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1. SCN1A-related epilepsy with recessive inheritance: Two further families

Author

Julien Buratti, Isabelle Gourfinkel-An, Oriane Trouillard, Raffaella Moretti, Cyril Mignot, Delphine Bouteiller, Vincent des Portes, Patricia Moreau, Christel Depienne, Boris Keren, Agnès Rastetter, Lionel Arnaud, Joseph Toulouse, Caroline Nava, and Eric LeGuern

Subjects
Medizin, Epilepsies, Myoclonic, Biology, Asymptomatic, Seizures, Febrile, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Dravet syndrome, 030225 pediatrics, medicine, Humans, Missense mutation, Allele, Gene, Genetics, Seizure threshold, General Medicine, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Phenotype, Mutation, Pediatrics, Perinatology and Child Health, Epilepsy syndromes, Neurology (clinical), medicine.symptom, Epileptic Syndromes, 030217 neurology & neurosurgery
Abstract

Background Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. Methods and results We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. Conclusion This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.

Published
2021

2. Juvenile myoclonic epilepsy phenotype in a family with Unverricht-Lundborg disease

Author

Amina Gargouri, Berrechid, Mouna, Bendjebara, Delphine, Bouteiller, Amina, Nasri, Jean-Noël, Peuvion, Yannick, Marie, Stéphanie, Baulac, Saloua, Mrabet, Théo, Ribierre, Cecile, Cazeneuve, Imenkacem, Eric, Leguern, and Riadh, Gouider

Subjects
Adult, Male, Phenotype, Adolescent, Unverricht-Lundborg Syndrome, Mutation, Myoclonic Epilepsy, Juvenile, Humans, Female, Genetic Testing, Myoclonic Epilepsies, Progressive
Abstract

Unverricht-Lundborg disease (ULD), an autosomal recessive progressive myoclonus epilepsy, is due to an expansion, or less commonly a mutation, of the cystatin B (CSTB) gene. We report a clinical and molecular study of a Tunisian ULD family with five affected members presenting with a juvenile myoclonic epilepsy (JME)-like phenotype. The expansion of dodecamers was detected by a deamination/PCR assay. The expression profiles of CSTB and other candidate modifying genes, cathepsin B and cystatin C, were established by quantitative RT-PCR, and their respective transcription levels were compared with those from patients with a classic picture of ULD. Three patients had a fixed phenotype mimicking JME after 29 years of evolution. Only a discrete dysarthria was noticed in the two other patients. No correlation was observed between transcription level and severity of disease. Genetic screening should be performed in patients with a JME-like phenotype, when careful examination reveals discrete atypical signs of JME. This particular phenotype may be due to modifying genes and/or gene-environment interactions which require further clarification.

Published
2019

3. PRRT2 mutations: A major cause of paroxysmal kinesigenic dyskinesia in the European population

Author

Domitille Gras, Emmanuel Roze, Thierry Billette de Villemeur, Charles Pierre Jedynak, Fabienne Picard, Christine Tranchant, Mathieu Anheim, Cécile Gaudebout, Dominique Steschenko, Pierre Burbaud, Delphine Bouteiller, David Devos, Alexandra Durr, Isabelle Lagroua, Marie Vidailhet, Alexis Brice, David Grabli, Christel Depienne, Diane Doummar, Cyril Mignot, and Aurélie Méneret

Subjects
Adult, Pediatrics, medicine.medical_specialty, Movement disorders, Mutation/genetics, Choreoathetosis, Nerve Tissue Proteins, Genetic analysis, White People, Epilepsy, Epilepsy, Benign Neonatal/diagnosis/genetics, Seizures/diagnosis/genetics, Chorea, Seizures, medicine, Nerve Tissue Proteins/genetics, Humans, European Continental Ancestry Group/genetics, Membrane Proteins/genetics, Age of Onset, Dyskinesias, business.industry, Membrane Proteins, Syndrome, European population, Paroxysmal dyskinesia, musculoskeletal system, medicine.disease, Epilepsy, Benign Neonatal, ddc:616.8, Pedigree, Mutation, Chorea/diagnosis/genetics, Dyskinesias/diagnosis/genetics, cardiovascular system, Neurology (clinical), Age of onset, medicine.symptom, business, PRRT2
Abstract

Objective: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by recurrent attacks of hyperkinetic movements. PKD can be isolated or associated with benign infantile seizures as part of the infantile convulsions with choreoathetosis (ICCA) syndrome. Mutations in the PRRT2 gene were recently identified in patients with PKD and ICCA. We studied the prevalence of PRRT2 mutations and characteristics of the patients in a European population of patients with PKD and ICCA. Methods: Patients were recruited through the 1996−2011 database of our DNA bank, to which physicians refer DNA with a putative diagnosis and clinical information. Two movement disorders experts reviewed the information on patients with a putative diagnosis of PKD. Patients who fulfilled the criteria for PKD and ICCA were included. The PRRT2 coding sequence was analyzed by direct sequencing. Results: Among 42 index cases of unrelated families referred with a putative diagnosis of PKD, a total of 34 patients, including 32 with isolated PKD and 2 with ICCA, were selected for genetic analysis. Mutations introducing premature termination codons were identified in 22 of 34 patients including 13 of 14 families and 9 of 20 patients with sporadic cases. The previously described c.649dupC/pArg217ProfsX8 and c.629dupC/pAla211SerfsX14 were present, respectively, in 17 patients and 1 patient; we also report 3 novel mutations: c.649delC/pArg217GlufsX12 in 2 patients, and c.562C>T/pGln188X and c.649C>T/pArg217X, each in 1 patient. The group with mutations was characterized by a younger age at onset (9 years) compared with the patients without mutations (15 years; p Conclusion: Mutations in PRRT2 are a major cause of PKD in familial and sporadic cases in the European population.

Published
2012

4. RAD51 Haploinsufficiency Causes Congenital Mirror Movements in Humans

Author

Delphine Bouteiller, Vanessa Brochard, Emmanuel Roze, Christel Depienne, Jean-Paul Saraiva, Sabine Meunier, Kailash P. Bhatia, Aurélie Méneret, Ségolène Billot, Constance Flamand-Roze, Rosine Wehrlé, Stephan Klebe, Jean-Christophe Corvol, Isabelle Dusart, Massimo Cincotta, Sergiu Groppa, Y. Marie, Norbert Brueggemann, Giovanni Stevanin, Wassila Carpentier, Marion Gaussen, Marie Vidailhet, Alexis Brice, Christine Klein, Fanny Charbonnier-Beaupel, Développement et plasticité des réseaux neuronaux = Development and Plasticity of Neural Networks (NPS-14), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Heterozygote, DNA Repair, DNA repair, RAD51, Down-Regulation, Receptors, Cell Surface, Haploinsufficiency, Biology, medicine.disease_cause, Congenital Abnormalities, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Report, Netrin, medicine, Genetics, Humans, DNA Breaks, Double-Stranded, Exome, Genetics(clinical), Nerve Growth Factors, RNA, Messenger, Homologous Recombination, Genetics (clinical), Exome sequencing, 030304 developmental biology, Family Health, 0303 health sciences, Mutation, Dyskinesias, Movement Disorders, Tumor Suppressor Proteins, Motor Cortex, Netrin-1, DCC Receptor, Axons, Pedigree, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rad51 Recombinase, 030217 neurology & neurosurgery, Genome-Wide Association Study, Motor cortex
Abstract

International audience; Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans.

Published
2012
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5. KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

Author

Emeline Mundwiller, Bat-El Zimmerman, Israela Lerer, Hamid Azzedine, Gabor Gyapay, Stephan Klebe, Vincent Meyer, Wassila Carpentier, Alexander Lossos, Agnès Rastetter, Elodie Martin, Laurent Orlando, Alexis Brice, Moriya Gamliel, Cecilia Marelli, Alexandra Durr, Magdalena Nawara, Ruth Sheffer, Marion Gaussen, Delphine Bouteiller, Khalid H. El-Hachimi, Giovanni Stevanin, Adel Misk, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hadassah Hebrew University Medical Center [Jerusalem], Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
[SDV]Life Sciences [q-bio], Mutation, Missense, Kinesins, Genes, Recessive, Biology, medicine.disease_cause, Article, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Hereditary sensory and autonomic neuropathy, Genetics, medicine, Humans, Missense mutation, Family, Genetics (clinical), 030304 developmental biology, KIF1A, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Spastic Paraplegia, Hereditary, Genetic heterogeneity, Homozygote, Chromosome Mapping, medicine.disease, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Chromosomes, Human, Pair 2, Chromosomal region, Candidate Gene Analysis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa.

Published
2012

6. Mutations and Deletions in PCDH19 Account for Various Familial or Isolated Epilepsies in Females

Author

Eric LeGuern, François Rivier, Brigitte Gilbert-Dussardier, Denys Chaigne, Delphine Bouteiller, Karine Poirier, Agathe Roubertie, Anne Dusser, Sandra Whalen, Marie Bru, Dominique Steschenko, Oriane Trouillard, Isabelle Gourfinkel-An, Stéphanie Baulac, Alexis Arzimanoglou, Agnès Gautier, Dorota Hoffman-Zacharska, Christel Depienne, Anna Kaminska, Hélène Maurey, Cyril Mignot, Gaetan Lesca, Annie Lannuzel, Marilyn Lackmy-Port-Lis, Rima Nabbout, Patrick Berquin, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Pôle d'Epileptologie, AP-HP, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neuropédiatrie, CHU Hôpital Nord Amiens, Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Clinique Sainte-Odile, Strasbourg, Unité de Neurologie Pédiatrique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Serice de Neuropédiatrie, Institute of Mother and Child Department of Medical Genetics, Department of neurology, CHU Pointe-à-Pitre/Abymes [Guadeloupe], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de neurologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Hôpital Mère-Enfant, CHU de Nantes, Service de Genetique medicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Hôpital, CHU Trousseau [APHP], Pavillon E, Laboratoire de Genetique, Unité d'Epileptologie Pédiatrique, Service de Neurologie Pédiatrique et des Maladies Métaboliques, AP-HP, Hôpital Robert Debré, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, and Centre hospitalier universitaire de Poitiers ( CHU Poitiers )

Subjects
Adult, Male, PCDH19, Adolescent, Febrile seizures, Protocadherin, Mutation in Brief, Biology, medicine.disease_cause, 03 medical and health sciences, Exon, Epilepsy, Young Adult, 0302 clinical medicine, Genetics, medicine, Humans, Family history, Child, Genetics (clinical), X chromosome, cognitive function, 030304 developmental biology, 0303 health sciences, Mutation, Polymorphism, Genetic, Point mutation, Life Sciences, Infant, Exons, Middle Aged, medicine.disease, Cadherins, Protocadherins, Pedigree, Child, Preschool, Female, microdeletion, Generalized epilepsy with febrile seizures plus, 030217 neurology & neurosurgery, Gene Deletion
Abstract

International audience; Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation.

Published
2011

7. Hypomorphic variants of cationic amino acid transporter 3 in males with autism spectrum disorders

Author

Caroline, Nava, Johanna, Rupp, Jean-Paul, Boissel, Cyril, Mignot, Agnès, Rastetter, Claire, Amiet, Aurélia, Jacquette, Céline, Dupuits, Delphine, Bouteiller, Boris, Keren, Merle, Ruberg, Anne, Faudet, Diane, Doummar, Anne, Philippe, Didier, Périsse, Claudine, Laurent, Nicolas, Lebrun, Vincent, Guillemot, Jamel, Chelly, David, Cohen, Delphine, Héron, Alexis, Brice, Ellen I, Closs, Christel, Depienne, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Department of pharmacology, Johannes Gutemberg Universität Mainz, Service de neuropédiatrie [Trousseau], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de psychiatrie enfant et adolescent, CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre diagnostic autisme, CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), iCONICS, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Institut des Systèmes Intelligents et de Robotique ( ISIR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), CHU Trousseau [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut des Systèmes Intelligents et de Robotique (ISIR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de psychiatrie enfant et adolescent [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Administateur, HAL Sorbonne Université

Subjects
Male, Exome sequencing, Chromosome X, Autism Spectrum Disorder, Molecular Sequence Data, Clinical Biochemistry, Molecular Conformation, Mutation, Missense, Loss of Heterozygosity, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, Xenopus laevis, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Gene Frequency, Animals, Humans, Biotinylation, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Chromosomes, Human, X, Epilepsy, Cell Membrane, Organic Chemistry, Brain, Autism spectrum disorders, Pedigree, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Oocytes, Oligogenism, Amino Acid Transport Systems, Basic, Original Article, Cationic amino acid transporter
Abstract

Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors. Electronic supplementary material The online version of this article (doi:10.1007/s00726-015-2057-3) contains supplementary material, which is available to authorized users.

Published
2015

8. Congenital mirror movements: Mutational analysis of RAD51 and DCC in 26 cases

Author

Jean Louis Golmard, Marcello Romano, Karolina Dzieżyc, Delphine Bouteiller, Pierre Bitoun, Christel Depienne, Luc Defebvre, Oriane Trouillard, Florence Riant, Simona Fiori, M. Cincotta, Simone Rossi, Pierre Pollak, Stephan Klebe, Linda De Meirleir, Marie Vidailhet, Ghislaine Plessis, Chloé Quélin, Aurélie Méneret, Alberto J. Espay, Ana Westenberger, Sabine Rudnik-Schöneborn, Isabelle Lagroua, Alexis Brice, Susan Sklower Brooks, Russell C. Dale, Diane Doummar, Julia Wickert, Emmanuel Roze, Alessandra Borgheresi, Clinical sciences, Reproduction and Genetics, and Neurogenetics

Subjects
Population, Nonsense mutation, DNA Mutational Analysis, Mutation, Missense, Receptors, Cell Surface, Biology, medicine.disease_cause, Severity of Illness Index, Article, Frameshift mutation, symbols.namesake, Arts and Humanities (miscellaneous), Receptors, medicine, Missense mutation, Humans, education, Codon, Exome, Genetics, Sanger sequencing, education.field_of_study, Mutation, Movement Disorders, Tumor Suppressor Proteins, fungi, DCC Receptor, Pedigree, Carrier Proteins, Codon, Nonsense, Neurology (clinical), Nonsense, Cell Surface, symbols, Missense
Abstract

Objective: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51 . Methods: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. Results: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC , one DCC mutation leading to a frameshift, 5 missense variants in DCC , and 2 missense variants in RAD51 . All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls ( p RAD51 and DCC ). Conclusion: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered.

Published
2014

9. A novel DCC mutation and genetic heterogeneity in congenital mirror movements

Author

Vanessa Brochard, Fabio Giovannelli, Christel Depienne, Sabine Meunier, Cécile Hubsch, M. Cincotta, Sergiu Groppa, M. Vidailhet, Alexis Brice, Jean-Christophe Corvol, Delphine Bouteiller, Emmanuel Roze, Ségolène Billot, Stephan Klebe, and C. Flamand

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Neurology, Deleted in Colorectal Cancer, Pain, Stereotypic Movement Disorder, Locus (genetics), Severity of Illness Index, Upper Extremity, Genetic Heterogeneity, Severity of illness, Netrin, medicine, Humans, Age of Onset, Aged, Dyskinesias, Genetic heterogeneity, fungi, Middle Aged, medicine.disease, Pedigree, Stereotypic movement disorder, Genes, DCC, Phenotype, Mutation, Female, Neurology (clinical), France, Age of onset, Psychology
Abstract

Objective: DCC is the receptor for netrin, a protein that guides axon migration of developing neurons across the body's midline. Mutations in the DCC gene were recently identified in 2 families with congenital mirror movements (MM). The objective was to study clinical and genetic characteristics of 3 European families with MM and to test whether this disorder is genetically homogeneous. Methods: We studied 3 MM families with a total of 13 affected subjects. Each patient had a standardized interview and neurologic examination, focusing on the phenomenology and course of the MM. The severity of MM was also assessed. Molecular analysis of DCC was performed in the index cases. In addition, linkage analysis of the DCC locus was performed in a large French family. Results: The clinical expression and course of MM were very similar in all the affected subjects, regardless of DCC mutational status. However, slight intersubject variability in the severity of MM was noted within each family. Onset always occurred in infancy or early childhood, and MM did not deteriorate over time. Motor disability due to MM was mild and restricted to activities that require independent movements of the 2 hands. We found a novel mutation in the DCC gene in an Italian family with MM associated with abnormal ipsilateral corticospinal projection. The DCC locus was excluded in the French family. Conclusion: DCC has a crucial role in the development of corticospinal tracts in humans. Congenital MM is genetically heterogeneous, despite its clinical homogeneity. Neurology (R) 2011; 76:260-264

Published
2011

10. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome

Author

Charlotte Dravet, Oriane Trouillard, Claude Adam, Cécile Saint-Martin, Clothilde Rivier-Ringenbach, Sophie Dupont, Eric LeGuern, Stéphanie Baulac, Isabelle Gourfinkel-An, Marie-Anne Barthez-Carpentier, Marie-Odile Livet, Rima Nabbout, Delphine Bouteiller, Delphine Héron, Denis Graber, Nathalie Villeneuve, Christel Depienne, Agnès Gautier, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique de l'Enfant, CH La Rochelle, Service de Neuropédiatrie [Clocheville], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Gatien de Clocheville, Serice de Neuropédiatrie, Service de Neurologie, Hôpital Henri Gastaut, Service de Pédiatrie, Centre Hospitalier du Pays d'Aix, Service de pédiatre-Néonatologie, CH Villefranche s/Saone, Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de référence des épilepsies rares, CHRU Tours-Hôpital Gatien de Clocheville, Epilepsies de l'Enfant et Plasticité Cérébrale ( U1129 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Peer, Hal, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
Proband, Male, medicine.medical_specialty, DNA Mutational Analysis, Mutation, Missense, Epilepsies, Myoclonic, Nerve Tissue Proteins, Genetic screening/counselling, Biology, medicine.disease_cause, Sodium Channels, 03 medical and health sciences, 0302 clinical medicine, Dravet syndrome, Molecular genetics, Genetics, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Missense mutation, Humans, Genetic Predisposition to Disease, Clinical genetics, Allele, Child, Genetics (clinical), 030304 developmental biology, Sequence Deletion, Family Health, 0303 health sciences, Mutation, Syndrome, medicine.disease, Phenotype, 3. Good health, Pedigree, Epilepsy and seizures, NAV1.1 Voltage-Gated Sodium Channel, Codon, Nonsense, Medical genetics, Female, RNA Splice Sites, 030217 neurology & neurosurgery
Abstract

International audience; Background. Mutations in SCN1A can cause Genetic Epilepsy with Febrile Seizures Plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation. Objectives and patients. We studied 19 selected families with at least one DS patients to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele-specific assays. Results. Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04% to 85%. In the 6 remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture. Conclusion. Our results indicate that mosaicism is found in at least 7% of families with at least one DS patient and that it accounts for 68 % (13/19) of inherited mutations associated with DS. On the contrary, in the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.

Published
2010

11. Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Author

Baya Benyahia, Marie Hélias, François Rivier, Chloé Quélin, Patrick Berquin, Nadia Bahi-Buisson, Merle Ruberg, Sophie Julia, Cécile Cazeneuve, Sophie Meyer, Christel Depienne, Wassila Carpentier, Isabelle Gourfinkel-An, Alexis Brice, Karine Poirier, Oriane Trouillard, Delphine Bouteiller, Isabelle Py, Boris Keren, Alexandra Afenjar, Rima Nabbout, Serge Rivera, Emmanuel Cheuret, Agnès Gautier, Eric LeGuern, Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Toulouse [Toulouse], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Gestionnaire, Hal Sorbonne Université, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Proband, Male, Cancer Research, Chromosomes, Human, Pair 22, Epilepsies, Myoclonic, medicine.disease_cause, Epilepsy, 0302 clinical medicine, Missense mutation, Child, Genetics (clinical), Genetics and Genomics/Genetics of Disease, Genetics, Genetics and Genomics/Medical Genetics, 0303 health sciences, Mutation, Sex Characteristics, Cadherins, Pedigree, Child, Preschool, Genetics and Genomics/Gene Discovery, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, lcsh:QH426-470, Adolescent, Cell Biology/Neuronal Signaling Mechanisms, Nonsense mutation, Molecular Sequence Data, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Dravet syndrome, Neurological Disorders/Epilepsy, medicine, SNP, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Base Sequence, Point mutation, medicine.disease, Protocadherins, lcsh:Genetics, Cell Biology/Cell Adhesion, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism., Author Summary Severe epilepsies associated with cognitive impairment in children are multifarious and most affected patients are sporadic cases. Thus, there is a challenge to identify which of these epilepsies are genetically determined, since their sporadic status excludes the use of classical genetic approaches. We have used microarrays, which are new technological tools to investigate the whole genome of an individual, to search for small genomic abnormalities and identify novel genes in 41 patients with a clinically well-characterized severe infantile epileptic disorder called Dravet syndrome. We have identified PCDH19, a new gene on chromosome X, which was recently found in a familial epileptic syndrome known as female-limited epilepsy and cognitive impairment. This gene was mutated in 12 out of 74 patients with clinical features compatible with Dravet syndrome. Eleven of these patients were females. The single male with a PCDH19 deficiency was mosaic in his skin; i.e., some of his cells express PCDH19 and others do not. This finding suggests that a new pathogenic mechanism—cellular interference—is associated with an unusual X-linked mode of inheritance in which females are more frequently affected than males.

Published
2009

12. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Author

Stéphane Thobois, Alexandra Durr, Agnès Camuzat, Diane Doummar, Cécile Cazeneuve, Emmanuel Roze, Chankannira Sân, Alexis Brice, Delphine Bouteiller, Brigitte Chabrol, Myriem Abada, Pierre Castelnau, David Grabli, Fabienne Clot, Estelle Fedirko, Karine Nguyen, G. Ponsot, Alana Ward, Michael Hutchinson, Marie Vidailhet, Roger Gil, Pierre Landrieu, Fabienne Picard, Annick Toutain, Philippe Damier, and Eric LeGuern

Subjects
Adult, Male, medicine.medical_specialty, Heterozygote, Tyrosine 3-Monooxygenase, Adolescent, Dopamine, Ubiquitin-Protein Ligases, Dopamine Agents, Dystonic Disorders/drug therapy/*genetics/metabolism, Biology, medicine.disease_cause, Parkin, Levodopa, Alcohol Oxidoreductases/genetics, Young Adult, Internal medicine, medicine, Tyrosine 3-Monooxygenase/genetics, Humans, Point Mutation, Ubiquitin-Protein Ligases/genetics, Age of Onset, Sepiapterin reductase, GTP Cyclohydrolase, Child, Genetics, Dystonia, Mutation, Parkinsonism, Point mutation, Biopterin/*analogs & derivatives/biosynthesis, Middle Aged, medicine.disease, Biopterin, nervous system diseases, ddc:616.8, Levodopa/*therapeutic use, Alcohol Oxidoreductases, Endocrinology, Sepiapterin reductase deficiency, Dystonic Disorders, Child, Preschool, Female, Neurology (clinical), Dopamine/*biosynthesis, GTP Cyclohydrolase/genetics, Dystonic disorder, Dopamine Agents/*therapeutic use
Abstract

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.

Published
2009

13. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients

Author

Cécile Cazeneuve, Cécile Saint-Martin, Stéphanie Baulac, Alexis Arzimanoglou, Isabelle Gourfinkel-An, Christel Depienne, Oriane Trouillard, B Abert, Wassila Carpentier, Rima Nabbout, Delphine Bouteiller, Boris Keren, Agnès Gautier, Eric LeGuern, Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre hospitalier universitaire de Nantes (CHU Nantes), Hospices Civils de Lyon (HCL), Épilepsie de l'enfant et plasticité cérébrale (Inserm U663), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, Mutation rate, [SDV]Life Sciences [q-bio], Epilepsies, Myoclonic, Nerve Tissue Proteins, Biology, medicine.disease_cause, Sodium Channels, 03 medical and health sciences, 0302 clinical medicine, Dravet syndrome, Genetics, medicine, Humans, Missense mutation, Multiplex ligation-dependent probe amplification, Genetics (clinical), 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Point mutation, Infant, Newborn, Infant, Sequence Analysis, DNA, Gene rearrangement, medicine.disease, 3. Good health, NAV1.1 Voltage-Gated Sodium Channel, [SDV] Life Sciences [q-bio], Female, Haploinsufficiency, Nucleic Acid Amplification Techniques, Gene Deletion, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; INTRODUCTION:Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI).OBJECTIVE:To characterise in more detail the mutation spectrum associated with Dravet syndrome.METHODS:A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened.RESULTS:SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients.CONCLUSION:These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.

Published
2008

14. The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V

Author

Merle Ruberg, A. Barois, Vincent Meininger, Delphine Bouteiller, Alexis Brice, Jean Pouget, Hamid Azzedine, R. Ben Yaou, Odile Dubourg, and Eric LeGuern

Subjects
Glycine-tRNA Ligase, Pathology, medicine.medical_specialty, Heterozygote, DNA Mutational Analysis, Motor nerve, Biology, medicine.disease_cause, Asymptomatic, Risk Assessment, Glycine—tRNA ligase, Muscular Atrophy, Spinal, Risk Factors, medicine, Missense mutation, Humans, Family, Genetic Predisposition to Disease, Age of Onset, Mutation, Incidence, Anatomy, Penetrance, medicine.anatomical_structure, Jews, Female, Neurology (clinical), France, Age of onset, medicine.symptom, Sensory nerve
Abstract

Background: Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (dSMA) is a heterogeneous group of disorders characterized almost exclusively by degeneration of motor nerve fibers, predominantly in the distal part of the limbs. One subtype, dHMN type V (dHMN-V), is transmitted by autosomal dominant inheritance and predominantly involves the hands. It is allelic with Charcot–Marie–Tooth disease 2D (CMT2D), in which a similar phenotype is associated with sensory signs. Missense mutations in the glycyl-tRNA synthetase ( GARS ) gene have been recently reported in families with either dHMN-V, CMT2D, or both. Methods: The authors searched for GARS mutations in eight dHMN-V families. Results: The authors found the G526R missense mutation in three families (16 patients) of Algerian Sephardic Jewish origin. All patients shared a common disease haplotype, suggestive of a founder effect. The clinical phenotype consists of a slowly progressive, purely motor distal neuropathy. It starts in the hands in most patients, but also in both distal upper and lower limbs or in distal lower limbs alone. The age at onset in symptomatic individuals was between the second to fourth decades, but four mutation carriers were still asymptomatic, two of whom were already age 49 years. Electrophysiology showed that the motor fibers of the median nerve were the most affected in upper limbs. Sensory nerve action potentials were normal. Conclusions: The age at onset of patients with the G526R mutation in the GARS gene varied widely, but the clinical and electrophysiologic presentation was uniform and progressed slowly. Glycyl-tRNA synthetase mutations are a frequent cause of familial distal hereditary motor neuropathy type V but, because of the reduced penetrance of the disease, could also account for isolated cases.

Published
2006

15. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE

Author

Didier Périsse, Clement A. Gautier, Guillaume Huguet, Anne Faudet, Claudine Laurent, C Dupuits, Christopher Gillberg, Delphine Bouteiller, Cyril Mignot, Delphine Héron, Sandra Whalen, David Cohen, Mylène Gilleron, Marion Leboyer, Boris Keren, Thomas Bourgeron, Marion Gérard, Alexis Brice, C. Depienne, Alexandra Afenjar, Agnès Rastetter, Foudil Lamari, Richard Delorme, Aurélia Jacquette, Caroline Nava, S Caillet, and Bruno Leheup

Subjects
Adult, Male, Candidate gene, TMLHE, Nonsense mutation, Biology, medicine.disease_cause, Polymerase Chain Reaction, Mixed Function Oxygenases, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genes, X-Linked, medicine, Humans, Missense mutation, Exome, Family, Sex Distribution, Child, Genetic Association Studies, Biological Psychiatry, X chromosome, 030304 developmental biology, Genetics, Chromosomes, Human, X, 0303 health sciences, Mutation, carnitine, Autism spectrum disorders, medicine.disease, Psychiatry and Mental health, Child Development Disorders, Pervasive, male excess, Case-Control Studies, chromosome X, Autism, Original Article, next-generation sequencing, Female, 030217 neurology & neurosurgery
Abstract

The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.

Published
2012

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