Majida Charif1, Alessia Nasca2, Kyle Thompson3, Sylvie Gerber4, Christine Makowski5, Neda Mazaheri6,7, Céline Bris1, David Goudenège1, Andrea Legati2, Reza Maroofian8, Gholamreza Shariati9, Eleonora Lamantea2, Sila Hopton3, Anna Ardissone10, Isabella Moroni10, Melania Giannotta11, Corinna Siegel12, Tim M Strom12,13, Holger Prokisch12,13, Catherine Vignal-Clermont14, Sabine Derrien14, Xavier Zanlonghi15, Josseline Kaplan4, Christian P Hamel16, Stephanie Leruez1, Vincent Procaccio1, Dominique Bonneau1, Pascal Reynier1, Frances E White3, Steven A Hardy3, Inês A Barbosa17, Michael A Simpson17, Roshni Vara18, Yaumara Perdomo Trujillo19, Hamind Galehdari7, Charu Deshpande20, Tobias B Haack12,13,21, Jean-Michel Rozet4, Robert W Taylor3, Daniele Ghezzi2, Patrizia Amati-Bonneau1, Guy Lenaers1. 1. MitoLab Team, Unités Mixtes de Recherche Centre National de la Recherche Scientifique 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital, Angers, France. 2. Unit of Molecular Neurogenetics, Istituto di Ricovero e Cura a Carattere Scientifico, Foundation of the Carlo Besta Neurological Institute, Milan, Italy. 3. Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, England. 4. Laboratory of Genetics in Ophthalmology, INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris, France. 5. Department of Paediatrics, Technische Universität München, Munich, Germany. 6. Department of Genetics, Shahid Chamran University of Ahvaz, Ahvaz, Iran. 7. Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran. 8. University of Exeter Medical School, Research, Innovation, Learning and Development, Wellcome Wolfson Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, England. 9. Department of Medical Genetic, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Ahvaz, Iran. 10. Child Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Foundation of the Carlo Besta Neurological Institute, Milan, Italy. 11. Child Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Institute of Neurological Sciences, Bologna, Italy. 12. Institute of Human Genetics, Technische Universität München, Munich, Germany. 13. Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany. 14. Département de Neurochirurgie, Service Explorations Neuro-Ophtalmologiques, Fondation Rothschild, Paris, France. 15. Clinique Pluridisciplinaire Jules Verne, Nantes, France. 16. INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France. 17. Division of Genetics and Molecular Medicine, King's College London School of Medicine, London, England. 18. Department of Paediatric Inherited Metabolic Diseases, Evelina Children's Hospital, London, England. 19. Centre de Référence Pour Les Affections Rares en Génétique Ophtalmologique, CHU de Strasbourg, Strasbourg, France. 20. Clinical Genetics Unit, Guy's and St Thomas' National Health Service Foundation Trust, London, England. 21. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Abstract
Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies. Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase. Design, Setting, and Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016. Main Outcomes and Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies. Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation. Conclusions and Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies.
Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies. Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase. Design, Setting, and Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016. Main Outcomes and Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies. Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation. Conclusions and Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies.
Authors: A S Lebre; M Rio; L Faivre d'Arcier; D Vernerey; P Landrieu; A Slama; C Jardel; P Laforêt; D Rodriguez; N Dorison; D Galanaud; B Chabrol; V Paquis-Flucklinger; D Grévent; S Edvardson; J Steffann; B Funalot; N Villeneuve; V Valayannopoulos; P de Lonlay; I Desguerre; F Brunelle; J P Bonnefont; A Rötig; A Munnich; N Boddaert Journal: J Med Genet Date: 2010-10-23 Impact factor: 6.318
Authors: Estelle Colin; Jens Daniel; Alban Ziegler; Jamal Wakim; Aurora Scrivo; Tobias B Haack; Salim Khiati; Anne-Sophie Denommé; Patrizia Amati-Bonneau; Majida Charif; Vincent Procaccio; Pascal Reynier; Kyrieckos A Aleck; Lorenzo D Botto; Claudia Lena Herper; Charlotte Sophia Kaiser; Rima Nabbout; Sylvie N'Guyen; José Antonio Mora-Lorca; Birgit Assmann; Stine Christ; Thomas Meitinger; Tim M Strom; Holger Prokisch; Antonio Miranda-Vizuete; Georg F Hoffmann; Guy Lenaers; Pascale Bomont; Eva Liebau; Dominique Bonneau Journal: Am J Hum Genet Date: 2016-08-18 Impact factor: 11.025
Authors: M Bugiani; F Invernizzi; S Alberio; E Briem; E Lamantea; F Carrara; I Moroni; L Farina; M Spada; M A Donati; G Uziel; M Zeviani Journal: Biochim Biophys Acta Date: 2004-12-06
Authors: Majida Charif; Agathe Roubertie; Sara Salime; Sonia Mamouni; Cyril Goizet; Christian P Hamel; Guy Lenaers Journal: Front Genet Date: 2015-10-19 Impact factor: 4.599
Authors: Charlotte L Alston; Caoimhe Howard; Monika Oláhová; Steven A Hardy; Langping He; Philip G Murray; Siobhan O'Sullivan; Gary Doherty; Julian P H Shield; Iain P Hargreaves; Ardeshir A Monavari; Ina Knerr; Peter McCarthy; Andrew A M Morris; David R Thorburn; Holger Prokisch; Peter E Clayton; Robert McFarland; Joanne Hughes; Ellen Crushell; Robert W Taylor Journal: J Med Genet Date: 2016-04-18 Impact factor: 6.318
Authors: Alissa M D'Gama; Eleina England; Jill A Madden; Jiahai Shi; Katherine R Chao; Monica H Wojcik; Alcy R Torres; Wen-Hann Tan; Gerard T Berry; Sanjay P Prabhu; Pankaj B Agrawal Journal: Am J Med Genet A Date: 2020-10-09 Impact factor: 2.802