Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.
Journal: The lancet. Diabetes & endocrinology
Volume: 8
Issue: 7
Year of Publication: 2020
Affiliated Institutions:
Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands.
Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey.
Pediatric Neurology Section, Hospital Francesc de Borja de Gandia, Valencia, Spain.
Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
University of Louisville, Louisville, KY, USA.
Paediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania; Department of Neurosciences, Paediatric Neurology Discipline II, Carol Davila University of Medicine, Bucharest, Romania.
Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy.
Sophia Children's Hospital, Division of Paediatric Cardiology, Erasmus Medical Centre, Rotterdam, Netherlands.
Department of Translational Medicine, Federico II University, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
Department of Child Neurology, Center for Childhood White Matter Diseases, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, Amsterdam, Netherlands; Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Division of Endocrinology, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy.
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Departamento de Neurologia Pediatrica, Clinica Las Condes, Santiago, Chile.
Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Department of Paediatric Neurology, Erasmus Medical Centre, Rotterdam, Netherlands.
Department of Pediatric Endocrinology and Diabetology, University Hospital, Angers, France.
John Hunter Children's Hospital and University of Newcastle, Newcastle, NSW, Australia.
Lancashire Teaching Hospitals NHS Trust, Lancashire, UK.
Sheffield Children's NHS Foundation Trust, Sheffield Hallam University and University of Sheffield, Sheffield, UK.
Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands; Università Vita-Salute San Raffaele, Milan, Italy.
Division of Paediatric Radiology, Erasmus Medical Centre, Rotterdam, Netherlands.
Medanta Superspeciality Hospital, Indore, India.
Department of Neuropediatrics, University Children's Hospital Zurich, Zürich, Switzerland.
Department of Diabetes and Endocrinology, Women's and Children's Hospital, North Adelaide, SA, Australia.
Plymouth Hospitals NHS Trust, Plymouth, UK.
Department of Endocrinology, St. John's Medical College Hospital, Bengaluru, Karnataka, India.
Centre for Endocrinology, William Harvey Research institute, Queen Mary University London, London, UK; Dept of Paediatric Endocrinology, Barts Health NHS Trust, London, UK.
Department of Paediatrics, Semmelweis University, Budapest, Hungary.
Department of Endocrinology & Diabetes, Queensland Children's Hospital, South Brisbane, QLD, Australia; Department of Chemical Pathology, Mater Pathology, South Brisbane, QLD, Australia; Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
Medical University of Gdańsk, Department of Paediatrics, Haematology & Oncology, Department of General Nursery, Gdańsk, Poland.
Department of Child Neurology, Center for Childhood White Matter Diseases, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, Amsterdam, Netherlands.
Division of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center (Radboudumc), Nijmegen, Netherlands.
Department of Paediatric Endocrinology and Diabetology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Genomics Institute Mary Bridge Children's Hospital, MultiCare Health System Tacoma, WA, USA.
Department of Paediatrics, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic.
Division of Neuropediatrics and Muscular Disorders, Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
Teaching Hospital of Universidade Federal de Pelotas, Pelotas, Brazil.
Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, Brazil.
Department of Child Neurology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA, USA.
Institute of Maternal and Child Research, University of Chile, Santiago, Chile; Department of Pediatrics, Clinica Las Condes, Santiago, Chile.
Pediatric Endocrinology Group, Santa Catarina Hospital, São Paulo, Brazil.
University of Debrecen, Pediatric Institute, Debrecen, Hungary.
Department of Paediatric Endocrinology and Genetics, Children's Hospital, Toulouse University Hospital, Toulouse, France.
Department of Paediatrics, Christian Medical College, Vellore, India.
Paediatric Endocrinology, Diabetology and Gynaecology Department, Necker Children's University Hospital, Imagine Institute, Paris, France.
Department of Paediatrics, AOU Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Duesseldorf, Germany.
Marmara University School of Medicine Department of Pediatric Endocrinology, Istanbul, Turkey.
Royal Children's Hospital, Parkville, Melbourne, VIC, Australia.
Department of Paediatric Cardiology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Child Neurology Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy.
Department of Cardiology and Intensive Care Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
Panorama Medical Centre, Cape Town, South Africa.
University of Lille, Lille, France.
Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany; KUNO Children's University Hospital, Campus St. Hedwig, University of Regensburg, Regensburg, Germany.
Paediatric Endocrinology Unit, Kaplan Medical Center, Rehovot, Israel; Hebrew University of Jerusalem, Jerusalem, Israel.
Emma Children's Hospital, Department of Paediatric Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands. Electronic address: w.e.visser@erasmusmc.nl.
Abstract summary
Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency.We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings.Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients.Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies.Netherlands Organisation for Health Research and Development, and the Sherman Foundation.
Authors & Co-authors:
Groeneweg Stefan S
van Geest Ferdy S FS
Abacı Ayhan A
Alcantud Alberto A
Ambegaonkar Gautem P GP
Armour Christine M CM
Bakhtiani Priyanka P
Barca Diana D
Bertini Enrico S ES
van Beynum Ingrid M IM
Brunetti-Pierri Nicola N
Bugiani Marianna M
Cappa Marco M
Cappuccio Gerarda G
Castellotti Barbara B
Castiglioni Claudia C
Chatterjee Krishna K
de Coo Irenaeus F M IFM
Coutant Régis R
Craiu Dana D
Crock Patricia P
DeGoede Christian C
Demir Korcan K
Dica Alice A
Dimitri Paul P
Dolcetta-Capuzzo Anna A
Dremmen Marjolein H G MHG
Dubey Rachana R
Enderli Anina A
Fairchild Jan J
Gallichan Jonathan J
George Belinda B
Gevers Evelien F EF
Hackenberg Annette A
Halász Zita Z
Heinrich Bianka B
Huynh Tony T
Kłosowska Anna A
van der Knaap Marjo S MS
van der Knoop Marieke M MM
Konrad Daniel D
Koolen David A DA
Krude Heiko H
Lawson-Yuen Amy A
Lebl Jan J
Linder-Lucht Michaela M
Lorea Cláudia F CF
Lourenço Charles M CM
Lunsing Roelineke J RJ
Lyons Greta G
Malikova Jana J
Mancilla Edna E EE
McGowan Anne A
Mericq Veronica V
Lora Felipe M FM
Moran Carla C
Müller Katalin E KE
Oliver-Petit Isabelle I
Paone Laura L
Paul Praveen G PG
Polak Michel M
Porta Francesco F
Poswar Fabiano O FO
Reinauer Christina C
Rozenkova Klara K
Menevse Tuba S TS
Simm Peter P
Simon Anna A
Singh Yogen Y
Spada Marco M
van der Spek Jet J
Stals Milou A M MAM
Stoupa Athanasia A
Subramanian Gopinath M GM
Tonduti Davide D
Turan Serap S
den Uil Corstiaan A CA
Vanderniet Joel J
van der Walt Adri A
Wémeau Jean-Louis JL
Wierzba Jolante J
de Wit Marie-Claire Y MY
Wolf Nicole I NI
Wurm Michael M
Zibordi Federica F
Zung Amnon A
Zwaveling-Soonawala Nitash N
Visser W Edward WE
Study Outcome
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