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1. Recessive <scp> NUP54 </scp> Variants Underlie Early‐Onset Dystonia with Striatal Lesions

Author

Philip Harrer, Audrey Schalk, Masaru Shimura, Sarah Baer, Nadège Calmels, Marie Aude Spitz, Marie‐Thérèse Abi Warde, Elise Schaefer, Volker M.Sc Kittke, Yasemin Dincer, Matias Wagner, Ivana Dzinovic, Riccardo Berutti, Tatsuharu Sato, Toshihiko Shirakawa, Yasushi Okazaki, Kei Murayama, Konrad Oexle, Holger Prokisch, Volker Mall, Ivo Melčák, Juliane Winkelmann, and Michael Zech

Subjects
Neurology, Neurology (clinical), Brief Communication, ddc
Abstract

Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear-pore complex (NPC) gene NUP62, involved in nucleo-cytoplasmic trafficking. By querying sequencing-datasets of patients with dystonia and/or Leigh(-like) syndromes, we identified 3 unrelated individuals with biallelic variants in NUP54. All variants clustered in the C-terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62-related disease, including early-onset dystonia with dysphagia, choreoathetosis, and T2-hyperintense lesions in striatum. In silico and protein-biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component-associated dystonic conditions with localized basal-ganglia abnormalities. ANN NEUROL 2022.

Published
2022
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2. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics

Subjects
Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023
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3. Molecular and clinical descriptions of patients with GABA

Author

Pierre-Yves, Maillard, Sarah, Baer, Élise, Schaefer, Béatrice, Desnous, Nathalie, Villeneuve, Anne, Lépine, Alexandre, Fabre, Caroline, Lacoste, Salima, El Chehadeh, Amélie, Piton, Louise Frances, Porter, Caroline, Perriard, Marie-Thérèse Abi, Wardé, Marie-Aude, Spitz, Vincent, Laugel, Gaëtan, Lesca, Audrey, Putoux, Dorothée, Ville, Cyril, Mignot, Delphine, Héron, Rima, Nabbout, Giulia, Barcia, Marlène, Rio, Agathe, Roubertie, Pierre, Meyer, Véronique, Paquis-Flucklinger, Olivier, Patat, Jérémie, Lefranc, Marion, Gerard, Julietta, de Bellescize, Laurent, Villard, Anne, De Saint Martin, and Mathieu, Milh

Subjects
Cohort Studies, Epilepsy, Phenotype, Mutation, Humans, Epilepsy, Generalized, Receptors, GABA-A, Genetic Association Studies, gamma-Aminobutyric Acid
Abstract

γ-Aminobutyric acid (GABA)We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABAWe gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABAGABA

Published
2022

4. Movement disorders in valine métabolism diseases caused by HIBCH and ECHS1 deficiencies

Author

Marie‐Céline François‐Heude, Elise Lebigot, Emmanuel Roze, Marie Thérèse Abi Warde, Claude Cances, Lena Damaj, Caroline Espil, Joel Fluss, Pascale de Lonlay, Ilse Kern, Guy Lenaers, Arnold Munnich, Pierre Meyer, Marie‐Aude Spitz, Stéphanie Torre, Diane Doummar, Guy Touati, Nicolas Leboucq, Agathe Roubertie, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Bicêtre, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-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), CHU Strasbourg, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], CHU Bordeaux [Bordeaux], Hôpitaux Universitaires de Genève (HUG), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Cochin [AP-HP], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), CHU Trousseau [APHP], Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and MORNET, Dominique

Subjects
Movement Disorders, ECHS1, [SDV]Life Sciences [q-bio], Valine, [SDV] Life Sciences [q-bio], Dystonia, Neurology, Chorea, Dystonic Disorders, Humans, Abnormalities, Multiple, Coenzyme A, Neurology (clinical), Thiolester Hydrolases, HIBCH, Leigh Disease, inherited metabolic disease, Amino Acid Metabolism, Inborn Errors, Enoyl-CoA Hydratase
Abstract

International audience; Background and purpose: HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC.Methods: We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs.Results: The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants.Conclusions: Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.

Published
2022
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5. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

Author

Shinichi Moriwaki, Donata Orioli, Marie-Aude Spitz, Nadège Calmels, Nan Jia, Katsuo Sugita, Elena Botta, Alan R. Lehmann, Miria Stefanini, Vincent Laugel, Heather Fawcett, Masaya Kubota, Cathy Obringer, Tiziana Nardo, Tomoo Ogi, Yuka Nakazawa, and Manuela Lanzafame

Subjects
Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Adolescent, Ultraviolet Rays, Postnatal growth failure, Mutation, Missense, Cockayne syndrome, Cohort Studies, Young Adult, 03 medical and health sciences, Pregnancy, Genetics, Humans, Medicine, Genetic Predisposition to Disease, Cutaneous photosensitivity, Clinical significance, Photosensitivity Disorders, Child, Cockayne Syndrome, Poly-ADP-Ribose Binding Proteins, Genetics (clinical), business.industry, DNA Helicases, Infant, medicine.disease, Introns, Large cohort, DNA Repair Enzymes, 030104 developmental biology, ERCC8, Child, Preschool, Female, Skeletal abnormalities, business, ERCC6, Transcription Factors
Abstract

BackgroundCockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8/CSA or ERCC6/CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS.Methods and resultsWe assigned 39 patients to the ERCC8/CSA and 85 to the ERCC6/CSB genes. Most of the genetic variants were truncations. The missense variants were distributed non-randomly with concentrations in relatively short regions of the respective proteins. Our analyses revealed several hotspots and founder mutations in ERCC6/CSB. Although no unequivocal genotype-phenotype relationships could be made, patients were more likely to have severe clinical features if the mutation was downstream of the PiggyBac insertion in intron 5 of ERCC6/CSB than if it was upstream. Also a higher proportion of severely affected patients was found with mutations in ERCC6/CSB than in ERCC8/CSA.ConclusionBy identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the CSA and CSB mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS.

Published
2018
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6. Relapsing encephalopathy with cerebellar ataxia are caused by variants involving p.Arg756 in ATP1A3

Author

Gaetan Lesca, Vincent Laugel, Diane Doummar, Marie-Aude Spitz, Kumaran Deiva, Audrey Riquet, Cyril Mignot, Sona Nevsimalova, Nathalie Bednarek, Pascal Sabouraud, Christine Pietrement, Les Hôpitaux Universitaires de Strasbourg (HUS), and Hospices Civils de Lyon (HCL)

Subjects
Male, Pediatrics, medicine.medical_specialty, Ataxia, Adolescent, Cerebellar Ataxia, Fever, [SDV]Life Sciences [q-bio], Encephalopathy, 03 medical and health sciences, 0302 clinical medicine, Recurrence, 030225 pediatrics, ATP1A3, medicine, Humans, Decompensation, Child, Genetic Association Studies, First episode, Brain Diseases, Cerebellar ataxia, business.industry, Alternating hemiplegia of childhood, General Medicine, medicine.disease, Hypotonia, 3. Good health, Phenotype, Pediatrics, Perinatology and Child Health, Mutation, Female, Neurology (clinical), medicine.symptom, Sodium-Potassium-Exchanging ATPase, business, 030217 neurology & neurosurgery
Abstract

Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype-genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3.

Published
2019
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7. Renal disease in Cockayne syndrome

Author

Vincent Laugel, Karen Fieggen, Jérôme Olagne, Nadège Calmels, Marie-Aude Spitz, Komala Pillay, Cathy Obringer, Ariane Zaloszyc, Myriam Durand, and Amélie Stern-Delfils

Subjects
Adult, medicine.medical_specialty, Renal function, Angiotensin-Converting Enzyme Inhibitors, Kidney, urologic and male genital diseases, Gastroenterology, Cockayne syndrome, Young Adult, chemistry.chemical_compound, Internal medicine, Genetics, medicine, Humans, Renal Insufficiency, Hyperuricemia, Renal Insufficiency, Chronic, Cockayne Syndrome, Genetics (clinical), Proteinuria, medicine.diagnostic_test, business.industry, General Medicine, medicine.disease, Blood pressure, chemistry, Kidney Failure, Chronic, Uric acid, Female, Renal biopsy, medicine.symptom, business, Nephrotic syndrome
Abstract

Background Cockayne Syndrome (CS) is a rare autosomal recessive multi-systemic disorder, characterized; by developmental delay, microcephaly, severe growth failure and sensorial impairment. Renal complications have been reported but remain underinvestigated. The objective of this study was to perform a review of renal disease in a cohort of CS patients. Methods We retrospectively collected relevant clinical, biochemical and genetic data from a cohort of 136 genetically confirmed CS patients. Blood pressure (BP), proteinuria, albuminemia, uric acid, creatinine clearance, renal ultrasounds and renal biopsy result were analysed. Results Thirty-two patients had a renal investigation. We found that 69% of investigated patients had a renal disorder and/or an elevated BP. Fifteen out of 21 patients (71% of investigated patients) had an increased BP, 10 out of 16 patients (62% of investigated patients) presented with proteinuria and 4 of them had a nephrotic syndrome. Thirteen patients out of 29 (45%) had a decreased Glomerular Filtration Rate (GFR), 18 out of 25 patients (72%) had a hyperuricemia. No correlation with the genetic background or clinical types of CS was found, except for the renal clearance. Conclusions Renal disease, increased blood pressure and hyperuricemia were highly prevalent in our study. We believe that CS patients should benefit from a nephrological follow-up and that anti-uric acid drug and Angiotensin-converting enzyme (ACE) inhibitor should be discussed in these patients.

Published
2020
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8. Homozygous truncating variants in TBC1D23 cause pontocerebellar hypoplasia and alter cortical development

Author

H.H. Ropers, Hélène Dollfus, Arjan P.M. de Brouwer, Frédéric Tran Mau-Them, Patrick Nitchké, Karen Runge, Jamel Chelly, Sheikh Riazuddin, Hans van Bokhoven, Saima Riazuddin, Hossein Najmabadi, Elise Schaefer, Attia Razzaq, Kimia Kahrizi, Zafar Iqbal, Jean-François Deleuze, Bénédicte Gérard, Anne de Saint Martin, Marie Aude Spitz, Ekaterina L. Ivanova, Mary Laura, Maria Victoria Hinckelmann, Nathalie Drouot, Muhammad Zaman Khan Assir, Vincent Laugel, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), University of Maryland [Baltimore], University of Social Welfare and Rehabilitation Sciences [Tehran], CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Radboud University Medical Center [Nijmegen], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Male, Microcephaly, Cerebellum, GTPase-activating protein, Developmental Disabilities, medicine.disease_cause, Mice, Neuroblastoma, 0302 clinical medicine, small normally proportioned cerebellum, microcephaly, Child, Genetics (clinical), Cells, Cultured, Genetics, Neurons, Mutation, TBC1D23, GTPase-Activating Proteins, Homozygote, Hypoplasia, Pedigree, medicine.anatomical_structure, Child, Preschool, Female, Protein family, Adolescent, Neuronal Outgrowth, Pontocerebellar hypoplasia, Biology, Nervous System Malformations, Article, 03 medical and health sciences, Cerebellar Diseases, Intellectual Disability, medicine, Animals, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], pontocerebellar hypoplasia, medicine.disease, Embryo, Mammalian, 030104 developmental biology, Rab, 030217 neurology & neurosurgery
Abstract

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.

Published
2017
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9. Delineating FOXG1 syndrome

Author

Benedicte Pontier, Mathieu Milh, Stéphanie Arpin, Thierry Bienvenu, Delphine Héron, Mathilde Nizon, Camille Maillard, Bertrand Isidor, Sylvie Odent, Christophe Philippe, Marie-Aude Spitz, Barth Magalie, Tally Lerman-Sagie, Baptiste Troude, Stéphane Rondeau, Eric Haan, Jean Michel Pedespan, Anne Marie Guerrot, Elise Schaefer, Sabrina Wagner, Nadia Bahi-Buisson, Isabelle Caubel, Caroline Michot, Nathalie Boddaert, Stéphanie Valence, Joseph Toulouse, Benjamin Cogné, Marie Hully, Alexandre N. Datta, Mara Cavallin, Cyril Mignot, Amandine Bery, Leila Lazaro, Marie Vincent, François Rivier, Sébastien Moutton, Alice Masurel, Dorit Lev, Nancy Vegas, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Embryology and genetics of human malformation (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institute of Medical Genetics, Wolfson Medical Center, Service de Génétique Médicale du CHU de Bordeaux, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Rouen, Normandie Université (NU), Molecular and Physiopathological bases of osteochondrodysplasia - Bases moléculaires et physiopathologiques des ostéochondrodysplasies (Equipe Inserm U1163), 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), Université Sorbonne Paris Cité (USPC), Hôpital Nord Franche-Comté [Hôpital de Trévenans] (HNFC), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Nantes (UN), Service de pédiatrie, Centre Hospitalier de la Côte Basque (CHCB), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, CHU Pellegrin, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Genome dynamics in the immune system (Equipe Inserm U1163), Fondation Maladies Rares, DESIRE (grant agreement 60253), European Network on Brain Malformations (COST ActionCA16118), ANR-16-CE16-0011,DYNEINOPATHY,Mecanismes moléculaires et cellulaires des dyneinopathies(2016), Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], 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 Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Le CHCB, Centre Hospitalier de la Côte Basque, SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Pitié-Salpêtrière [APHP], Centre de Recherche sur le Cancer Nantes-Angers (LUNAM), Université d'Angers (UA)-Université de Nantes (UN), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, business.industry, Corpus Callosum Agenesis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genetic counseling, Pachygyria, Encephalopathy, Nonsense mutation, Postnatal microcephaly, Corpus callosum, medicine.disease, 3. Good health, Frameshift mutation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine, Neurology (clinical), business, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract

ObjectiveTo provide new insights into theFOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation inFOXG1syndrome.MethodsWe analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenicFOXG1variant and performed phenotype-genotype correlations.ResultsA total of 37FOXG1different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus ofFOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.ConclusionsThese findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severeFOXG1syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view thatFOXG1syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

Published
2018
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10. Voltage-gated potassium channels autoantibodies in a child with rasmussen encephalitis

Author

Marie-Aude Spitz, Fanny Dubois-Teklali, Frédérique Nugues, Viviana Oliver, Christine Bulteau, Angela Vincent, Cécile Sabourdy, and Laurent Vercueil

Subjects
Pathology, medicine.medical_specialty, Encephalopathy, Central nervous system, Epilepsia partialis continua, Aphasia, Medicine, Humans, Cognitive decline, Autoantibodies, business.industry, Limbic encephalitis, Autoantibody, Brain, Electroencephalography, General Medicine, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Potassium Channels, Voltage-Gated, Child, Preschool, Pediatrics, Perinatology and Child Health, Etiology, Encephalitis, Female, Neurology (clinical), medicine.symptom, business
Abstract

Rasmussen encephalitis (RE) is a severe epileptic and inflammatory encephalopathy of unknown etiology, responsible for focal neurological signs and cognitive decline. The current leading hypothesis suggests a sequence of immune reactions induced by an indeterminate factor. This sequence is thought to be responsible for the production of autoantibody-mediated central nervous system degeneration. However, these autoantibodies are not specific to the disease and not all patients present with them. We report the case of a 4-year-old girl suffering from RE displaying some atypical features such as fast evolution and seizures of left parietal onset refractory to several antiepileptics, intravenous immunoglobulins, and corticosteroids. Serum autoantibodies directed against voltage-gated potassium channels (VGKC) were evidenced at 739 pM, a finding never previously reported in children. This screening was performed because of an increased signal in the temporolimbic areas on brain magnetic resonance imaging, which was similar to what is observed during limbic encephalitis. The patient experienced epilepsia partialis continua with progressive right hemiplegia and aphasia. She underwent left hemispherotomy at the age of 5.5 years after which she became seizure free with great cognitive improvement. First described in adults, VGKC autoantibodies have been recently described in children with various neurological manifestations. The implication of VGKC autoantibodies in RE is a new observation and opens up new physiopathological and therapeutic avenues of investigation.

Published
2014

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