2. Academic Validation
  3. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

  • Am J Hum Genet. 2016 Dec 1;99(6):1368-1376. doi: 10.1016/j.ajhg.2016.10.009.
Mirna Assoum 1,  Christophe Philippe 2,  Bertrand Isidor 3,  Laurence Perrin 4,  Periklis Makrythanasis 5,  Neal Sondheimer 6,  Caroline Paris 7,  Jessica Douglas 8,  Gaetan Lesca 9,  Stylianos Antonarakis 10,  Hanan Hamamy 11,  Thibaud Jouan 1,  Yannis Duffourd 12,  Stéphane Auvin 13,  Aline Saunier 2,  Amber Begtrup 14,  Catherine Nowak 8,  Nicolas Chatron 9,  Dorothée Ville 15,  Kamiar Mireskandari 16,  Paolo Milani 17,  Philippe Jonveaux 2,  Guylène Lemeur 18,  Mathieu Milh 19,  Masano Amamoto 20,  Mitsuhiro Kato 21,  Mitsuko Nakashima 22,  Noriko Miyake 22,  Naomichi Matsumoto 22,  Amira Masri 23,  Christel Thauvin-Robinet 24,  Jean-Baptiste Rivière 25,  Laurence Faivre 24,  Julien Thevenon 26
Affiliations

Affiliations

  • 1 Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France.
  • 2 Laboratoire de Génétique Médicale, INSERM U954 (Nutrition-Genetics-Environmental Risk Exposure), Centre Hospitalier Universaire Hôpitaux de Brabois, 54511 Vandoeuvre les Nancy, France.
  • 3 Service de Génétique Médicale, Centre Hospitalier Universaire de Nantes, 44093 Nantes, France; INSERM UMR_S957, 44093 Nantes, France.
  • 4 Département de Génétique, Centre Hospitalier Universaire Paris - Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, 75019 Paris, France.
  • 5 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.
  • 6 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
  • 7 Centre Hospitalier Régional Universitaire, Hôpital Jean Minjoz, 25030 Besançon, France.
  • 8 Boston Children's Hospital, Feingold Center, Boston, MA 02115, USA.
  • 9 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.
  • 10 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.
  • 11 Department of Genetic Medicine and Development, University of Geneva, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland.
  • 12 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.
  • 13 INSERM 1141, Service de Neurologie Pédiatrique, Hôpital Robert Debré, 75019 Paris, France.
  • 14 GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 15 Department of Pediatric Neurology, Groupement Hospitalier Est, Hospices Civils de Lyon, 69677 Bron, France.
  • 16 Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
  • 17 Service de Physiologie Clinique et Explorations Fonctionnelles, Hôpital Lariboisière, Assistance Publique - Hôpitaux de Paris, 75475 Paris, France.
  • 18 Service d'Ophtalmologie, Centre Hospitalo-Universitaire de Nantes, 44093 Nantes, France.
  • 19 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.
  • 20 Pediatrics Emergency Center, Kitakyushu Municipal Yahata Hospitals, Kitakyushu 803-8501, Japan.
  • 21 Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8555, Japan.
  • 22 Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
  • 23 Department of Paediatrics, Faculty of Medicine, Jordan University, Amman 11942, Jordan.
  • 24 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.
  • 25 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.
  • 26 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: [email protected].
PMID: 27889060 DOI: 10.1016/j.ajhg.2016.10.009
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.

Keywords

AP3B2; EOEE syndrome; developmental delay; epilepsy; microcephaly; optic atrophy.

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