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

Maas RR 1 , Iwanicka-Pronicka K 2 , Kalkan Ucar S 3 , Alhaddad B 4 , AlSayed M 5 , Al-Owain MA 5 Show all authors , Al-Zaidan HI 5 , Balasubramaniam S 6 , Barić I 7 , Bubshait DK 8 , Burlina A 9 , Christodoulou J 10 , Chung WK 11 , Colombo R 12 , Darin N 13 , Freisinger P 14 , Garcia Silva MT 15 , Grunewald S 16 , Haack TB 4 , van Hasselt PM 17 , Hikmat O 18 , Hörster F 19 , Isohanni P 20 , Ramzan K 5 , Kovacs-Nagy R 4 , Krumina Z 21 , Martin-Hernandez E 15 , Mayr JA 22 , McClean P 23 , De Meirleir L 24 , Naess K 25 , Ngu LH 26 , Pajdowska M 27 , Rahman S 28 , Riordan G 29 , Riley L 30 , Roeben B 31 , Rutsch F 32 , Santer R 33 , Schiff M 34 , Seders M 35 , Sequeira S 36 , Sperl W 22 , Staufner C 19 , Synofzik M 31 , Taylor RW 37 , Trubicka J 38 , Tsiakas K 33 , Unal O 39 , Wassmer E 40 , Wedatilake Y 28 , Wolff T 41 , Prokisch H 4 , Morava E 42 , Pronicka E 43 , Wevers RA 1 , de Brouwer AP 35 , Wortmann SB 4

Affiliations 

  • 1 Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
  • 2 Department of Audiology and Phoniatrics, Children's Memorial Health Institute, Warsaw, Poland
  • 3 Division of Metabolic Disease, Ege University Medical Faculty, Department of Pediatrics, Izmir, Turkey
  • 4 Institute of Human Genetics, Technische UniversitätMünchen, Munich, Germany
  • 5 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 6 Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia
  • 7 Department of Pediatrics, University Hospital Center, Zagreb, Croatia
  • 8 Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
  • 9 Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital of Padua, Padua, Italy
  • 10 Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, and Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia
  • 11 Departments of Pediatrics and Medicine, Columbia University, New York, NY
  • 12 Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy
  • 13 Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Queen Silvia's Children's Hospital, Gothenburg, Sweden
  • 14 Childrens Hospital, Klinikum Reutlingen, Reutlingen, Germany
  • 15 Inborn 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
  • 16 Metabolic Medicine Department, Great Ormond Street Hospital for Children National Health Service Foundation Trust, University College London Institute of Child Health, London, United Kingdom
  • 17 Wilhelmina Children's Hospital Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands
  • 18 Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
  • 19 Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
  • 20 Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 21 Department of Biology and Microbiology, Riga Stradin's University, Riga, Latvia
  • 22 Department of Pediatrics, Salzburg State Hospitals and Paracelsus Medical University, Salzburg, Austria
  • 23 Leeds Teaching Hospitals National Health Service Trust, Leeds, United Kingdom
  • 24 Pediatric Neurology, Brussels University Hospital, Brussels, Belgium
  • 25 Department of Pediatric Neurology, Karolinska University Hospital, Stockholm, Sweden
  • 26 Division of Clinical Genetics, Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
  • 27 Department of Clinical Biochemistry, Radioimmunology, and Experimental Medicine, Children's Memorial Health Institute, Warsaw, Poland
  • 28 University College London Great Ormond Street Institute of Child Health, London, United Kingdom
  • 29 Department of Pediatric Neurology, Red Cross War Memorial Children's Hospital, Cape Town, South Africa
  • 30 Genetic Metabolic Disorders Research Unit and Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia
  • 31 Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  • 32 Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany
  • 33 Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany
  • 34 Reference Center for Inherited Metabolic Diseases, AP-HP, Robert Debré Hospital, University Paris Diderot-Sorbonne Paris Cité, Paris, France AND INSERM U1141, Paris, France
  • 35 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
  • 36 Metabolic Unit, Dona Estefânia Hospital, Lisbon, Portugal
  • 37 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
  • 38 Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland
  • 39 Division of Metabolic Diseases, Hacettepe University Children's Hospital, Ankara, Turkey
  • 40 Birmingham Children's Hospital, Birmingham, United Kingdom
  • 41 Nottingham University Hospitals National Health Service Trust, Nottingham Children's Hospital, Nottingham, United Kingdom
  • 42 Hayward Genetics Center and Department of Pediatrics, Tulane University Medical School, New Orleans, LA
  • 43 Department of Pediatrics, Nutrition and Metabolic Diseases, Children's Memorial Health Institute, Warsaw, Poland
Ann Neurol, 2017 Dec;82(6):1004-1015.
PMID: 29205472 DOI: 10.1002/ana.25110

Abstract

OBJECTIVE: 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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