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JAMA Neurol. 2018 Jan 1;75(1):105-113. doi: 10.1001/jamaneurol.2017.2065.

Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults.

Author information

MitoLab Team, Unités Mixtes de Recherche Centre National de la Recherche Scientifique 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital, Angers, France.
Unit of Molecular Neurogenetics, Istituto di Ricovero e Cura a Carattere Scientifico, Foundation of the Carlo Besta Neurological Institute, Milan, Italy.
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, England.
Laboratory of Genetics in Ophthalmology, INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris, France.
Department of Paediatrics, Technische Universität München, Munich, Germany.
Department of Genetics, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran.
University of Exeter Medical School, Research, Innovation, Learning and Development, Wellcome Wolfson Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, England.
Department of Medical Genetic, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Ahvaz, Iran.
Child Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Foundation of the Carlo Besta Neurological Institute, Milan, Italy.
Child Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Institute of Neurological Sciences, Bologna, Italy.
Institute of Human Genetics, Technische Universität München, Munich, Germany.
Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany.
Département de Neurochirurgie, Service Explorations Neuro-Ophtalmologiques, Fondation Rothschild, Paris, France.
Clinique Pluridisciplinaire Jules Verne, Nantes, France.
INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France.
Division of Genetics and Molecular Medicine, King's College London School of Medicine, London, England.
Department of Paediatric Inherited Metabolic Diseases, Evelina Children's Hospital, London, England.
Centre de Référence Pour Les Affections Rares en Génétique Ophtalmologique, CHU de Strasbourg, Strasbourg, France.
Clinical Genetics Unit, Guy's and St Thomas' National Health Service Foundation Trust, London, England.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.



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.


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.


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.

[Indexed for MEDLINE]
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