Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases

PubMed ID: 29205472Objective: 3-Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days–33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic “putaminal eye” was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. Interpretation: MEGDHEL syndrome is a progressive deafness–dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004–1015. © 2017 American Neurological AssociationTulane University Newcastle upon Tyne Hospitals NHS Foundation Trust Helsingin Yliopisto Department of Genetics, University of Alabama at Birmingham Newcastle University UCL Institute for Global Health, University College London UCL Institute for Global Health, University College London 2741-B26 M.S.I. Foundation Bundesministerium für Bildung und Forschung: Horizon2020, 01GM1603, 01GM1207 G0800674 Mauritius Research Council Lily Mae Foundation Medical Research Council 203105/Z/16/ZUniversity Hospital of Padua, Padua, Italy; 13Neurodevelopmental Genomics Research Group, Murdoch Children’s Research Institute, and Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia; 14Genetic Metabolic Disorders Research Unit and Western Sydney Genetics Program, Children’s Hospital at Westmead, Sydney, New South Wales, Australia; 15Discipline of Child and Adolescent Health and Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; 16Departments of Pediatrics and Medicine, Columbia University, New York, NY; 17Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy; 18Center for the Study of Rare Hereditary Diseases, Niguarda Ca’ Granda Metropolitan Hospital, Milan, Italy; 19Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Queen Silvia’s Children’s Hospital, Gothenburg, Sweden; 20Childrens Hospital, Klinikum Reutlingen, Reutlingen, Germany; 21Inborn Errors of Metabolism and Mitochondrial Disease Unit, “12 de Octubre” University Hospital, Avenida de Cordoba sn, 28041 Madrid, Spain. Rare Diseases Biomedical Research Centre (CIBERER), Madrid, Spain; 22Complutense University, Madrid, Spain; 23Metabolic Medicine Department, Great Ormond Street Hospital for Children National Health Service Foundation Trust, University College London Institute of Child Health, London, United Kingdom; 24Institute of Medical Genetics and Applied Genomics, Tu€bingen, Germany; 25Wilhelmina Children’s Hospital Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands; 26Department of Pediatrics, Haukeland University Hospital, Bergen, Norway; 27Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway; 28Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany; 29Childrens Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 30Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; 31Department of Biology and Microbiology, Riga Stradin’s University, Riga, Latvia; 32Department of Pediatrics, Salzburg State Hospitals and Paracelsus Medical University, Salzburg, Austria; 33Leeds Teaching Hospitals National Health Service Trust, Leeds, United Kingdom; 34Pediatric Neurology, Brussels University Hospital, Brussels, Belgium; 35Department of Pediatric Neurology, Karolinska University Hospital, Stockholm, Sweden; 36Division of Clinical Genetics, Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia; 37Department of Clinical Biochemistry, Radioimmunology, and Experimental Medicine, Children’s Memorial Health Institute, Warsaw, Poland; 38University College London Great Ormond Street Institute of Child Health, London, United Kingdom; 39Department of Pediatric Neurology, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; 40Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tu€bingen, Tu€bingen, Germany; 41German Center for Neurodegenerative Diseases (DZNE), Tu€bingen, Germany; 42Department of General Pediatrics, Mu€nster University Children’s Hospital, Mu€nster, Germany; 43Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany; 44Reference Center for Inherited Metabolic Diseases, AP-HP, Robert Debré Hospital, University Paris Diderot-Sorbonne Paris Cité, Paris, France AND INSERM U1141, Paris, France; 45Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 46Metabolic Unit, Dona Estefânia Hospital, Lisbon, Portugal; 47Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom; 48Department of Medical Genetics, Children’s Memorial Health Institute, Warsaw, Poland; 49Division of Metabolic Diseases, Hacettepe University Children’s Hospital, Ankara, Turkey; 50Birmingham Children’s Hospital, Birmingham, United Kingdom; 51Nottingham University Hospitals National Health Service Trust, Nottingham Children’s Hospital, Nottingham, United Kingdom; 52Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany; 53Hayward Genetics Center and Department of Pediatrics, Tulane University Medical School, New Orleans, LA; 54Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, Warsaw, Poland; and 55Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. -- M.S. was supported by the Else Kr€oner-Fresenius Stiftung” This study was supported by the German Bun-desministerium fu€r Bildung und Forschung (BMBF) and Horizon2020 through the E-Rare project GENOMIT (01GM1603 and 01GM1207 for HP and FWF I 2741-B26 for J.A.M. J.A.M., S.B.W., W.S. were supported by the Vereinigung zur F€orderung P€adiatrischer Forschung und Fortbildung Salzburg. R.W.T. was supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. -