title: Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy.
abstract: Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France.
authors.forename: Mirna
authors.initials: M
authors.lastname: Assoum
authors.affiliation: Laboratoire de Génétique Médicale, INSERM U954 (Nutrition-Genetics-Environmental Risk Exposure), Centre Hospitalier Universaire Hôpitaux de Brabois, 54511 Vandoeuvre les Nancy, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Universaire de Nantes, 44093 Nantes, France; INSERM UMR_S957, 44093 Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Département de Génétique, Centre Hospitalier Universaire Paris - Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, 75019 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Perrin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Neal
authors.initials: N
authors.lastname: Sondheimer
authors.affiliation: Centre Hospitalier Régional Universitaire, Hôpital Jean Minjoz, 25030 Besançon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Paris
authors.affiliation: Boston Children's Hospital, Feingold Center, Boston, MA 02115, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Douglas
authors.affiliation: Department of Medical Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, 69677 Bron, France; Université de Lyon, 69100 Villeurbanne, France; Centre Nationnal de la Recherche Scientifique UMR 5292, INSERM U1028, Centre de Recherche en Neurosciences de Lyon, bâtiment l'Institut Multidisciplinaire de Biochimie des Lipides, 69621 Villeurbanne, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1211 Geneva 4, Switzerland; Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Antonarakis
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland.
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Jouan
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Duffourd
authors.affiliation: INSERM 1141, Service de Neurologie Pédiatrique, Hôpital Robert Debré, 75019 Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Auvin
authors.affiliation: Laboratoire de Génétique Médicale, INSERM U954 (Nutrition-Genetics-Environmental Risk Exposure), Centre Hospitalier Universaire Hôpitaux de Brabois, 54511 Vandoeuvre les Nancy, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Saunier
authors.affiliation: GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Begtrup
authors.affiliation: Boston Children's Hospital, Feingold Center, Boston, MA 02115, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Nowak
authors.affiliation: Department of Medical Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, 69677 Bron, France; Université de Lyon, 69100 Villeurbanne, France; Centre Nationnal de la Recherche Scientifique UMR 5292, INSERM U1028, Centre de Recherche en Neurosciences de Lyon, bâtiment l'Institut Multidisciplinaire de Biochimie des Lipides, 69621 Villeurbanne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chatron
authors.affiliation: Department of Pediatric Neurology, Groupement Hospitalier Est, Hospices Civils de Lyon, 69677 Bron, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.affiliation: Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Kamiar
authors.initials: K
authors.lastname: Mireskandari
authors.affiliation: Service de Physiologie Clinique et Explorations Fonctionnelles, Hôpital Lariboisière, Assistance Publique - Hôpitaux de Paris, 75475 Paris, France.
authors.forename: Paolo
authors.initials: P
authors.lastname: Milani
authors.affiliation: Laboratoire de Génétique Médicale, INSERM U954 (Nutrition-Genetics-Environmental Risk Exposure), Centre Hospitalier Universaire Hôpitaux de Brabois, 54511 Vandoeuvre les Nancy, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jonveaux
authors.affiliation: Service d'Ophtalmologie, Centre Hospitalo-Universitaire de Nantes, 44093 Nantes, France.
authors.forename: Guylène
authors.initials: G
authors.lastname: Lemeur
authors.affiliation: Service de Neurologie Pédiatrique, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, 13005 Marseille, France; INSERM UMR_S910, Aix-Marseille Université, 13005 Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.affiliation: Pediatrics Emergency Center, Kitakyushu Municipal Yahata Hospitals, Kitakyushu 803-8501, Japan.
authors.forename: Masano
authors.initials: M
authors.lastname: Amamoto
authors.affiliation: Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8555, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Paediatrics, Faculty of Medicine, Jordan University, Amman 11942, Jordan.
authors.forename: Amira
authors.initials: A
authors.lastname: Masri
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France; INSERM 1141, Service de Neurologie Pédiatrique, Hôpital Robert Debré, 75019 Paris, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France; INSERM 1141, Service de Neurologie Pédiatrique, Hôpital Robert Debré, 75019 Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France; INSERM 1141, Service de Neurologie Pédiatrique, Hôpital Robert Debré, 75019 Paris, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France; INSERM 1141, Service de Neurologie Pédiatrique, Hôpital Robert Debré, 75019 Paris, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France. Electronic address: jthevenon@chu-grenoble.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics*; D033966:Adaptor Protein Complex beta Subunits / Q000235:genetics*; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics; D004827:Epilepsy / Q000150:complications* / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D009896:Optic Atrophy / Q000150:complications* / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome
chemical_list: C095597:AP3B2 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits
keywords: AP3B2; EOEE syndrome; developmental delay; epilepsy; microcephaly; optic atrophy