormalities. Materials and methods: Two centers included in a retrospective study all fetuses...
Diagn. Interv. Imaging - issue: 11 - volume: 95 - pages: 1045-1053.

Mignon-Ravix, C.  et al. 2014

Intragenic Rearrangements in X-Linked Intellectual Deficiency: Results of a-CGH in a Series of 54 Patients and Identification of TRPC5 and KLHL15 As Potential XLID Genes

High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the...
Am. J. Med. Genet. A - issue: 8 - volume: 164 - pages: 1991-1997.

Thevenon, J.  et al. 2014

Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay,...
Am. J. Hum. Genet. - issue: 1 - volume: 95 - pages: 113-120.

Tardy-Guidollet, V.  et al. 2014

New Management Strategy of Pregnancies at Risk of Congenital Adrenal Hyperplasia Using Fetal Sex Determination in Maternal Serum: French Cohort of 258 Cases (2002-2011)

Context: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if...
J. Clin. Endocrinol. Metab. - issue: 4 - volume: 99 - pages: 1180-1188.

El-Khoury, R.  et al. 2014

GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

Proper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT)...
PLoS One - issue: 3 - volume: 9 - pages: e92169.

Cacciagli, P.  et al. 2014

AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome)

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker...
Eur. J. Hum. Genet. - issue: 3 - volume: 22 - pages: 363-368.

Cordier, C.  et al. 2013

French Professionals in Genetic Counselor Careers

The profession of genetic counseling in France was recognized in 2004, based on the recommendations of a mandate commissioned by the Health Minister to explore the medical demographics of France. The...
J. Genet. Couns. - issue: 6 - volume: 22 - pages: 844-848.

Tanyalcin, I.  et al. 2013

Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review

Background: The BIG2 protein, coded by ARFGEF2 indirectly assists neuronal proliferation and migration during cortical development. Mutations in ARFGEF2 have been reported as a rare cause of...
Eur. J. Paediatr. Neurol. - issue: 6 - volume: 17 - pages: 666-670.

Michot, C.  et al. 2013

Finger creases lend a hand in Kabuki syndrome

Kabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early...
Eur. J. Med. Genet. - issue: 10 - volume: 56 - pages: 556-560.

Cacciagli, P.  et al. 2013

Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus

BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to...
Am. J. Hum. Genet. - issue: 3 - volume: 93 - pages: 579-586.

Van Maldergem, L.  et al. 2013

Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth

Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID...
Hum. Mol. Genet. - issue: 16 - volume: 22 - pages: 3306-3314.

Popovici, C.  et al. 2013

Mosaic 15q13.3 deletion including CHRNA7 gene in monozygotic twins

Deletions in 15q13.3 belong to the most frequently identified recurrent CNVs, and lead to mental retardation, seizures and minor dysmorphism. We report on two monozygotic twin boys with a mosaic 1.5...
Eur. J. Med. Genet. - issue: 5 - volume: 56 - pages: 274-277.

Delio, M.  et al. 2013

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic...
Am. J. Hum. Genet. - issue: 3 - volume: 92 - pages: 439-447.

Roux, J.  et al. 2012

Modification of Mecp2 dosage alters axonal transport through the Huntingtin/Hap1 pathway

Mecp2 deficiency or overexpression causes a wide spectrum of neurological diseases in humans among which Rett Syndrome is the prototype. Pathogenic mechanisms are thought to involve transcriptional...
Neurobiol. Dis. - issue: 2 - volume: 45 - pages: 786-795.

Am J Hum Genet. 2019"", .  et al. 0


; Analysis of the Phenotypes in the Rett Networked Database.
Armstrong J - issue: Pineda M - volume: Bahi-Buisson N - pages: Clarke A.

Am J Hum Genet. 2019"", .  et al. 0


; Analysis of the Phenotypes in the Rett Networked Database.
Armstrong J - issue: Pineda M - volume: Bahi-Buisson N - pages: Clarke A.