DiseasecharacteristicsofMCT8deiciency: aninternational ...
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Year: 2020
Disease characteristics of MCT8 deficiency: an international, retrospective,multicentre cohort study
Groeneweg, Stefan ; van Geest, Ferdy S ; et al ; Enderli, Anina ; Hackenberg, Annette ; Konrad, Daniel; Heinrich, Bianka
Abstract: Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 geneencoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disabilityresulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematicallyassess the phenotypic characteristics and natural history of patients with MCT8 deficiency. Methods:We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. Thekey inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Ourprimary objective was to analyse the overall survival of patients with MCT8 deficiency and documentcauses of death. We also compared survival between patients who did or did not attain full head controlby age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as abodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectiveswere to assess neurocognitive function and outcomes, and clinical parameters including anthropometriccharacteristics, biochemical markers, and neuroimaging findings. Findings: Between Oct 14, 2014, andJan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age atdiagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; themain 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 attainhead control by age 1·5 years had an increased risk of death compared with patients who did attainhead control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who wereunderweight during age 1-3 years had an increased risk for death compared with patients who were ofnormal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitiveabilities of patients did not improve with age, as evidenced by the absence of significant correlationsbetween biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of InfantDevelopment III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic bloodpressure 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. Interpretation: Our description of characteristics of MCT8deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlyingrisk factors, and provides knowledge that might inform clinical management and future evaluation oftherapies. Funding: Netherlands Organisation for Health Research and Development, and the ShermanFoundation.
DOI: https://doi.org/10.1016/s2213-8587(20)30153-4
Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-188600Journal ArticleAccepted Version
Originally published at:Groeneweg, Stefan; van Geest, Ferdy S; et al; Enderli, Anina; Hackenberg, Annette; Konrad, Daniel;Heinrich, Bianka (2020). Disease characteristics of MCT8 deficiency: an international, retrospective,multicentre cohort study. The Lancet. Diabetes Endocrinology, 8(7):594-605.DOI: https://doi.org/10.1016/s2213-8587(20)30153-4
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The Lancet Diabetes & Endocrinology
Disease characteristics of MCT8 deficiency: an international, retrospective, multicentrecohort study
--Manuscript Draft--
Manuscript Number: THELANCETDE-D-20-00091R2
Article Type: Article (Original Research)
Keywords: MCT8; monocarboxylate transporter 8; MCT8 deficiency; Allan-Herndon-Dudleysyndrome; AHDS; natural history; Survival; life expectancy; prognosis; diseaseoutcomes
Corresponding Author: Stefan GroenewegErasmus Medical CentreRotterdam, NETHERLANDS
First Author: Stefan Groeneweg, MD PhD
Order of Authors: Stefan Groeneweg, MD PhD
Ferdy S van Geest, MD
Ayhan Abacı, Prof. Dr.
Alberto Alcantud, MD
Gautem Ambegaonkar, MD
Christine Armour, MD
Priyanka Bakhtiani, MD
Diana Barca, MD
Enrico S Bertini, Prof. Dr.
Ingrid M van Beynum, MD PhD
Nicola Brunetti-Pierri, Prof. Dr.
Marianna Bugiani, MD
Marco Cappa, Prof. Dr.
Gerarda Cappuccio, MD
Barbara Castellotti, MD
Claudia Castiglioni, MD
Krishna Chatterjee, Prof. Dr.
Irenaeus FM de Coo, MD PhD
Régis Coutant, Prof. Dr.
Dana Craiu, Prof. Dr.
Patricia Crock, DMed
Christian DeGoede, FRCPCH
Korcan Demir, Assoc. Prof. Dr.
Alice Dica, MD
Paul Dimitri, Prof. BSc, MBChB, FRCPCH, PhD
Anna Dolcetta Capuzzo, MD
Marjolein HG Dremmen, MD
Rachana Dubey, MD
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Anina Enderli, MD
Jan Fairchild, MD PhD
Jonathan Gallichan, MBChB
Belinda George, MD, DM
Evelien F Gevers, MD
Annette Hackenberg, MD
Zita Halász, MD PhD
Bianka Heinrich
Tony Huynh, MBBS PhD FRACP RCPA
Anna Kłosowska, MD
Marjo S van der Knaap, Prof. Dr.
Marieke M van der Knoop, MSc
Daniel Konrad, Prof. Dr.
David A Koolen, MD PhD
Heiko Krude, Prof. Dr.
Amy Lawson-Yuen, MD PhD
Jan Lebl, Prof. Dr.
Michaela Linder-Lucht, MD
Cláudia F Lorea, MD
Charles M Lourenço, MD PhD
Roelineke J Lunsing, MD PhD
Greta Lyons
Jana Malikova, MD
Edna E Mancilla, MD
Anne McGowan, MD
Veronica Mericq, Prof. Dr.
Felipe Monti Lora, MD
Carla Moran, MD PhD
Katalin E Müller, MD PhD
Isabelle Oliver-Petit, MD
Laura Paone, MD
Praveen G Paul, MD
Michel Polak, Prof. Dr.
Francesco Porta, MD
Fabiano O Poswar, MD
Christina Reinauer, MD
Klara Rozenkova, MD
Tuba Seven Menevse, MD
Peter Simm, MD
Anna Simon, Prof. Dr.
Yogen Singh, MDPowered by Editor ial Manager® and ProduXion Manager® from Aries System s Corporat ion
Marco Spada, MD PhD
Jet van der Spek, MD
Milou AM Stals, MD
Athanasia Stoupa, MD
Gopinath M Subramanian, MD
Davide Tonduti, MD PhD
Serap Turan, Prof. Dr.
Corstiaan A den Uil, MD PhD
Joel Vanderniet, MBBS
Adri van der Walt, MD
Jean-Louis Wémeau, Prof. Dr.
Jolante Wierzba, MD
Marie-Claire Y de Wit, MD PhD
Nicole I Wolf, MD PhD
Michael Wurm, MD
Federica Zibordi, MD
Amnon Zung, MD
Nitash Zwaveling-Soonawala, MD
W Edward Visser, MD PhD
Manuscript Region of Origin: NETHERLANDS
Abstract: Background: Disordered thyroid hormone transport, due to mutations inmonocarboxylate transporter 8 (MCT8; gene: SLC16A2 ), is characterized byintellectual and motor disability due to cerebral hypothyroidism and chronic peripheralthyrotoxicosis. Phenotypic characteristics and natural history of MCT8 deficiency havenot been systematically evaluated.Methods: In this international, multicentre, study, retrospective data (2003 to 2019)from patients with MCT8 deficiency followed in 47 centres, was analysed. Our primaryobjectives were to determine neurocognitive outcomes and overall survival. We alsoassessed clinical parameters, including anthropometric characteristics, biochemicalmarkers and neuroimaging findings.Results: 151 subjects with 73 different MCT8 ( SLC16A2 ) mutations were included.21·2% (32/151) of patients died, with main causes of mortality in these patients beingpulmonary infection (18·8%) and sudden death (18·8%). The median overall survivalwas 35·0 (95%CI 8·3-61·7) years. Survival differed significantly between individualswho attained head control by the age of 1·5 years or not (log-rank test: p=0·0041;hazard ratio 3·46 95%CI 1·76-8·34). Patients who were underweight during earlychildhood (1-3 years of age) had an increased risk for death compared with patientswho were not underweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). Thelimited motor and cognitive abilities of patients did not improve with age. T3concentrations were elevated in 95·1% (96/101) and total T4 concentrations werereduced in 89·5% (94/105) of patients. 71·1% (59/83) patients were underweight (<-2SD). Cardiovascular abnormalities were frequent, with 53·2% (25/47) of patientsexhibiting elevated systolic blood pressure, and 75·6% (34/45) of patients havingpremature atrial contractions and 31·3% (20/60) having resting tachycardia.Interpretation Our description of characteristics of MCT8 deficiency in a large patientcohort reveals poor survival with a high prevalence of treatable underlying risk factorsand provides knowledge which informs clinical management and future evaluation oftherapies. Funding Our study was funded by the Netherlands Organisation for Health Researchand Development (project number 113303005; to WEV), and the Sherman Foundation(to WEV).
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1
Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre
cohort study
Stefan Groeneweg MD1, Ferdy S van Geest MD1, Prof Ayhan Abacı MD2, Alberto Alcantud MD3,
Gautem P Ambegaonkar MRCPCH4, Christine M Armour MD5, Priyanka Bakhtiani MD6, Diana
Barca MD7, Prof Enrico S Bertini MD8, Ingrid M van Beynum MD9, Prof Nicola Brunetti-Pierri
MD10,11, Marianna Bugiani MD12,13, Marco Cappa MD14, Gerarda Cappuccio MD10,11, Barbara
Castellotti MD15, Claudia Castiglioni MD16, Prof Krishna Chatterjee FRCP17, Irenaeus FM de Coo
MD18, Prof Régis Coutant MD19, Prof Dana Craiu MD7, Patricia Crock DMed20, Christian
DeGoede FRCPCH21, Korcan Demir MD2, Alice Dica MD7, Prof Paul Dimitri PhD22, Anna Dolcetta
Capuzzo MD1,23, Marjolein HG Dremmen MD24, Rachana Dubey DM25, Anina Enderli MD26, Jan
Fairchild FRACP27, Jonathan Gallichan MBChB28, Belinda George DM29, Evelien F Gevers PhD30,
Annette Hackenberg MD26, Zita Halász MD31, Bianka Heinrich26, Tony Huynh PhD32,33,34, Anna
Kłosowska MD35, Prof Marjo S van der Knaap MD12, Marieke M van der Knoop MSc18, Prof
Daniel Konrad MD36, David A Koolen MD37, Prof Heiko Krude MD38, Amy Lawson–Yuen MD39,
Prof Jan Lebl MD40, Michaela Linder-Lucht MD41, Cláudia F Lorea MD42, Charles M Lourenço
MD43, Roelineke J Lunsing MD44, Greta Lyons RGN17, Jana Malikova MD40, Edna E Mancilla
MD45, Anne McGowan MD17, Prof Veronica Mericq MD46,47, Felipe Monti Lora MD48, Carla
Moran MB17, Katalin E Müller MD49, Isabelle Oliver-Petit MD50, Laura Paone MD14, Praveen G
Paul MD51, Prof Michel Polak MD52, Francesco Porta MD53, Fabiano O Poswar MD54, Christina
Reinauer MD55, Klara Rozenkova MD40, Tuba Seven Menevse MD56, Peter Simm MBBS57, Anna
Simon MD51, Yogen Singh MD58, Marco Spada MD53, Jet van der Spek MD37, Milou AM Stals
MD1, Athanasia Stoupa MD52, Gopinath M Subramanian FRACP20, Davide Tonduti MD59, Prof
Serap Turan MD56, Corstiaan A den Uil MD60, Joel Vanderniet MBBS20, Adri van der Walt MD61,
Prof Jean-Louis Wémeau MD62, Jolante Wierzba MD35, Marie-Claire Y de Wit MD18, Nicole I
Wolf MD12, Michael Wurm MD63,64, Federica Zibordi MD59, Prof Amnon Zung MD65,66, Nitash
Zwaveling-Soonawala MD67, W Edward Visser MD1
1 Academic Center for Thyroid Diseases, Erasmus Medical Centre, Rotterdam, Netherlands
2 Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
3 Pediatric neurology section, Hospital Francesc de Borja de Gandia, Spain
4 Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University
Hospitals NHS Foundation Trust, Cambridge, UK
5 Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital
of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
6 University of Louisville, Kentucky, USA
7 Paediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania; Department
of Neurosciences, Paediatric Neurology Discipline II, Carol Davila University of Medicine,
Bucharest, Romania
8 Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's
Research Hospital IRCCS, Rome, Italy
Manuscript
2
9 Sophia Children's Hospital, Division of Paediatric Cardiology, Erasmus Medical Centre,
Rotterdam, Netherlands
10 Department of Translational Medicine, Federico II University, 80131 Naples, Italy
11 Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy
12 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, The Netherlands.
13 Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical
Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
14 Division of Endocrinology, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy
15 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo
Besta, Milan
16 Departamento de Neurologia Pediatrica, Clinica Las Condes, Santiago, Chile
17 Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of
Cambridge, Cambridge, UK
18 Sophia Children's Hospital, Department of Paediatric Neurology, Erasmus Medical Centre,
Rotterdam, Netherlands
19 Department of Pediatric Endocrinology and Diabetology, University Hospital, Angers,
France
20 John Hunter Children’s Hospital and University of Newcastle, Newcastle, NSW Australia
21 Lancashire Teaching Hospitals NHS Trust
22 Sheffield Children’s NHS Foundation Trust, Sheffield Hallam University and University of
Sheffield
23 Università Vita-Salute San Raffaele, Milan, Italy
24 Sophia Children's Hospital, Division of Paediatric Radiology, Erasmus Medical Centre,
Rotterdam, Netherlands
25 Medanta Superspeciality Hospital, Indore, India
26 Department of Neuropediatrics, University Children’s Hospital Zurich, Steinwiesstrasse 75, 8032 Zürich, Switzerland
27 Department of Diabetes and Endocrinology, Women’s and Children’s Hospital , North Adelaide 5066 South Australia
28 Plymouth Hospitals NHS Trust, Plymouth, PL6 8DH, UK
29 Department of Endocrinology, St. John’s Medical College Hospital, Bengaluru
30 Centre for Endocrinology, William Harvey Research institute, Queen Mary University
London and Dept of Paediatric Endocrinology, Barts Health NHS Trust
31 Department of Paediatrics, Semmelweis University, Budapest
32 Department of Endocrinology & Diabetes, Queensland Children’s Hospital, South Brisbane Queensland, Australia
33 Department of Chemical Pathology, Mater Pathology, South Brisbane, Queensland,
Australia
34 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
35 Medical University of Gdańsk, Department of Paediatrics, Haemathology & Oncology, Department of General Nursery, Gdańsk, Poland
36 Division of Pediatric Endocrinology and Diabetology and Children’s Research Center, University Children's Hospital, CH-8032 Zurich, Switzerland
37 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour,
Radboud university medical center (Radboudumc), Nijmegen, The Netherlands
3
38 Department of Paediatric Endocrinology and Diabetology, Charité-Universitätsmedizin
Berlin, Berlin, Germany
39 Genomics Institute Mary Bridge Children's Hospital, MultiCare Health System Tacoma
Washington
40 Department of Paediatrics, Second Faculty of Medicine, Charles University, University
Hospital Motol, Prague, Czech Republic
41 Division of Neuropediatrics and Muscular Disorders, Department of Pediatrics and
Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
42 Teaching Hospital of Universidade Federal de Pelotas, Brazil
43 Faculdade de Medicina - Centro Universitario Estácio de Ribeirão Preto, Brazil
44 Department of Child Neurology, University Medical Center Groningen, University of
Groningen, Groningen, Netherlands
45 Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman
School of Medicine, University of Pennsylvania
46 Institute of Maternal and child Research University of Chile
47 Department of Pediatrics, Clinica Las Condes, Santiago Chile
48 Pediatric Endocrinology Group, Santa Catarina Hospital, São Paulo, Brazil
49 University of Debrecen, Pediatric Institute, Debrecen, Hungary
50 Department of Paediatric Endocrinology and Genetics, Children's Hospital, Toulouse
University Hospital, Toulouse, France
51 Department of Paediatrics, Christian Medical College, Vellore, South India
52 Paediatric Endocrinology, Diabetology and Gynaecology Department, Necker Children's
University Hospital, Imagine Institute, Paris, France
53 Department of Paediatrics, AOU Città della Salute e della Scienza di Torino, University of
Torino, Italy
54 Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
55 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University
Children's Hospital, Medical Faculty, Duesseldorf, Germany
56 Marmara University School of Medicine Department of Pediatric Endocrinology, Istanbul,
Turkey
57 Royal Children's Hospital, Parkville, Australia
58 Department of Paediatric Cardiology, Addenbrooke's Hospital, Cambridge University
Hospitals NHS Foundation Trust, Cambridge, UK
59 Child Neurology Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy
60 Department of Cardiology and Intensive Care Medicine, Erasmus Medical Centre,
Rotterdam, Netherlands
61 Private practice Dr A van der Walt, Durbanville, South Africa
62 University of Lille, France
63 Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of
Freiburg, Germany
64 KUNO Children’s University Hospital, Campus St. Hedwig, University of Regensburg, Germany
65 Paediatric Endocrinology Unit, Kaplan Medical Center
66 Hebrew University of Jerusalem, Israel
67 Emma Children’s Hospital, Department of Paediatric Endocrinology, Amsterdam UMC,
University of Amsterdam, Amsterdam, The Netherlands
4
Corresponding author
Dr. W. Edward Visser, Department of Internal Medicine, Erasmus Medical Centre Rotterdam,
Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands ([email protected];
telephone 0031107040570).
5
Abstract 1
Background: Disordered thyroid hormone transport, due to mutations in monocarboxylate 2
transporter 8 (MCT8; gene: SLC16A2), is characterized by intellectual and motor disability due 3
to cerebral hypothyroidism and chronic peripheral thyrotoxicosis. Phenotypic characteristics 4
and natural history of MCT8 deficiency have not been systematically evaluated. 5
Methods: In this international, multicentre, study, retrospective data (2003 to 2019) from 6
patients with MCT8 deficiency followed in 47 centres, was analysed. Our primary objectives 7
were to determine neurocognitive outcomes and overall survival. We also assessed clinical 8
parameters, including anthropometric characteristics, biochemical markers and neuroimaging 9
findings. 10
Results: 151 subjects with 73 different MCT8 (SLC16A2) mutations were included. 21·2% 11
(32/151) of patients died, with main causes of mortality in these patients being pulmonary 12
infection (18·8%) and sudden death (18·8%). The median overall survival was 35·0 (95%CI 8·3-13
61·7) years. Survival differed significantly between individuals who attained head control by 14
the age of 1·5 years or not (log-rank test: p=0·0041; hazard ratio 3·46 95%CI 1·76-8·34). 15
Patients who were underweight during early childhood (1-3 years of age) had an increased 16
risk for death compared with patients who were not underweight at this age (HR 4·71, 95% CI 17
1·26-17·58, p=0·021). The limited motor and cognitive abilities of patients did not improve 18
with age. T3 concentrations were elevated in 95·1% (96/101) and total T4 concentrations were 19
reduced in 89·5% (94/105) of patients. 71·1% (59/83) patients were underweight (<-2SD). 20
Cardiovascular abnormalities were frequent, with 53·2% (25/47) of patients exhibiting 21
elevated systolic blood pressure, and 75·6% (34/45) of patients having premature atrial 22
contractions and 31·3% (20/60) having resting tachycardia. 23
6
Interpretation Our description of characteristics of MCT8 deficiency in a large patient cohort 24
reveals poor survival with a high prevalence of treatable underlying risk factors and provides 25
knowledge which informs clinical management and future evaluation of therapies. 26
Funding Our study was funded by the Netherlands Organisation for Health Research and 27
Development (project number 113303005; to WEV), and the Sherman Foundation (to WEV). 28
29
7
Research in context 30
31
Evidence before this study 32
Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disorder with devastating 33
consequences including intellectual and motor disability due to cerebral hypothyroidism and 34
severe clinical sequelae secondary to chronic peripheral thyrotoxicosis. We searched Pubmed 35
for studies published in English to January 1, 2020, using the search terms “MCT8 deficiency”, 36
“Allan-Herndon-Dudley Syndrome”, “AHDS”, “natural history” and “life expectancy”. Prior to 37
this study, given the rarity of the disorder, knowledge on the phenotypic characteristics, 38
natural history and life expectancy of monocarboxylate transporter 8 (MCT8) deficiency was 39
limited. Previous studies consisted of case reports, had small patient cohorts (<25 patients), 40
and neglected the peripheral features of the disorder. Comprehensive and structured in-depth 41
characterisation of the phenotype of MCT8 deficiency is urgently needed to accelerate early 42
diagnosis and inform management, including the use of a new disease-modifying therapy. 43
44
Added value of this study 45
151 patients from 47 centres across the world were included in the largest study on MCT8 46
deficiency, to our knowledge. This is the first multicentre, international study to provide in-47
depth quantitative data on the natural history and life expectancy of patients with MCT8 48
deficiency. Our data report poor survival in this disorder, with 30% of patients dying in 49
childhood. Having identified pulmonary infection and sudden death (our data suggests cardiac 50
arrhythmia as underlying basis) as the major causes of mortality, timely intervention with Triac 51
8
therapy may ameliorate the poor prognosis in this disease. Also, the identification of 52
underweight being strongly linked to survival provides a direct target for clinical management. 53
Our detailed description of key clinical features together with biochemical and radiological 54
correlates constitutes a signature for the disorder which may facilitate its early diagnosis and 55
discrimination of this entity from other developmental disorders. Our data will be used as 56
natural history control data for an ongoing trial of with Triac in young children with MCT8 57
deficiency (NCT02396459). These data will also be important for future clinical trials 58
investigating treatment options for MCT8 deficiency, such as gene therapy. 59
60
Implications of all the available evidence 61
Systemic in-depth description of international natural history data will inform clinical 62
management of patients with MCT8 deficiency. Our findings underscore the need for a 63
multidisciplinary approach in the management and follow-up of patients with MCT8 64
deficiency. The current data indicate a unique combination of clinical presentation, 65
biochemical markers and brain imaging features that will enhance early diagnosis. The low T4 66
concentrations measured in the neonatal screening indicates that current neonatal screening 67
strategy holds potential to detect MCT8 deficiency. These observations hinting at the 68
possibility of early diagnosis are particularly relevant in the context of Triac therapy recently 69
reported, which has the potential to ameliorate the devastating course of the disorder if left 70
untreated. In addition, robust natural history data can be used as controls in clinical trials for 71
rare diseases in which accrual of placebo controls in group might not be feasible. 72
73
9
Introduction 74
Thyroid hormones are crucial for normal physiological processes, particularly 75
neurodevelopment, and regulation of basal metabolic rate, throughout life (1, 2). Intracellular 76
bioavailability of thyroid hormones is governed by membrane transporter proteins that 77
facilitate their cellular entry (3). Monocarboxylate transporter 8 (MCT8) is a specific thyroid 78
hormone transporter that is crucial for transport of triiodothyronine (T3) and thyroxine (T4) 79
in several tissues, including the brain (4-8). Mutations in the gene encoding MCT8 (SLC16A2 80
on chromosome Xq13.2) cause MCT8 deficiency, also known as Allan-Herndon-Dudley 81
syndrome (AHDS), a debilitating disorder with an estimated prevalence of 1 in 70 000 male 82
individuals (9-11). 83
MCT8 deficiency is characterized by profound neurodevelopmental delay and a wide 84
range of severe clinical sequelae secondary to chronic peripheral thyrotoxicosis which cannot 85
be effectively treated with conventional (anti)thyroid drugs (3, 10, 11). In 2019, a clinical trial 86
showed that treatment with triiodothyroacetic acid (Triac) ameliorates key features of 87
peripheral thyrotoxicosis and might improve neurocognitive outcomes if treatment is 88
commenced early in life (12). 89
Robust, comprehensive data regarding the phenotypic characteristics and natural 90
history of patients with MCT8 deficiency are lacking, as the phenotype has only been recorded 91
in single case reports or small case series with related patients [e.g. (13, 14)]. Furthermore, 92
these reports used differing clinical methods precluding consistent assessments, and merely 93
focused on the neurological phenotype, neglecting the peripheral clinical features of the 94
disorder (3, 14). Data on survival and neurodevelopmental outcomes in this disorder are not 95
known. The lack of consistent quantitative knowledge of the natural history and the 96
10
phenotypic spectrum of MCT8 deficiency hampers early diagnosis and uniform clinical 97
management including the evaluation of a disease-modifying therapy. 98
Given the paucity of recorded data and with access to a large patient cohort via an 99
international collaborative network for this rare disorder, we have sought to provide 100
comprehensive and uniform phenotypic characterization of MCT8 deficiency using clinical, 101
radiological, and biochemical data. 102
Methods 103
Study design and participants 104
This international study was initiated on 14 October 2014 by founding a consortium of 105
centres where patients with MCT8 deficiency were followed before and after this date. 106
The key inclusion criterion was genetically confirmed MCT8 deficiency. Additionally, 107
data on first-degree and second-degree male relatives with clinical MCT8 deficiency (when 108
genetic testing was not available at that time) were included. There were no exclusion criteria. 109
Our cohort consisted of patients, evaluated with a standardized protocol, who had been 110
enrolled in the international, multicentre Triac Trial [NCT02060474, (12)] and patients who 111
participated in the named patient program for Triac treatment and historical cases for whom 112
Erasmus MC fulfilled a consultancy role following the first reports of MCT8 deficiency in 2004 113
(10, 11) (figure s1). The group of historical cases therefore contain patients who were alive 114
and patients who were already deceased at time of enrollment. A subgroup of participants 115
has been reported before with available individual case descriptions (n=47), or has been 116
reported on aggregated level (n=46, (12)) (figure s2). For such patients, updated and 117
exhaustive data were collected. For analysis of serum thyroid function tests, only patients 118
11
whose measurements were performed in the central laboratory of the Erasmus MC were 119
considered to avoid inter-assay variation. For in-depth clinical and biochemical phenotyping 120
only those patients were enrolled that either participated in the Triac Trial (12) or in the 121
named patient program to ensure data had been captured by trained personnel and according 122
to standard operating procedures. 123
Ethical considerations 124
This study conforms to the Declaration of Helsinki, Good Clinical Practice guidelines 125
and was evaluated and approved by the appropriate local institutional review boards or ethics 126
committees. However, for the retrospective analysis of existing datasets of patients in routine 127
clinical care, the majority of centres did not require additional specific institutional review 128
board approval. For other centres, studies were either ethically approved or the ethics 129
committee provided a waiver for approval. Informed consent was obtained from the parents 130
or legal representatives of all enrolled patients, unless the relevant institutional review board 131
and/or local regulations had authorized the use of anonymised patient data without additional 132
consent. 133
Procedures 134
An overview of study assessments and investigations is provided in figure s1 and in the 135
Supplementary Methods. 136
Outcomes 137
Our primary objective was to analyse the overall survival of patients with MCT8 138
deficiency and document causes of death. We also compared survival between patients who 139
12
did or did not attain full head control by the age of 1·5 years and between patients who were 140
or were not already underweight by early childhood (between 1-3 years of age). 141
Other key objectives were to document neurocognitive function using uniform criteria 142
and assess their relationship to biological age as a measure of disease progression and 143
developmental outcome and to describe the occurrence of extra-neurological features. 144
Statistical analysis 145
We summarised continuous variables as mean and standard deviation (SD), or median 146
and range. We established overall survival and compared patients with and without full head 147
control and cases who were or were not underweight during early childhood with log-rank 148
analysis. Survival was defined as the age at last date known alive. Hazard ratios were 149
calculated using Cox regression models. Correlations between biological age and scores on 150
different neuropsychological assessments were explored using linear regression. For these 151
analyses, we excluded patients with a less severe neurocognitive phenotype, defined as 152
individuals that attained at least two of the following developmental milestones: talking in 153
simple words, achieving head control, sitting independently, and/or walking with assistance. 154
Higher developmental attainment in these patients is more likely to be due to the milder 155
impact of the underlying MCT8 mutation than to the effect of aging. Assumptions for linear 156
regression analyses were met. All statistical tests were two-sided, and p values of less than 157
0·05 were considered statistically significant. Statistical analyses were performed using 158
GraphPad Prism, version 6 (GraphPad, La Jolla, CA, USA). 159
Role of funding source 160
13
The funder of the study had no role in study design, data collection, data analysis, data 161
interpretation, or writing of the report. The corresponding author had full access to all the 162
data in the study and final responsibility for the decision to submit for publication. 163
Results 164
In 47 centres, 151 patients of 22 different nationalities (8 ethnicities) were enrolled 165
between October 14th 2014 and January 17th 2020 (figure s1), thereby including 50 percent of 166
families reported thus far (figure s2). In 106 cases serum thyroid function tests had been 167
measured in the central laboratory, and 86 had been checked according to standardised 168
protocols for in-depth phenotyping at a median age of 4·8 years (interquartile range [IQR] 1·9-169
9·8, range 0·4-66·8) (figure s1). 170
The demographics and characteristics of the enrolled patients are summarised in table 171
s1. In the 151 enrolled cases, 73 different underlying MCT8 mutations were identified, of 172
which 36 had not been reported before (figure s3). A total of 17 mutations were identified in 173
at least two unrelated families. All 35 missense mutations were located in the transmembrane 174
helices (figure s4). The median age at diagnosis was 24·0 months (range: 0·0-744·0) (figure 175
1A), but the median age at onset of first symptoms was 4·0 months (range: 0·0-13·0) (figure 176
1A). Consequently, the median time to diagnosis was 18·0 months (IQR 7·8-63·0, range 0·0-177
738·0). The most frequently reported initial concerns that prompted medical evaluation were 178
gross developmental delay (78·6%), hypotonia (39·8%), feeding problems (8·2%), and poor 179
weight gain (7·1%) (figure 1B). 180
32 (21·2%) patients had died and the median age of their demise was 10·5 years (IQR 181
5·3-18·8, range 1·6-71·0). The main causes of death reported for these patients were 182
14
pulmonary infections (18·8%), sudden death (18·8%), and aspiration pneumonia (9·4%) (figure 183
1C). In 15 (46·9 %) of 32 deceased subjects the cause of death was unclear and postmortem 184
examinations had not been performed. The median overall survival was 35·0 years (95% CI 185
8·3-61·7; figure 1D). The 10-, 18-, and 60-year survival probabilities were 85% (95% CI 78·0-186
92·0), 69·8% (58·2-80·3), and 34·8% (10·2-59·3), respectively. Patients not attaining full head 187
control by the age of 1·5 years had an increased risk for death compared with patients who 188
did attain head control (HR 3·46, 95% CI 1·76-8·34, p=0·0041; figure 1E). Patients who were 189
underweight during early childhood (1-3 years of age) had an increased risk for death 190
compared with patients who had a normal body weight by this age (HR 4·71, 95% CI 1·26-191
17·58, p=0·021, figure 1F). 192
The prevalence of specific neurological features in patients included in the in-depth 193
phenotyped cohort (N=86, median age 4·8 years, IQR 1·9-9·8, range 0·4-66·8) is reported in 194
table 1 and figure 2, and neurological sequelae are summarized in figure s5 and figure s6. All 195
patients had moderate-to-severe intellectual disability with a severe delay in motor and 196
language development (table s2). Only 6 (7·7%) patients achieved independent sitting and 197
were less severely affected than the other patients (figure 2A). The median score on the Gross 198
Motor Function Measure (GMFM)-88 (15) did not exceed 10% of the total score that should 199
be obtained by healthy 4-year old children (figure 2B, table s2). Among 28 subjects that had 200
been evaluated at a median age of 6·4 years (range 0·4-44·6) with the Bayley Scales of Infant 201
Development (BSID)-III (16), the median developmental age was well-below 12 months on all 202
tested sub-domains (figure 2C-G, figure s7B-F, table s2). Similar findings were obtained with 203
the Vineland Adaptive Behavior Scale (VABS)-II (figure s8, table s2). The scores in any of the 204
developmental domains did not correlate positively with age (e.g. motor skills: GMFM-88 B=-205
0·10 (95% CI, -0·29-0·09; p=0.29), BSID-III fine motor skills B= -0·11 (-0·23 - 0·01; p=0.072), and 206
15
BSID-III gross motor skills B= -0·04(-0·11- 0·02; p=0.17); figure 2C-G) and scores of patients 207
with different age categories were not different (table s2)). 208
Pregnancy and delivery were unremarkable in the majority of cases, with most infants 209
having normal birth weight and head circumference (table 1). At first presentation, most 210
patients had global hypotonia with a pronounced head-lag on vertical suspension and upper 211
trunk slipping through. Typically, by the end of the first year, dystonic posturing of the limbs 212
and neck were noted. Exaggerated deep tendon reflexes were present in 80·3% (57/71) of 213
cases, and 90·5% (67/74) of patients developed hypertonia in wrists, knees or heels with age 214
attributed to dystonia and spasticity. Primitive reflexes remained present in 91·1% (51/56) 215
cases, with a positive tonic neck reflex (81·0%) and glabellar sign (80·0%) being most prevalent, 216
irrespective of patient age. Electro-encephalogram (EEG)-confirmed seizures were observed 217
in 15 (23·1%) of 65 patients, and mostly involved generalized, absence-like episodes without 218
a clear motor component. 219
MRI scans of the brain were available in 13 patients, performed at a median age of 8·0 220
months (range: 5·0-187·0), with 8 patients having at least one follow-up scan available (table 221
1, figure s5, table s3). The most consistent finding was a global delay in myelination, evidenced 222
by diffuse residual hyperintense white matter in specific brain regions on T2-weighted images. 223
Myelination improved with age, but had not fully normalized in the oldest patient (15 years) 224
with available data. The neuroradiological findings were supported by postmortem findings 225
(see supplementary results). 226
Serum thyroid function tests were available in 106 treatment-naïve patients at a 227
median age of 5·3 years (IQR 2·1-11·0, range 0·4-66·8). Serum TSH concentrations were within 228
the normal range in 93 (88·6 %) of 105 patients (figure 3A). Serum free and total T4 229
16
concentrations were below the age-specific lower limit in 94 (88·7 %) of 106 and 94 (89·5%) 230
of 105 patients, respectively (figure 3B and figure s9A). Mean serum T3 concentrations 231
exceeded the age-specific upper limit in 96 (95·1%) of 101 patients (figure 3C), which resulted 232
in a pronounced increase in the T3/T4 ratio (figure s9B). Reverse T3 (rT3) concentrations were 233
decreased in 76 (90·5%) of 84 patients (figure s9C), with a concomitant increase in the T3/rT3 234
ratio (figure s9D). This endocrine signature was present regardless of age (figure s9E-H). In 3 235
out of 7 subjects TRH-stimulation tests showed an inadequate TSH response. In 7 (87·5%) out 236
of 8 subjects in whom T4-based neonatal screening results were available, total T4 237
concentrations were below the 20th percentile (figure 3D), and in 5 out of 8 (60%) below the 238
10th percentile. By contrast, neonatal TSH concentrations were <15 mU/L in 8/8 (100%) of 239
patients with available data (figure s9I). Serum total T4 concentrations were significantly less 240
reduced in patients with less severe versus those with a severe neurocognitive phenotype 241
(1·05±0·22 vs 0·71±0·18 times the age-specific lower limit of normal, p<0·0001) (figure s10A). 242
Serum T3 concentrations were not significantly different between these groups (1·46±0·23 vs 243
1·51±0·44 times the age-specific upper limit of normal, p=0·76)(figure s10B). Consequently, 244
the T3/T4 ratio, a marker of thyroid hormone metabolism in peripheral tissues, was 245
significantly lower in patients with a less severe phenotype (1·44±0·40 vs 2·27±0·91 times the 246
age-specific upper limit of normal, p=0·019) (figure s10C). 247
The main findings of in-depth phenotyping of peripheral clinical features (n=86) are 248
summarised in table 2 and table s4. Body weight for age showed progressive deterioration 249
over time, with 59 (71·1%) of 83 patients being severely underweight (<-2SD) (figure 3E, table 250
2). 27 (35·5%) of 76 patients were tube fed, although impaired swallowing function was 251
reported in 55 (71·4%) of 77 patients. Body height for age also deteriorated with age (figure 252
3F). Delayed sexual maturation was present in 5 (26·3%) patients (figure s11A-D). Among 253
17
patients over 8 years of age, bone mineral density (BMD) was below the 5th percentile, but 254
bone turnover markers were generally within the low-normal range (figure s12A-D). 255
The mean resting heart rate was 110 (±20) beats per minute, with 20 (31·3%) of 64 256
patients exceeding the 90th percentile for age (figure 3G) (17). Systolic blood pressure 257
exceeded the 90th percentile in 25 (53·2%) of 47 patients whereas the diastolic blood pressure 258
exceeded the 90th percentile in 17 (36·2%) of 47 patients (figure 3H) (18, 19). Detailed 259
cardiovascular assessment was available in 50 patients. At the time of evaluation, 47 (94%) of 260
50 patients reportedly had no cardiovascular abnormalities and were not receiving any 261
treatment. 3 (6·0%) of 50 patients had second-degree atrioventricular block (Mobitz I: 1; 262
Mobitz II: 2) and 6 (12·0%) of 50 patients had (incomplete) right bundle branch block. In 263
addition, corrected QT interval (QTc) was above the 98th percentile in three out of 39 (7·7%) 264
patients (table 2, figure s13A). Even though most patients were completely immobile, 24h 265
ambulatory cardiac monitoring showed a high resting heart rate (103±13 beats per minute) 266
with frequent episodes of tachycardia and premature atrial or ventricular contractions (figure 267
3I, table s4). One childhood patient had an episode of atrial fibrillation and another had non-268
sustained ventricular tachycardia (table 2). Cardiac echocardiography studies performed in 26 269
patients revealed dilated aortic root (>+2SD for age, range 2·0-3·4 SD) in 7 (26·9%) patients, 270
and relatively small left ventricular wall dimensions (figure s13B). 271
Serum concentrations of sex hormone binding globulin were elevated in 69 (88·5%) of 272
78 patients (figure 3J, figure s14). Serum alanine aminotransferase, aspartate 273
aminotransferase, and gamma-glutamyl transferase concentrations were mildly elevated in a 274
substantial proportion of patients (table 2, figure s15D-F), and two patients reportedly had an 275
episode of hepatic dysfunction following a (viral) infection. 276
18
43 (84·3%) of 51 patients had low muscle mass. Creatinine concentrations in serum 277
were within the low-normal range for age (figure 3K, s14B). Serum creatine kinase 278
concentrations were mostly low-normal (figure 3L, s14C), with some exceptions in patients 279
with recent seizures or severe dystonic episodes. Other biochemical tests are shown in table 280
s4 and figure s15A-O. 281
Gastroesophageal reflux disease was present in 79·2% (38/48) of patients and this 282
often required pharmacological intervention. Spontaneous gastrointestinal bleeding was 283
reported in 2 patients and was the cause of death in one of them. Constipation was present 284
in 62·3% (37/63) of patients. 29 (69·1%) of 42 patients had recurrent (pulmonary) infections 285
(table 2). 286
Discussion 287
To our knowledge, this international, multicentre, retrospective study reports the 288
quantitative evaluation of the disease characteristics of MCT8 deficiency, in the largest cohort 289
of patients with this disorder. We have documented key clinical features together with 290
biochemical and radiological correlates as well as outcomes in this rare but potentially 291
treatable condition. Our findings will facilitate accurate diagnosis, guide management, and 292
inform conduct of future therapeutic intervention trials. 293
A principal finding is that overall survival of patients with MCT8 deficiency is greatly 294
diminished, with an overall median life expectancy of 35 years. Stratification of analyses 295
revealed that patients who attain full head control are more likely to survive longer than those 296
who do not. Accordingly, attaining full head control, as a marker of improved 297
19
neurodevelopment, could be a relevant endpoint for future therapeutic trials in MCT8 298
deficiency. 299
The most common cause of death was pneumonia, caused either by aspiration or by 300
infections. Aspiration, due to impaired swallowing function, is frequently observed in patients 301
with MCT8 deficiency, and could be mitigated by tube feeding. However, a substantial number 302
of patients that exhibited swallowing problems were not tube fed and thus remained at risk 303
for aspiration. With our study suggesting that being underweight is strongly linked to reduced 304
survival, tube feeding can prevent adverse clinical sequelae and potentially improve life 305
expectancy (20). The second major cause of mortality was sudden death. Although its 306
aetiology remains unclear, available data may suggest a cardiac cause, with the high 307
prevalence of premature atrial and ventricular contractions, which are uncommon in healthy 308
individuals especially in childhood (21-25). We also observed non-sustained ventricular 309
tachycardia and QTc prolongation in some patients, with both considered risk factors for 310
sudden cardiac death. Moreover, a substantial proportion of patients exhibited systolic 311
hypertension and/or tachycardia and had several echocardiographic and electrophysiological 312
cardiac changes that have been linked to these traits. As the vast majority (94·0%) of patients 313
reportedly had no history of cardiac problems, these cardiovascular abnormalities likely 314
remain clinically undiagnosed in this population. This observation calls for inclusion of 315
cardiovascular assessment in the management of this disorder. With loss of body weight and 316
many cardiovascular abnormalities being attributable to chronic thyrotoxicosis, reduction in 317
circulating T3 concentrations in patients could represent effective treatment for these aspects 318
of the disorder. Indeed, in a recent clinical trial, treatment with the thyroid hormone analogue 319
Triac efficiently reduced serum T3 concentrations and improved key clinical features such as 320
20
loss of body weight and reversal of abnormal cardiovascular parameters in MCT8 deficiency 321
(12). 322
The current study also identified several other clinical features that require treatment 323
or close follow-up, of which gastro-esophageal reflux disease, scoliosis, hip luxation, and 324
constipation have the highest prevalence. The presence of mildly elevated aminotransferases 325
and the occurrence of transient hepatic failure in at least three reported cases following a viral 326
infection [this report and (11)], suggests that drugs with hepatotoxic side effects (e.g. anti-327
epileptic drugs as frequently used in this population) should be used with extra caution. 328
Our comprehensive documentation of neurological sequelae in patients with MCT8 329
deficiency revealed that the combination of global hypotonia, hypertonia due to dystonia and 330
spasticity and persistence of primitive reflexes was present in up to 90% of patients. Delayed 331
myelination on MRI was consistent with other studies (14, 26, 27). Taken together, these 332
clinical and neuroimaging characteristics may facilitate early diagnosis of MCT8 deficiency and 333
in discriminating this entity from other neurodevelopmental disorders. 334
Our study highlights major delay in diagnosis of this disorder, with a minority of cases 335
being identified in the first year of life. This is mainly attributable to the non-specific initial 336
clinical features with lack of awareness of the specific characteristics of this disorder among 337
clinicians. Having documented that circulating T3 concentrations are elevated in patients 338
below one year of age, the combination of clinical and radiological features with measurement 339
of serum T3 concentrations may constitute a key clue for early diagnosis. The low T4 340
concentrations measured in patients with MCT8 deficiency in the neonatal screening indicates 341
the potential to diagnose MCT8 deficiency in newborns. This may engender debate on 342
whether modification of the current neonatal screening strategy is warranted. The importance 343
21
of early diagnosis is supported by preclinical studies in which Triac completely prevented 344
abnormal neurological development in animal models of MCT8 deficiency when administrated 345
at birth (28). A future phase 2 clinical trial will investigate the effects of Triac on 346
neurodevelopment, with treatment being commenced at a very young age (NCT02396459). 347
This study has limitations inherent to its retrospective design. In general, such study 348
design is prone to collection of an incomplete dataset, possibly resulting in selection bias. 349
Indeed, most assessments could not be carried out in all patients, resulting in missing data. 350
The cause of this mostly reflected disease characteristics, such as a poor clinical condition of 351
patients, their inability to follow instructions and dystonic posturing that hampered 352
investigations for which patients needed proper positioning. Therefore, some conclusions are 353
based on a limited number of observations. Yet, calculated prevalence rates for many clinical 354
features were similar to those observed in smaller cohort studies and through analysis of 355
existing literature (14). It was also not possible to obtain uniform long-term follow-up data. 356
However, MCT8 deficiency is a rare disorder with surviving patients being located throughout 357
the world such that retrospective analysis of available clinical data was the most suitable way 358
of increasing our understanding of this disorder. In the majority of cases data had been 359
collected uniformly during baseline assessment of patients whether participating in the Triac 360
Trial or in named patient treatment programs, providing an unique opportunity for systematic 361
cross-sectional evaluation of key clinical outcomes. Should MCT8 deficiency result in an 362
increased rate of miscarriage this will likely remain unascertained, resulting in survivor bias. 363
Although selection bias cannot be excluded, probably because not all newly diagnosed cases 364
are brought to our attention and patients who die before the diagnosis has been established 365
are being missed, our study included a substantial proportion of currently diagnosed patients. 366
22
With advent of Triac as possible disease-modifying therapy, a future, prospective cohort study 367
of the natural history of the disorder is unlikely to be possible. 368
In summary, this study provides a comprehensive and structured in-depth 369
characterisation of the phenotype of MCT8 deficiency. The current study first reports poor 370
survival in this disorder, with 30% of patients dying in childhood. Having identified pulmonary 371
infection and sudden death (our data suggests cardiac arrhythmia as underlying basis) as the 372
major causes of mortality, timely intervention with Triac therapy may ameliorate the poor 373
prognosis in this disease. Furthermore, our finding that survival is particularly poor in patients 374
with impaired neurological development (head control) or who are underweight, provides a 375
basis for therapeutic intervention targeted at this subgroup. Our findings underscore the need 376
for a multidisciplinary approach in the management and follow-up of patients with MCT8 377
deficiency. In addition, our observations represent an unique, quantitative dataset of the 378
characteristics of this disorder which may serve as a historical control for future interventional 379
studies in this rare disorder, for which a biological control group is often deemed not feasible. 380
Accordingly, we suggest that this study enhances our understanding of the clinical sequelae 381
and longterm outcome of MCT8 deficiency and also facilitates the diagnosis and management 382
of this disorder. 383
Contributors 384
SG, FSvG, WEV, IFMdC, and MD designed the study, acquired and analysed the results and 385
drafted and approved the manuscript. All other authors contributed to the acquisition, 386
analysis, and interpretation of data, and approved the manuscript. 387
388
23
Declaration of Interest 389
WEV reports grants from Netherlands Organisation for Health Research and Development 390
and from Sherman Foundation during the conduct of the study. WEV, SG, FSvG report other 391
from Rare Thyroid Therapeutics, outside the submitted work. DC reports grants from 392
BioMarine, grants from UCB, grants from A&D pharma, outside the submitted work. 393
MCYdW reports other from Hoffmann-La Roche Ltd, other from Ionis, outside the submitted 394
work.. All other authors declare no competing interests. 395
Acknowledgements 396
We thank the patients for contributing to this study and their families for the ongoing support. 397
Our study was funded by the Netherlands Organisation for Health Research and Development 398
(project number 113303005; to WEV), and the Sherman Foundation (to WEV). The centres in 399
Rotterdam, Berlin, Paris, Prague, Angers and Toulouse are part of the European Reference 400
Network on rare endocrine conditions (Endo-ERN). The centre in Rome is part of the European 401
Reference Network for Rare Neurological Disorders (ERN RND). The centre in Cambridge is 402
supported by the Wellcome Trust and NIHR Biomedical Research Centre. 403
Data sharing 404
Because of the rarity of MCT8 deficiency, individual participant data beyond that reported 405
here will not be shared, to safeguard patient privacy. 406
407
408
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Legends to the Figures 508
Figure 1 – Panel A graphically presents the mean ± SEM (black lines) age at onset of symptoms 509
and the age at time of diagnosis. Grey dots represent measurements in individual patients. 510
Panel B shows the most commonly reported features that prompted parents to seek medical 511
attention. Panel C shows the causes of death in patient with MCT8 deficiency based on the 512
available information derived from the 32 patients in our cohort who died at a median age of 513
10·5 years (IQR 5·3-18·8, range 1·6-71·0). HR: hazard ratio, calculated using Cox regression 514
models. Panel D shows the overall survival based on age at last follow-up (Kaplan-Meier 515
estimates). Panel E shows the Kaplan-Meier estimates of MCT8-specific survival in patients 516
who attained head control (red line) by the age of 1·5 years versus those who did not (blue 517
line) and panel F those in patients with underweight (blue line) versus normal body weight 518
(red line) in early childhood (1-3 years of age). Underweight was defined as a body weight for 519
age z score <-2SDs (or below the fifth percentile), following the definition of the World Health 520
Organization. Please note, since potential confounding factors could not be accounted for, a 521
causal relationship on survival cannot be inferred from the applied stratification variables. 522
Figure 2 – Panel A shows the prevalence of clinical, radiological and developmental key 523
features in MCT8 deficiency. Bars indicate the proportion of patients presenting the indicated 524
feature at first presentation. Panel B represents the gross motor function development in 525
patients with MCT8 deficiency measured by the Gross Motor Function Measure (GMFM)-88 526
(15). A 100% score indicates the level of development that is achieved by a healthy 4-year old 527
child. Panel C shows cognition, panel D receptive language, panel E expressive language, panel 528
F fine motor skills and panel G gross motor skills, measured by the respective sub-domains of 529
the Bayley Scales of Infant Development (BSID)-III (16). Scores are expressed as developmental 530
age in months. In panels B-G, the left figures indicate measurements in individual patients 531
27
(blue dots) and black lines indicate the median score and IQR from all patients with available 532
data. The right figures show the relation between the neurodevelopmental scores versus the 533
chronological age using linear regression. A few, predominantly older patients , with an 534
unexpectedly less severe neurocognitive phenotype (defined as having at least 2 of the 535
following abilities: talk in simple words, attain head control, independent sitting, and/or 536
walking with assistance) were excluded from the regression analysis (n=4 for GMFM-88 in 537
panel B, and n=1 for BSID-III in panel C-G), which focused on individuals with classical sequelae 538
of severe MCT8 deficiency (indicated with grey dashed lines in the left figure of each panel; 539
n=40 for GMFM-88 in panel A, and n=27 for BSID-III in panel C-G). Linear regression was used 540
to plot the trend (blue solid lines) and the 95% confidence intervals (blue dotted lines). Besides 541
age, no other factors were considered in the models. Patients harboring the same genetic 542
mutation are displayed in the same color: p.F230del (green), c.651-652+20del (blue), G564R 543
(purple), p.V566X (pink), and R271H (orange). Unique mutations are colored in grey. 544
Figure 3 – Mean ± SEM (black lines) serum concentrations of thyroid stimulating hormone 545
(TSH) (n=106) (panel A) and free T4 (n=106) (panel B). Blue dots represent measurements in 546
individual patients and grey areas the normal range. Panel C presents the serum total T3 547
concentrations versus age (n=101). Panel D shows the available results on total T4 548
measurements during neonatal screening expressed in SDs (n=8). See figure s9I for TSH 549
measurements during neonatal screening. Panel E shows the natural course of bodyweight 550
change in patients with MCT8 deficiency. Blue dots represent available historical bodyweight 551
measurements (n=300) in 86 untreated patients. Non-linear (third order) polynomial 552
regression was used to plot the trend with its 95% error band. Similarly, panel F shows the 553
natural course of body height. Accurate measurement of body height can be hampered by 554
muscle contractions and involuntary movements. Panel G shows the resting heart rate by age 555
28
(n=64). Normal range in healthy children is derived from (17). Panel H shows the mean ± SEM 556
diastolic and systolic blood pressure (n=47). The orange line represents the threshold for 557
classification as elevated blood pressure and the red line the threshold of hypertension, as 558
defined by the guidelines from the American Academy of Pediatrics (18) and the American 559
College of Cardiology and American Heart Association (19). Panel I shows the mean ± SEM 560
(black lines) occurrence of indicated features during 24h cardiac monitoring in 45 individuals. 561
Serum concentration of sex hormone binding globulin (SHBG) (n=78) (panel J), creatinine 562
(n=79) (panel K), and creatine kinase (n=79) (panel L) are expressed relative to the age-specific 563
lower (panel K) or upper (panel J and L) limit of the normal range. Abbreviations: TSH, thyroid 564
stimulating hormone; T4, thyroxine; T3, triiodothyronine; PACs, premature atrial contractions; 565
PVCs premature ventricular contractions; CK, creatine kinase; SHBG, sex hormone binding 566
globulin; LL, lower limit; UL, upper limit. The absolute mean values of all parameters are 567
summarized in table s4. 568
569
570
1
Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre
cohort study
Stefan Groeneweg MD1, Ferdy S van Geest MD1, Prof Ayhan Abacı MD2, Alberto Alcantud MD3,
Gautem P Ambegaonkar MRCPCH4, Christine M Armour MD5, Priyanka Bakhtiani MD6, Diana
Barca MD7, Prof Enrico S Bertini MD8, Ingrid M van Beynum MD9, Prof Nicola Brunetti-Pierri
MD10,11, Marianna Bugiani MD12,13, Marco Cappa MD14, Gerarda Cappuccio MD10,11, Barbara
Castellotti MD15, Claudia Castiglioni MD16, Prof Krishna Chatterjee FRCP17, Irenaeus FM de Coo
MD18, Prof Régis Coutant MD19, Prof Dana Craiu MD7, Patricia Crock DMed20, Christian
DeGoede FRCPCH21, Korcan Demir MD2, Alice Dica MD7, Prof Paul Dimitri PhD22, Anna Dolcetta
Capuzzo MD1,23, Marjolein HG Dremmen MD24, Rachana Dubey DM25, Anina Enderli MD26, Jan
Fairchild FRACP27, Jonathan Gallichan MBChB28, Belinda George DM29, Evelien F Gevers PhD30,
Annette Hackenberg MD26, Zita Halász MD31, Bianka Heinrich26, Tony Huynh PhD32,33,34, Anna
Kłosowska MD35, Prof Marjo S van der Knaap MD12, Marieke M van der Knoop MSc18, Prof
Daniel Konrad MD36, David A Koolen MD37, Prof Heiko Krude MD38, Amy Lawson–Yuen MD39,
Prof Jan Lebl MD40, Michaela Linder-Lucht MD41, Cláudia F Lorea MD42, Charles M Lourenço
MD43, Roelineke J Lunsing MD44, Greta Lyons RGN17, Jana Malikova MD40, Edna E Mancilla
MD45, Anne McGowan MD17, Prof Veronica Mericq MD46,47, Felipe Monti Lora MD48, Carla
Moran MB17, Katalin E Müller MD49, Isabelle Oliver-Petit MD50, Laura Paone MD14, Praveen G
Paul MD51, Prof Michel Polak MD52, Francesco Porta MD53, Fabiano O Poswar MD54, Christina
Reinauer MD55, Klara Rozenkova MD40, Tuba Seven Menevse MD56, Peter Simm MBBS57, Anna
Simon MD51, Yogen Singh MD58, Marco Spada MD53, Jet van der Spek MD37, Milou AM Stals
MD1, Athanasia Stoupa MD52, Gopinath M Subramanian FRACP20, Davide Tonduti MD59, Prof
Serap Turan MD56, Corstiaan A den Uil MD60, Joel Vanderniet MBBS20, Adri van der Walt MD61,
Prof Jean-Louis Wémeau MD62, Jolante Wierzba MD35, Marie-Claire Y de Wit MD18, Nicole I
Wolf MD12, Michael Wurm MD63,64, Federica Zibordi MD59, Prof Amnon Zung MD65,66, Nitash
Zwaveling-Soonawala MD67, W Edward Visser MD1
1 Academic Center for Thyroid Diseases, Erasmus Medical Centre, Rotterdam, Netherlands
2 Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
3 Pediatric neurology section, Hospital Francesc de Borja de Gandia, Spain
4 Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University
Hospitals NHS Foundation Trust, Cambridge, UK
5 Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital
of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
6 University of Louisville, Kentucky, USA
7 Paediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania; Department
of Neurosciences, Paediatric Neurology Discipline II, Carol Davila University of Medicine,
Bucharest, Romania
8 Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's
Research Hospital IRCCS, Rome, Italy
Manuscript with revisions highlighted
2
9 Sophia Children's Hospital, Division of Paediatric Cardiology, Erasmus Medical Centre,
Rotterdam, Netherlands
10 Department of Translational Medicine, Federico II University, 80131 Naples, Italy
11 Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy
12 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, The Netherlands.
13 Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical
Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
14 Division of Endocrinology, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy
15 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo
Besta, Milan
16 Departamento de Neurologia Pediatrica, Clinica Las Condes, Santiago, Chile
17 Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of
Cambridge, Cambridge, UK
18 Sophia Children's Hospital, Department of Paediatric Neurology, Erasmus Medical Centre,
Rotterdam, Netherlands
19 Department of Pediatric Endocrinology and Diabetology, University Hospital, Angers,
France
20 John Hunter Children’s Hospital and University of Newcastle, Newcastle, NSW Australia
21 Lancashire Teaching Hospitals NHS Trust
22 Sheffield Children’s NHS Foundation Trust, Sheffield Hallam University and University of
Sheffield
23 Università Vita-Salute San Raffaele, Milan, Italy
24 Sophia Children's Hospital, Division of Paediatric Radiology, Erasmus Medical Centre,
Rotterdam, Netherlands
25 Medanta Superspeciality Hospital, Indore, India
26 Department of Neuropediatrics, University Children’s Hospital Zurich, Steinwiesstrasse 75, 8032 Zürich, Switzerland
27 Department of Diabetes and Endocrinology, Women’s and Children’s Hospital , North Adelaide 5066 South Australia
28 Plymouth Hospitals NHS Trust, Plymouth, PL6 8DH, UK
29 Department of Endocrinology, St. John’s Medical College Hospital, Bengaluru
30 Centre for Endocrinology, William Harvey Research institute, Queen Mary University
London and Dept of Paediatric Endocrinology, Barts Health NHS Trust
31 Department of Paediatrics, Semmelweis University, Budapest
32 Department of Endocrinology & Diabetes, Queensland Children’s Hospital, South Brisbane Queensland, Australia
33 Department of Chemical Pathology, Mater Pathology, South Brisbane, Queensland,
Australia
34 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
35 Medical University of Gdańsk, Department of Paediatrics, Haemathology & Oncology, Department of General Nursery, Gdańsk, Poland
36 Division of Pediatric Endocrinology and Diabetology and Children’s Research Center, University Children's Hospital, CH-8032 Zurich, Switzerland
37 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour,
Radboud university medical center (Radboudumc), Nijmegen, The Netherlands
3
38 Department of Paediatric Endocrinology and Diabetology, Charité-Universitätsmedizin
Berlin, Berlin, Germany
39 Genomics Institute Mary Bridge Children's Hospital, MultiCare Health System Tacoma
Washington
40 Department of Paediatrics, Second Faculty of Medicine, Charles University, University
Hospital Motol, Prague, Czech Republic
41 Division of Neuropediatrics and Muscular Disorders, Department of Pediatrics and
Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
42 Teaching Hospital of Universidade Federal de Pelotas, Brazil
43 Faculdade de Medicina - Centro Universitario Estácio de Ribeirão Preto, Brazil
44 Department of Child Neurology, University Medical Center Groningen, University of
Groningen, Groningen, Netherlands
45 Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman
School of Medicine, University of Pennsylvania
46 Institute of Maternal and child Research University of Chile
47 Department of Pediatrics, Clinica Las Condes, Santiago Chile
48 Pediatric Endocrinology Group, Santa Catarina Hospital, São Paulo, Brazil
49 University of Debrecen, Pediatric Institute, Debrecen, Hungary
50 Department of Paediatric Endocrinology and Genetics, Children's Hospital, Toulouse
University Hospital, Toulouse, France
51 Department of Paediatrics, Christian Medical College, Vellore, South India
52 Paediatric Endocrinology, Diabetology and Gynaecology Department, Necker Children's
University Hospital, Imagine Institute, Paris, France
53 Department of Paediatrics, AOU Città della Salute e della Scienza di Torino, University of
Torino, Italy
54 Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
55 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University
Children's Hospital, Medical Faculty, Duesseldorf, Germany
56 Marmara University School of Medicine Department of Pediatric Endocrinology, Istanbul,
Turkey
57 Royal Children's Hospital, Parkville, Australia
58 Department of Paediatric Cardiology, Addenbrooke's Hospital, Cambridge University
Hospitals NHS Foundation Trust, Cambridge, UK
59 Child Neurology Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy
60 Department of Cardiology and Intensive Care Medicine, Erasmus Medical Centre,
Rotterdam, Netherlands
61 Private practice Dr A van der Walt, Durbanville, South Africa
62 University of Lille, France
63 Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of
Freiburg, Germany
64 KUNO Children’s University Hospital, Campus St. Hedwig, University of Regensburg, Germany
65 Paediatric Endocrinology Unit, Kaplan Medical Center
66 Hebrew University of Jerusalem, Israel
67 Emma Children’s Hospital, Department of Paediatric Endocrinology, Amsterdam UMC,
University of Amsterdam, Amsterdam, The Netherlands
4
Corresponding author
Dr. W. Edward Visser, Department of Internal Medicine, Erasmus Medical Centre Rotterdam,
Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands ([email protected];
telephone 0031107040570).
5
Abstract 1
Background: Disordered thyroid hormone transport, due to mutations in monocarboxylate 2
transporter 8 (MCT8; gene: SLC16A2), is characterized by intellectual and motor disability due 3
to cerebral hypothyroidism and chronic peripheral thyrotoxicosis. Phenotypic characteristics 4
and natural history of MCT8 deficiency have not been systematically evaluated. 5
Methods: In this international, multicentre, study, retrospective data (2003 to 2019) from 6
patients with MCT8 deficiency followed in 47 centres, was analysed. Our primary objectives 7
were to determine neurocognitive outcomes and overall survival. We also assessed clinical 8
parameters, including anthropometric characteristics, biochemical markers and neuroimaging 9
findings. 10
Results: 151 subjects with 73 different MCT8 (SLC16A2) mutations were included. 21·2% 11
(32/151) of patients died, with main causes of mortality in these patients being pulmonary 12
infection (18·8%) and sudden death (18·8%). The median overall survival was 35·0 (95%CI 8·3-13
61·7) years. Survival differed significantly between individuals who attained head control by 14
the age of 1·5 years or not (log-rank test: p=0·0041; hazard ratio 3·46 95%CI 1·76-8·34). 15
Patients who were underweight during early childhood (1-3 years of age) had an increased 16
risk for death compared with patients who were not underweight at this age (HR 4·71, 95% CI 17
1·26-17·58, p=0·021). The limited motor and cognitive abilities of patients did not improve 18
with age. T3 concentrations were elevated in 95·1% (96/101) and total T4 concentrations were 19
reduced in 89·5% (94/105) of patients. 71·1% (59/83) patients were underweight (<-2SD). 20
Cardiovascular abnormalities were frequent, with 53·2% (25/47) of patients exhibiting 21
elevated systolic blood pressure, and 75·6% (34/45) of patients having premature atrial 22
contractions and 31·3% (20/60) having resting tachycardia. 23
6
Interpretation Our description of characteristics of MCT8 deficiency in a large patient cohort 24
reveals poor survival with a high prevalence of treatable underlying risk factors and provides 25
knowledge which informs clinical management and future evaluation of therapies. 26
Funding Our study was funded by the Netherlands Organisation for Health Research and 27
Development (project number 113303005; to WEV), and the Sherman Foundation (to WEV). 28
29
7
Research in context 30
31
Evidence before this study 32
Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disorder with devastating 33
consequences including intellectual and motor disability due to cerebral hypothyroidism and 34
severe clinical sequelae secondary to chronic peripheral thyrotoxicosis. We searched Pubmed 35
for studies published in English to January 1, 2020, using the search terms “MCT8 deficiency”, 36
“Allan-Herndon-Dudley Syndrome”, “AHDS”, “natural history” and “life expectancy”. Prior to 37
this study, given the rarity of the disorder, knowledge on the phenotypic characteristics, 38
natural history and life expectancy of monocarboxylate transporter 8 (MCT8) deficiency was 39
limited. Previous studies consisted of case reports, had small patient cohorts (<25 patients), 40
and neglected the peripheral features of the disorder. Comprehensive and structured in-depth 41
characterisation of the phenotype of MCT8 deficiency is urgently needed to accelerate early 42
diagnosis and inform management, including the use of a new disease-modifying therapy. 43
44
Added value of this study 45
151 patients from 47 centres across the world were included in the largest study on MCT8 46
deficiency, to our knowledge. This is the first multicentre, international study to provide in-47
depth quantitative data on the natural history and life expectancy of patients with MCT8 48
deficiency. Our data report poor survival in this disorder, with 30% of patients dying in 49
childhood. Having identified pulmonary infection and sudden death (our data suggests cardiac 50
arrhythmia as underlying basis) as the major causes of mortality, timely intervention with Triac 51
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8
therapy may ameliorate the poor prognosis in this disease. Also, the identification of 52
underweight being strongly linked to survival provides a direct target for clinical management. 53
Our detailed description of key clinical features together with biochemical and radiological 54
correlates constitutes a signature for the disorder which may facilitate its early diagnosis and 55
discrimination of this entity from other developmental disorders. Our data will be used as 56
natural history control data for an ongoing trial of with Triac in young children with MCT8 57
deficiency (NCT02396459). These data will also be important for future clinical trials 58
investigating treatment options for MCT8 deficiency, such as gene therapy. 59
60
Implications of all the available evidence 61
Systemic in-depth description of international natural history data will inform clinical 62
management of patients with MCT8 deficiency. Our findings underscore the need for a 63
multidisciplinary approach in the management and follow-up of patients with MCT8 64
deficiency. The current data indicate a unique combination of clinical presentation, 65
biochemical markers and brain imaging features that will enhance early diagnosis. The low T4 66
concentrations measured in the neonatal screening indicates that current neonatal screening 67
strategy holds potential to detect MCT8 deficiency. These observations hinting at the 68
possibility of early diagnosis are particularly relevant in the context of Triac therapy recently 69
reported, which has the potential to ameliorate the devastating course of the disorder if left 70
untreated. In addition, robust natural history data can be used as controls in clinical trials for 71
rare diseases in which accrual of placebo controls in group might not be feasible. 72
73
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9
Introduction 74
Thyroid hormones are crucial for normal physiological processes, particularly 75
neurodevelopment, and regulation of basal metabolic rate, throughout life (1, 2). Intracellular 76
bioavailability of thyroid hormones is governed by membrane transporter proteins that 77
facilitate their cellular entry (3). Monocarboxylate transporter 8 (MCT8) is a specific thyroid 78
hormone transporter that is crucial for transport of triiodothyronine (T3) and thyroxine (T4) 79
in several tissues, including the brain (4-8). Mutations in the gene encoding MCT8 (SLC16A2 80
on chromosome Xq13.2) cause MCT8 deficiency, also known as Allan-Herndon-Dudley 81
syndrome (AHDS), a debilitating disorder with an estimated prevalence of 1 in 70 000 male 82
individuals (9-11). 83
MCT8 deficiency is characterized by profound neurodevelopmental delay and a wide 84
range of severe clinical sequelae secondary to chronic peripheral thyrotoxicosis which cannot 85
be effectively treated with conventional (anti)thyroid drugs (3, 10, 11). In 2019, a clinical trial 86
showed that treatment with triiodothyroacetic acid (Triac) ameliorates key features of 87
peripheral thyrotoxicosis and might improve neurocognitive outcomes if treatment is 88
commenced early in life (12). 89
Robust, comprehensive data regarding the phenotypic characteristics and natural 90
history of patients with MCT8 deficiency are lacking, as the phenotype has only been recorded 91
in single case reports or small case series with related patients [e.g. (13, 14)]. Furthermore, 92
these reports used differing clinical methods precluding consistent assessments, and merely 93
focused on the neurological phenotype, neglecting the peripheral clinical features of the 94
disorder (3, 14). Data on survival and neurodevelopmental outcomes in this disorder are not 95
known. The lack of consistent quantitative knowledge of the natural history and the 96
10
phenotypic spectrum of MCT8 deficiency hampers early diagnosis and uniform clinical 97
management including the evaluation of a disease-modifying therapy. 98
Given the paucity of recorded data and with access to a large patient cohort via an 99
international collaborative network for this rare disorder, we have sought to provide 100
comprehensive and uniform phenotypic characterization of MCT8 deficiency using clinical, 101
radiological, and biochemical data. 102
Methods 103
Study design and participants 104
This international study was initiated on 14 October 2014 by founding a consortium of 105
centres where patients with MCT8 deficiency were followed before and after this date. 106
The key inclusion criterion was genetically confirmed MCT8 deficiency. Additionally, 107
data on first-degree and second-degree male relatives with clinical MCT8 deficiency (when 108
genetic testing was not available at that time) were included. There were no exclusion criteria. 109
Our cohort consisted of patients, evaluated with a standardized protocol, who had been 110
enrolled in the international, multicentre Triac Trial [NCT02060474, (12)] and patients who 111
participated in the named patient program for Triac treatment and historical cases for whom 112
Erasmus MC fulfilled a consultancy role following the first reports of MCT8 deficiency in 2004 113
(10, 11) (figure s1). The group of historical cases therefore contain patients who were alive 114
and patients who were already deceased at time of enrollment. A subgroup of participants 115
has been reported before with available individual case descriptions (n=47), or has been 116
reported on aggregated level (n=46, (12)) (figure s2). For such patients, updated and 117
exhaustive data were collected. For analysis of serum thyroid function tests, only patients 118
11
whose measurements were performed in the central laboratory of the Erasmus MC were 119
considered to avoid inter-assay variation. For in-depth clinical and biochemical phenotyping 120
only those patients were enrolled that either participated in the Triac Trial (12) or in the 121
named patient program to ensure data had been captured by trained personnel and according 122
to standard operating procedures. 123
Ethical considerations 124
This study conforms to the Declaration of Helsinki, Good Clinical Practice guidelines 125
and was evaluated and approved by the appropriate local institutional review boards or ethics 126
committees. However, for the retrospective analysis of existing datasets of patients in routine 127
clinical care, the majority of centres did not require additional specific institutional review 128
board approval. For other centres, studies were either ethically approved or the ethics 129
committee provided a waiver for approval. Informed consent was obtained from the parents 130
or legal representatives of all enrolled patients, unless the relevant institutional review board 131
and/or local regulations had authorized the use of anonymised patient data without additional 132
consent. 133
Procedures 134
An overview of study assessments and investigations is provided in figure s1 and in the 135
Supplementary Methods. 136
Outcomes 137
Our primary objective was to analyse the overall survival of patients with MCT8 138
deficiency and document causes of death. We also compared survival between patients who 139
12
did or did not attain full head control by the age of 1·5 years and between patients who were 140
or were not already underweight by early childhood (between 1-3 years of age). 141
Other key objectives were to document neurocognitive function using uniform criteria 142
and assess their relationship to biological age as a measure of disease progression and 143
developmental outcome and to describe the occurrence of extra-neurological features. 144
Statistical analysis 145
We summarised continuous variables as mean and standard deviation (SD), or median 146
and range. We established overall survival and compared patients with and without full head 147
control and cases who were or were not underweight during early childhood with log-rank 148
analysis. Survival was defined as the age at last date known alive. Hazard ratios were 149
calculated using Cox regression models. Correlations between biological age and scores on 150
different neuropsychological assessments were explored using linear regression. For these 151
analyses, we excluded patients with a n unexpectedly less severe neurocognitive phenotype, 152
defined as individuals that attained at least two of the following developmental milestones: 153
talking in simple words, achieving head control, sitting independently, and/or walking with 154
assistance. Higher developmental attainment in these patients is more likely to be due to the 155
milder impact of the underlying MCT8 mutation than to the effect of aging. Assumptions for 156
linear regression analyses were met. All statistical tests were two-sided, and p values of less 157
than 0·05 were considered statistically significant. Statistical analyses were performed using 158
GraphPad Prism, version 6 (GraphPad, La Jolla, CA, USA). 159
Role of funding source 160
13
The funder of the study had no role in study design, data collection, data analysis, data 161
interpretation, or writing of the report. The corresponding author had full access to all the 162
data in the study and had final responsibility for the decision to submit for publication. 163
Results 164
In 47 centres, 151 patients of 22 different nationalities (8 ethnicities) were enrolled 165
between October 14th 2014 and January 17th 2020 (figure s1), thereby including 50 percent of 166
families reported thus far (figure s2). In 106 cases serum thyroid function tests had been 167
measured in the central laboratory, and 86 had been checked according to standardised 168
protocols for in-depth phenotyping at a median age of 4·8 years (interquartile range [IQR] 1·9-169
9·8, range 0·4-66·8) (figure s1). 170
The demographics and characteristics of the enrolled patients are summarised in table 171
s1. In the 151 enrolled cases, 73 different underlying MCT8 mutations were identified, of 172
which 36 had not been reported before (figure s3). A total of 17 mutations were identified in 173
at least two unrelated families. All 35 missense mutations were located in the transmembrane 174
helices (figure s4). The median age at diagnosis was 24·0 months (range: 0·0-744·0) (figure 175
1A), but the median age at onset of first symptoms was 4·0 months (range: 0·0-13·0) (figure 176
1A). Consequently, the median time to diagnosis was 18·0 months (IQR 7·8-63·0, range 0·0-177
738·0). The most frequently reported initial concerns that prompted medical evaluation were 178
gross developmental delay (78·6%), hypotonia (39·8%), feeding problems (8·2%), and poor 179
weight gain (7·1%) (figure 1B). 180
32 (21·2%) patients had died and the median age of their demise was 10·5 years (IQR 181
5·3-18·8, range 1·6-71·0). The main causes of death reported for these patients were 182
14
pulmonary infections (18·8%), sudden death (18·8%), and aspiration pneumonia (9·4%) (figure 183
1C). In 15 (46·9 %) of 32 deceased subjects the cause of death was unclear and postmortem 184
examinations had not been performed. The median overall survival was 35·0 years (95% CI 185
8·3-61·7; figure 1D). The 10-, 18-, and 60-year survival probabilities were 85% (95% CI 78·0-186
92·0), 69·8% (58·2-80·3), and 34·8% (10·2-59·3), respectively. Patients not attaining full head 187
control by the age of 1·5 years had an increased risk for death compared with patients who 188
did attain head control (HR 3·46, 95% CI 1·76-8·34, p=0·0041; figure 1E). Patients who were 189
underweight during early childhood (1-3 years of age) had an increased risk for death 190
compared with patients who were not underweighthad a normal body weight by this age (HR 191
4·71, 95% CI 1·26-17·58, p=0·021, figure 1F). 192
The prevalence of specific neurological features in patients included in the in-depth 193
phenotyped cohort (N=86, median age 4·8 years, IQR 1·9-9·8, range 0·4-66·8) is reported in 194
table 1 and figure 2, and neurological sequelae are summarized in figure s5 and figure s6. All 195
patients had moderate-to-severe intellectual disability with a severe delay in motor and 196
language development (table s2). Only 6 (7·7%) patients achieved independent sitting and 197
were less severely affected than the other patients (figure 2A). The median score on the Gross 198
Motor Function Measure (GMFM)-88 (15) did not exceed 10% of the total score that should 199
be obtained by healthy 4-year old children (figure 2B, table s2). Among 28 subjects that had 200
been evaluated at a median age of 6·4 years (range 0·4-44·6) with the Bayley Scales of Infant 201
Development (BSID)-III (16), the median developmental age was well-below 12 months on all 202
tested sub-domains (figure 2C-G, figure s7B-F, table s2). Similar findings were obtained with 203
the Vineland Adaptive Behavior Scale (VABS)-II (figure s8, table s2). The scores in any of the 204
developmental domains did not correlate positively with age (e.g. motor skills: GMFM-88 B=-205
0·10 (95% CI, -0·29-0·09; p=0.29), BSID-III fine motor skills B= -0·11 (-0·23 - 0·01; p=0.072), and 206
15
BSID-III gross motor skills B= -0·04(-0·11- 0·02; p=0.17); figure 2C-G) and scores of patients 207
with different age categories were not different (table s2)). 208
Pregnancy and delivery were unremarkable in the majority of cases, with most infants 209
having good Apgar scores, normal birth weight at term and head circumference (table 1). At 210
first presentation, most patients had global hypotonia with a pronounced head-lag on vertical 211
suspension and upper trunk slipping through. Typically, by the end of the first year, dystonic 212
posturing of the limbs and neck were noted. Exaggerated deep tendon reflexes were present 213
in 80·3% (57/71) of cases, and 90·5% (67/74) of patients developed hypertonia in wrists, knees 214
or heels with age attributed to dystonia and spasticity. Primitive reflexes remained present in 215
91·1% (51/56) cases, with a positive tonic neck reflex (81·0%) and glabellar sign (80·0%) being 216
most prevalent, irrespective of patient age. Electro-encephalogram (EEG)-confirmed seizures 217
were observed in 15 (23·1%) of 65 patients, and mostly involved generalized, absence-like 218
episodes without a clear motor component. 219
MRI scans of the brain were available in 13 patients, performed at a median age of 8·0 220
months (range: 5·0-187·0), with 8 patients having at least one follow-up scan available (table 221
1, figure s5, table s3). The most consistent finding was a global delay in myelination, evidenced 222
by diffuse residual hyperintense white matter in specific brain regions on T2-weighted images. 223
Myelination improved with age, but had not fully normalized in the oldest patient (15 years) 224
with available data. Most cases showed diffuse cortical and subcortical atrophy with dilatation 225
of the ventricles, widening of the subarachnoid spaces demonstrated by prominence of the 226
supra- and infra-tentorial sulci. These neuroradiological findings were supported by 227
postmortem findings (see supplementary results). 228
16
Serum thyroid function tests were available in 106 treatment-naïve patients at a 229
median age of 5·3 years (IQR 2·1-11·0, range 0·4-66·8). Serum TSH concentrations were within 230
the normal range in 93 (88·6 %) of 105 patients (figure 3A). Serum free and total T4 231
concentrations were below the age-specific lower limit in 94 (88·7 %) of 106 and 94 (89·5%) 232
of 105 patients, respectively (figure 3B and figure s9A). Mean serum T3 concentrations 233
exceeded the age-specific upper limit in 96 (95·1%) of 101 patients (figure 3C), which resulted 234
in a pronounced increase in the T3/T4 ratio (figure s9B). Reverse T3 (rT3) concentrations were 235
decreased in 76 (90·5%) of 84 patients (figure s9C), with a concomitant increase in the T3/rT3 236
ratio (figure s9D). This endocrine signature was present regardless of age (figure s9E-H). In 3 237
out of 7 subjects TRH-stimulation tests showed an inadequate TSH response. In 7 (87·5%) out 238
of 8 subjects in whom T4-based neonatal screening results were available, total T4 239
concentrations were below the 20th percentile (figure 3D), and in 5 out of 8 (60%) below the 240
10th percentile. By contrast, neonatal TSH concentrations were <15 mU/L in 8/8 (100%) of 241
patients with available data (figure s9I). Serum total T4 concentrations were significantly less 242
reduced in patients with less severe versus those with a severe neurocognitive phenotype 243
(1·05±0·22 vs 0·71±0·18 times the age-specific lower limit of normal, p<0·0001) (figure s10A). 244
Serum T3 concentrations were not significantly different between these groups (1·46±0·23 vs 245
1·51±0·44 times the age-specific upper limit of normal, p=0·76)(figure s10B). Consequently, 246
the T3/T4 ratio, a marker of thyroid hormone metabolism in peripheral tissues, was 247
significantly lower in patients with a less severe phenotype (1·44±0·40 vs 2·27±0·91 times the 248
age-specific upper limit of normal, p=0·019) (figure s10C). 249
The main findings of in-depth phenotyping of peripheral clinical features (n=86) are 250
summarised in table 2 and table s4. Body weight for age showed progressive deterioration 251
over time, with 59 (71·1%) of 83 patients being severely underweight (<-2SD) (figure 3E, table 252
17
2). 27 (35·5%) of 76 patients were tube fed, although impaired swallowing function was 253
reported in 55 (71·4%) of 77 patients. Body height for age also deteriorated with age (figure 254
3F). Delayed sexual maturation was present in 5 (26·3%) patients (figure s11A-D). Among 255
patients over 8 years of age, bone mineral density (BMD) was below the 5th percentile, but 256
bone turnover markers were generally within the low-normal range (figure s12A-D). 257
The mean resting heart rate was 110 (±20) beats per minute, with 20 (31·3%) of 64 258
patients exceeding the 90th percentile for age (figure 3G) (17). Systolic blood pressure 259
exceeded the 90th percentile in 25 (53·2%) of 47 patients whereas the diastolic blood pressure 260
exceeded the 90th percentile in 17 (36·2%) of 47 patients (figure 3H) (18, 19). Detailed 261
cardiovascular assessment was available in 50 patients. At the time of evaluation, 47 (94%) of 262
50 patients reportedly had no cardiovascular abnormalities and were not receiving any 263
treatment. 3 (6·0%) of 50 patients had second-degree atrioventricular block (Mobitz I: 1; 264
Mobitz II: 2) and 6 (12·0%) of 50 patients had (incomplete) right bundle branch block. In 265
addition, corrected QT interval (QTc) was above the 98th percentile in three out of 39 (7·7%) 266
patients (table 2, figure s13A). Even though most patients were completely immobile, 24h 267
ambulatory cardiac monitoring showed a high resting heart rate (103±13 beats per minute) 268
with frequent episodes of tachycardia and premature atrial or ventricular contractions (figure 269
3I, table s4). One childhood patient had an episode of atrial fibrillation and another had non-270
sustained ventricular tachycardia (table 2). Cardiac echocardiography studies performed in 26 271
patients revealed dilated aortic root (>+2SD for age, range 2·0-3·4 SD) in 7 (26·9%) patients, 272
and relatively small left ventricular wall dimensions (figure s13B). 273
Serum concentrations of sex hormone binding globulin were elevated in 69 (88·5%) of 274
78 patients (figure 3J, figure s14). Serum alanine aminotransferase, aspartate 275
18
aminotransferase, and gamma-glutamyl transferase concentrations were mildly elevated in a 276
substantial proportion of patients (table 2, figure s15D-F), and two patients reportedly had an 277
episode of hepatic dysfunction following a (viral) infection. 278
43 (84·3%) of 51 patients had low muscle mass. Creatinine concentrations in serum 279
were within the low-normal range for age (figure 3K, s14B). Serum creatine kinase 280
concentrations were mostly low-normal (figure 3L, s14C), with some exceptions in patients 281
with recent seizures or severe dystonic episodes. Other biochemical tests are shown in table 282
s4 and figure s15A-O. 283
Gastroesophageal reflux disease was present in 79·2% (38/48) of patients and this 284
often required pharmacological intervention. Spontaneous gastrointestinal bleeding was 285
reported in 2 patients and was the cause of death in one of them. Constipation was present 286
in 62·3% (37/63) of patients. 29 (69·1%) of 42 patients had recurrent (pulmonary) infections 287
(table 2). 288
Discussion 289
To our knowledge, this international, multicentre, retrospective study reports the 290
quantitative evaluation of the disease characteristics of MCT8 deficiency, in the largest cohort 291
of patients with this disorder. We have documented key clinical features together with 292
biochemical and radiological correlates as well as outcomes in this rare but potentially 293
treatable condition. Our findings will facilitate accurate diagnosis, guide management, and 294
inform conduct of future therapeutic intervention trials. 295
A principal finding is that overall survival of patients with MCT8 deficiency is greatly 296
diminished, with an overall median life expectancy of 35 years. Stratification of analyses 297
19
revealed that patients who attain full head control are more likely to survive longer than those 298
who do not. Accordingly, attaining full head control, as a marker of improved 299
neurodevelopment, could be a relevant endpoint for future therapeutic trials in MCT8 300
deficiency. 301
The most common cause of death was pneumonia, caused either by aspiration or by 302
infections. Aspiration, due to impaired swallowing function, is frequently observed in patients 303
with MCT8 deficiency, and could be mitigated by tube feeding. However, a substantial number 304
of patients that exhibited swallowing problems were not tube fed and thus remained at risk 305
for aspiration. With our study suggesting that being underweight is strongly linked to reduced 306
survival, tube feeding can prevent adverse clinical sequelae and potentially improve life 307
expectancy (20). The second major cause of mortality was sudden death. Although its 308
aetiology remains unclear, available data may suggest a cardiac cause, with the high 309
prevalence of premature atrial and ventricular contractions, which are uncommon in healthy 310
individuals especially in childhood (21-25). We also observed non-sustained ventricular 311
tachycardia and QTc prolongation in some patients, with both considered risk factors for 312
sudden cardiac death. Moreover, a substantial proportion of patients exhibited systolic 313
hypertension and/or tachycardia and had several echocardiographic and electrophysiological 314
cardiac changes that have been linked to these traits. As the vast majority (94·0%) of patients 315
reportedly had no history of cardiac problems, these cardiovascular abnormalities likely 316
remain clinically undiagnosed in this population. This observation calls for inclusion of 317
cardiovascular assessment in the management of this disorder. With loss of body weight and 318
many cardiovascular abnormalities being attributable to chronic thyrotoxicosis, reduction in 319
circulating T3 concentrations in patients could represent effective treatment for these aspects 320
of the disorder. Indeed, in a recent clinical trial, treatment with the thyroid hormone analogue 321
20
Triac efficiently reduced serum T3 concentrations and improved key clinical features such as 322
loss of body weight and reversal of abnormal cardiovascular parameters in MCT8 deficiency 323
(12). 324
The current study also identified several other clinical features that require treatment 325
or close follow-up, of which gastro-esophageal reflux disease, scoliosis, hip luxation, and 326
constipation have the highest prevalence. The presence of mildly elevated aminotransferases 327
and the occurrence of transient hepatic failure in at least three reported cases following a viral 328
infection [this report and (11)], suggests that drugs with hepatotoxic side effects (e.g. anti-329
epileptic drugs as frequently used in this population) should be used with extra caution. 330
Our comprehensive documentation of neurological sequelae in patients with MCT8 331
deficiency revealed that the combination of global hypotonia, hypertonia due to dystonia and 332
spasticity and persistence of primitive reflexes was present in up to 90% of patients. Delayed 333
myelination on MRI was consistent with other studies (14, 26, 27). Taken together, these 334
clinical and neuroimaging characteristics may facilitate early diagnosis of MCT8 deficiency and 335
in discriminating this entity from other neurodevelopmental disorders. 336
Our study highlights major delay in diagnosis of this disorder, with a minority of cases 337
being identified in the first year of life. This is mainly attributable to the non-specific initial 338
clinical features with lack of awareness of the specific characteristics of this disorder among 339
clinicians. Having documented that circulating T3 concentrations are elevated in patients 340
below one year of age, the combination of clinical and radiological features with measurement 341
of serum T3 concentrations may constitute a key clue for early diagnosis. The low T4 342
concentrations measured in patients with MCT8 deficiency in the neonatal screening indicates 343
the potential to diagnose MCT8 deficiency in newborns. This may engender debate on 344
21
whether modification of the current neonatal screening strategy is warranted. The importance 345
of early diagnosis is supported by preclinical studies in which Triac completely prevented 346
abnormal neurological development in animal models of MCT8 deficiency when administrated 347
at birth (28). A future phase 2 clinical trial will investigate the effects of Triac on 348
neurodevelopment, with treatment being commenced at a very young age (NCT02396459). 349
This study has limitations inherent to its retrospective design. In general, such study 350
design is prone to collection of an incomplete dataset, possibly resulting in selection bias. 351
Indeed, most assessments could not be carried out in all patients, resulting in missing data. 352
The cause of this mostly reflected disease characteristics, such as a poor clinical condition of 353
patients, their inability to follow instructions and dystonic posturing that hampered 354
investigations for which patients needed proper positioning. Therefore, some conclusions are 355
based on a limited number of observations. Yet, calculated prevalence rates for many clinical 356
features were similar to those observed in smaller cohort studies and through analysis of 357
existing literature (14). It was also not possible to obtain uniform long-term follow-up data. 358
However, MCT8 deficiency is a rare disorder with surviving patients being located throughout 359
the world such that retrospective analysis of available clinical data was the most suitable way 360
of increasing our understanding of this disorder. In the majority of cases data had been 361
collected uniformly during baseline assessment of patients whether participating in the Triac 362
Trial or in named patient treatment programs, providing an unique opportunity for systematic 363
cross-sectional evaluation of key clinical outcomes. Should MCT8 deficiency result in an 364
increased rate of miscarriage this will likely remain unascertained, resulting in survivor bias. 365
Although selection bias cannot be excluded, probably because not all newly diagnosed cases 366
are brought to our attention and patients who die before the diagnosis has been established 367
are being missed, our study included a substantial proportion of currently diagnosed patients. 368
22
With advent of Triac as possible disease-modifying therapy, a future, prospective cohort study 369
of the natural history of the disorder is unlikely to be possible. 370
In summary, this study provides a comprehensive and structured in-depth 371
characterisation of the phenotype of MCT8 deficiency. The current study first reports poor 372
survival in this disorder, with 30% of patients dying in childhood. Having identified pulmonary 373
infection and sudden death (our data suggests cardiac arrhythmia as underlying basis) as the 374
major causes of mortality, timely intervention with Triac therapy may ameliorate the poor 375
prognosis in this disease. Furthermore, our finding that survival is particularly poor in patients 376
with impaired neurological development (head control) or who are underweight, provides a 377
basis for therapeutic intervention targeted at this subgroup. Our findings underscore the need 378
for a multidisciplinary approach in the management and follow-up of patients with MCT8 379
deficiency. In addition, our observations represent an unique, quantitative dataset of the 380
characteristics of this disorder which may serve as a historical control for future interventional 381
studies in this rare disorder, for which a biological control group is often deemed not feasible. 382
Accordingly, we suggest that this study enhances our understanding of the clinical sequelae 383
and longterm outcome of MCT8 deficiency and also facilitates the diagnosis and management 384
of this disorder. 385
Contributors 386
SG, FSvG, WEV, IFMdC, and MD designed the study, acquired and analysed the results and 387
drafted and approved the manuscript. All other authors contributed to the acquisition, 388
analysis, and interpretation of data, and approved the manuscript. 389
390
23
Declaration of Interest 391
Dr. VisserWEV reports grants from Netherlands Organisation for Health Research and 392
Development and from Sherman Foundation during the conduct of the study. Drs 393
VisserWEV, GroenewegSG, Van GeestFSvG report other from Rare Thyroid Therapeutics, 394
outside the submitted work. Dr. CraiuDC reports grants from BioMarine, grants from UCB, 395
grants from A&D pharma, outside the submitted work. Dr. de WitMCYdW reports other 396
from Hoffmann-La Roche Ltd, other from Ionis, outside the submitted work.The Erasmus 397
Medical Centre (Rotterdam, Netherlands), which employs SG, FSvG, IMvB, MD, MMvdK, 398
CAU, MCYdW, and WEV, might receive royalties from Rare Thyroid Therapeutics (the 399
manufacturer of Triac) in the future, dependent on any future commercialisation. None of 400
the authors will benefit personally from any royalties. Rare Thyroid Therapeutics had no 401
influence on the conduct or analysis of this study. All other authors declare no competing 402
interests. 403
Acknowledgements 404
We thank the patients for contributing to this study and their families for the ongoing support. 405
Our study was funded by the Netherlands Organisation for Health Research and Development 406
(project number 113303005; to WEV), and the Sherman Foundation (to WEV). The centres in 407
Rotterdam, Berlin, Paris, Prague, Angers and Toulouse are part of the European Reference 408
Network on rare endocrine conditions (Endo-ERN). The centre in Rome is part of the European 409
Reference Network for Rare Neurological Disorders (ERN RND). The centre in Cambridge is 410
supported by the Wellcome Trust and NIHR Biomedical Research Centre. 411
Data sharing 412
24
Because of the rarity of MCT8 deficiency, individual participant data beyond that reported 413
here will not be shared, to safeguard patient privacy. 414
415
416
25
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Legends to the Figures 516
Figure 1 – Panel A graphically presents the mean ± SEM (black lines) age at onset of symptoms 517
and the age at time of diagnosis. Grey dots represent measurements in individual patients. 518
Panel B shows the most commonly reported features that prompted parents to seek medical 519
attention. Panel C shows the causes of death in patient with MCT8 deficiency based on the 520
available information derived from the 32 patients in our cohort who died at a median age of 521
10·5 years (IQR 5·3-18·8, range 1·6-71·0). HR: hazard ratio, calculated using Cox regression 522
models. Panel D shows the overall survival based on age at last follow-up (Kaplan-Meier 523
estimates). Panel E shows the Kaplan-Meier estimates of MCT8-specific survival in patients 524
who attained head control (red line) by the age of 1·5 years versus those who did not (blue 525
line) and panel F those in patients with underweight (blue line) versus without normal body 526
weight (red line) underweight in early childhood (1-3 years of age). Underweight was defined 527
as a body weight for age z score <-2SDs (or below the fifth percentile), following the definition 528
of the World Health Organization. Please note, since potential confounding factors could not 529
be accounted for, a causal relationship on survival cannot be inferred from the applied 530
stratification variables. 531
Figure 2 – Panel A shows the prevalence of clinical, radiological and developmental key 532
features in MCT8 deficiency. Bars indicate the proportion of patients presenting the indicated 533
feature at first presentation. Panel B represents the gross motor function development in 534
patients with MCT8 deficiency measured by the Gross Motor Function Measure (GMFM)-88 535
(15). A 100% score indicates the level of development that is achieved by a healthy 4-year old 536
child. Panel C shows cognition, panel D receptive language, panel E expressive language, panel 537
F fine motor skills and panel G gross motor skills, measured by the respective sub-domains of 538
the Bayley Scales of Infant Development (BSID)-III (16). Scores are expressed as developmental 539
28
age in months. In panels B-G, the left figures indicate measurements in individual patients 540
(blue dots) and black lines indicate the median score and IQR from all patients with available 541
data. The right figures show the relation between the neurodevelopmental scores versus the 542
chronological age using linear regression. A few, predominantly older patients , with an 543
unexpectedly less severe neurocognitive phenotype (defined as having at least 2 of the 544
following abilities: talk in simple words, attain head control, independent sitting, and/or 545
walking with assistance) were excluded from the regression analysis (n=4 for GMFM-88 in 546
panel B, and n=1 for BSID-III in panel C-G), which focused on individuals with classical sequelae 547
of severe MCT8 deficiency (indicated with grey dashed lines in the left figure of each panel ; 548
n=40 for GMFM-88 in panel A, and n=27 for BSID-III in panel C-G) Linear regression was used 549
to plot the trend (blue solid lines) and the 95% confidence intervals (blue dotted lines). Besides 550
age, no other factors were considered in the models. Patients harboring the same genetic 551
mutation are displayed in the same color: p.F230del (green), c.651-652+20del (blue), G564R 552
(purple), p.A565fs566X V566X (pink), and R271H (orange). Unique mutations are colored in 553
grey. 554
Figure 3 – Mean ± SEM (black lines) serum concentrations of thyroid stimulating hormone 555
(TSH) (n=106) (panel A) and free T4 (n=106) (panel B). Blue dots represent measurements in 556
individual patients and grey areas the normal range. Panel C presents the serum total T3 557
concentrations versus age (n=101). Panel D shows the available results on total T4 558
measurements during neonatal screening expressed in SDs (n=8). See figure s9I for TSH 559
measurements during neonatal screening. Panel E shows the natural course of bodyweight 560
change in patients with MCT8 deficiency. Blue dots represent available historical bodyweight 561
measurements (n=300) in 86 untreated patients. Non-linear (third order) polynomial 562
regression was used to plot the trend with its 95% error band. Similarly, panel F shows the 563
29
natural course of body height. Accurate measurement of body height can be hampered by 564
muscle contractions and involuntary movements. Panel G shows the resting heart rate by age 565
(n=64). Normal range in healthy children is derived from (17). Panel H shows the mean ± SEM 566
diastolic and systolic blood pressure (n=47). The orange line represents the threshold for 567
classification as elevated blood pressure and the red line the threshold of hypertension, as 568
defined by the guidelines from the American Academy of Pediatrics (18) and the American 569
College of Cardiology and American Heart Association (19). Panel I shows the mean ± SEM 570
(black lines) occurrence of indicated features during 24h cardiac monitoring in 45 individuals. 571
Serum concentration of sex hormone binding globulin (SHBG) (n=78) (panel J), creatinine 572
(n=79) (panel K), and creatine kinase (n=79) (panel L) are expressed relative to the age-specific 573
lower (panel K) or upper (panel J and L) limit of the normal range. Abbreviations: TSH, thyroid 574
stimulating hormone; T4, thyroxine; T3, triiodothyronine; PACs, premature atrial contractions; 575
PVCs premature ventricular contractions; CK, creatine kinase; SHBG, sex hormone binding 576
globulin; LL, lower limit; UL, upper limit. The absolute mean values of all parameters are 577
summarized in table s4. 578
579
580 Formatted: Normal
1
Table 1. In depth phenotyping of neurodevelopmental features
N=86
Age at assessment (years) 4·8 (0·44-66·8)
Perinatal features
Pregnancy duration (weeks) 40·0 (32·0-42·3)
Apgar scores >8 after 5 min (n=16) 15 (93·8)
Term birth weight (grams) 3584 (±517)
Microcephaly (<3th centile) at birth (n=11) 2 (18·2)
Neurological examination
Hypotonia (n=72) 72 (100%)
Primitive reflexes (>1 present) (n=56) 51 (91·1%)
Tonic neck reflex (n=21) 17 (81·0%)
Glabellar sign (n=55) 44 (80·0%)
Startle response (n=25) 17 (68·0%)
Scoliosis (>8 years) (n=17) 15 (88·2%)
Muscle hypoplasia (n=51) 43 (84·3%)
Dystonia (n=69) 57 (82·6%)
Spasticity (n=71) 57 (80·3%)
Urinary / faecal incontinence (>4 years) (n=41) 33 (80·5%)
Feeding problems (n=77) 55 (71·4%)
Hip dislocation (>8 years, n=15) 10 (66·7%)
Plantar extension response (Babinski sign, n=57) 38 (66·7%)
Delayed evoked potentials (<6 months, n=6)* 3 (50·0%)
Sleep problems (n=51) 20 (39·2%)
Tube feeding (n=76) 27 (35·5%)
Strabismus (n=54) 19 (35·2%)
Microcephaly (<3th centile) (n=59) 19 (32·2%)
Nystagmus (n=49) 13 (26·5%)
Extrapyramidal signs (other) (n=28) 7 (25·0%)
Seizures (EEG proven) (n=65) 15 (23·1%)
Apneusis (n=32) 7 (21·9%)
Abnormal hearing (n=44) 1 (2·3%)
Delayed evoked potentials (>1 year, n=3) 0 (0·0%)
Development
Head control (n=77) 19 (24·7%)
Speech (at least 1 word) (n=76) 5 (6·6%)
Independent sitting (n=78) 6 (7·7%)
Independent walking (n=77) 4 (5·2%)
MRI/MRS characteristics*
Normal global anatomy (n=13) 13 (100%)
Delayed myelination (n=13) 13 (100%)
Reduced cerebral white matter volume (n=13) 13 (100%)
Periventricular white matter lesions (n=10) 10 (100%)
Prominent supratentorial ventricular system (n=13) 13 (100%)
Prominent peripheral liquor spaces (n=13) 13 (100%)
Low NAA peak (n=7) 6 (85·7%)
High choline peak (n=7) 6 (85·7%)
Data are median (range), n (%), or mean (±SD). Systematic deep
phenotyping of neurological phenotype in 86 eligible patients. Median age
at last available MRI scan: 18·0 months, range 5·0-187·0); MRS was
available in 7 cases. Details are provided in table s2.
* In particular the brainstem-evoked response audiometry was abnormal
in children < 1 year of age and showed prolongation of the I-V interval.
1
Tables
2
2
Table 2. In depth phenotyping of peripheral features
Characteristic N=106
Serum thyroid function tests
Age at measurement (years) 5·3 (0·4-66·8)
Elevated T3 concentrations (n=101) 96 (95·1%)
Reduced free T4 concentrations (n=106) 94 (88·7%)
Deep phenotyping N=86
Age at assessment (years) 4·8 (0·44-66·8)
Biochemical measurements *
Elevated sex hormone binding globulin (n=78) 69 (88·5%)
Elevated alanine aminotransferase (n=65) 30 (46·2%)
Reduced creatinine (n=79) 22 (27·8%)
Elevated lactate (n=11) 3 (27·3%)
Reduced total cholesterol (n=65) 12 (18·5%)
Elevated aspartate aminotransferase (n=56) 11 (19·6%)
Elevated creatine kinase (n=79) 3 (3·8%)
Clinical features
Low bone mineral density (>8 years, n=5) 5 (100%)
Hypotrophic musculature (n=51) 43 (84·3%)
Gastro-esophageal reflux disease (n=48) 38 (79·2%)
Premature atrial complexes (n=45) 34 (75·6%)
Recurrent (pulmonary) infections (n=42) 29 (69·0%)
Underweight (<-2 SD, n=83) 59 (71·1%)
Constipation (n=63) 37 (58·7%)
Elevated systolic blood pressure ¶ (n=47) 25 (53·2%)
Increased perspiration (n=60) 29 (48·3%)
Short stature (<-2 SD, n=67) 27 (40·3%)
Premature ventricular complexes (n=45) 19 (42·2%)
Tachycardia in rest † (n=64) 20 (31·3%)
Aortic root dilatation (n=26) 7 (26·9%)
Elevated diastolic blood pressure ¶ (n=47) 17 (36·2%)
Delayed sexual maturation (>8 years, n=19) 5 (26·3%)
Cardiac conduction abnormalities ‡ (n=50) 9 (18·0%)
Cryptorchidism (n=49) 9 (18·4%)
Prolonged QTc interval (39) 3 (7·7%)
Supraventricular tachycardia (n=48) 2 (4·2%)
(Non-sustained) ventricular tachycardia (n=48) 2 (4·2%)
Atrial fibrillation (n=48) 1 (2·1%)
Data are median (range), or n (%). Systematic deep phenotyping of the
peripheral phenotype. Please note that most parameters have not been
captured in all patients. All absolute and relative values are provided in
table s4.
* Reduced and elevated indicated concentrations below or above the
normal range (2.5-97.5 centile in the healthy population). † Tachycardia was defined as a resting heart rate above the 90th
percentile for the corresponding age, with cut-offs described by
Fleming and colleagues (17).
‡Three out of 50 patients (5·5%) had a second degree atrioventricular
block (Mobitz I:1; Mobitz II:2) and 6 out of 50 patients (12·0%) had an
(incomplete) right bundle branch block and 1 patient (2·0%) had a left
posterior hemiblock. ¶ Elevated systolic and diastolic blood pressure were defined using the
guidelines from the American Academy of Pediatrics (18) and the
American College of Cardiology and American Heart Association (19).
3
3
0 2 0 4 0 6 0 8 0
0
5 0
1 0 0
U n d e rw e ig h t
N o rm a l w e ig h t
6 7
2 5
2 0
1 0
5
2
0
1
0
1
p a tie n ts even ts
6 7 1 1
2 5 1
H R : 4 · 7 1 (9 5 % C I 1 · 2 6 -1 7 · 5 8 , p = 0 · 0 2 1 )
In d iv id u a ls a t r is kA g e a t la s t fo llo w -u p ( in y e a rs )
Ov
era
ll s
urv
iva
l (%
)
E
BA
DC
OtherAspiration pneumonia
Respiratory infection
Sudden death
Unknown
47%
19%
19%
9%
6%
F
0 2 0 4 0 6 0 8 0 1 0 0
Infe c tio ns
A b no rm a l T F Ts
S e izure s
H yp e rto n ia
L o w b o d y w e ig ht
P o o r w e ig ht g a in
H yp o to nia
D e ve lo p m e nta l d e la y
P ro p o r t io n o f p a t ie n ts (% )
0 2 0 4 0 6 0 8 0
0
5 0
1 0 0
1 4 5 6 8 2 3 8 4
In d iv id u a ls a t r is k
T ota l
p a tie n ts even ts
1 4 5 3 2
A g e a t la s t fo llo w -u p ( in y e a rs )
Ov
era
ll s
urv
iva
l (%
)
1 1 0 1 0 0 1 0 0 0
D ia g no s is
O ns e t s ym p to m s
A g e ( in m o n th s )
0 2 0 4 0 6 0 8 0
0
5 0
1 0 0
N o h e a d c o n tro l
H e a d c o n tro l
9 5
2 3
4 3
1 5
1 0
9
0
5
0
4
p a tie n ts even ts
9 5 2 3
2 3 4
H R : 3 · 4 6 (9 5 % C I 1 · 7 6 -8 · 3 4 , p = 0 · 0 0 4 1 )
In d iv id u a ls a t r is kA g e a t la s t fo llo w -u p ( in y e a rs )
Ov
era
ll s
urv
iva
l (%
)
Figure 1
B
C
D
F
E
A
G
Clin
ical ch
ara
cte
risti
cs
Bra
in M
RI
Acq
uir
ed
skills
0 5 0 1 0 0
A b no rm a l M R S
P ro m ine nt ve ntric le s
P e rive ntric u la r W M L
R e d uc e d c e re b ra l W M V
D e la ye d m ye lina tio n
W a lk ing
S p e e c h
Ind e p e nd e nt s i tting
H e a d c o ntro l
A ta xia
A p ne us is
S e izure s (E E G p ro ve n)
C ho re o a the to s is
S le e p p ro b le m s
B a b ins k i s ig n
H ip luxa tio n (> 8 yrs )
F e e d ing p ro b le m s
S p a s tic i ty
D ys to nia
M us c ula r hyp o p la s ia
S c o lio s is (> 8 yrs )
P rim i tive re fle xe s
H yp o to nia
P re s e n c e ( in % )
0 1 0 2 0 3 0
0
2 5
5 0
7 5
1 0 0
A g e ( in y e a rs )
Gross motor function (GMFM-88)
0
2 5
5 0
7 5
1 0 0
P a tie n ts
To
tal
sc
ore
(%
)
B= -0·10 (-0·29-0·09; p=0.29)
0 1 0 2 0 3 0
0
1 2
2 4
3 6
A g e ( in y e a rs )
0
1 2
2 4
3 6
P a tie n ts
De
ve
lop
me
nta
l a
ge
(m
on
ths
)B= -0·04 (-0·18-0·10; p=0.61)
Cognition (BSID III)
0 1 0 2 0 3 0
0
1 2
2 4
3 6
A g e ( in y e a rs )
Receptive language (BSID III)
B= 0·01 (-0·26- 0·27; p=0.96)
0 1 0 2 0 3 0
0
1 2
2 4
3 6
A g e ( in y e a rs )
Expressive language (BSID III)
B= 0·05(- 0·15- 0·16; p=0.95)
0
1 2
2 4
3 6
P a tie n ts
De
ve
lop
me
nta
l a
ge
(m
on
ths
)
0
1 2
2 4
3 6
P a tie n ts
De
ve
lop
me
nta
l a
ge
(m
on
ths
)
0 1 0 2 0 3 0
0
1 2
2 4
3 6
A g e ( in y e a rs )
Fine motor skills (BSID III)
B= -0·11 (-0·23 - 0·01; p=0.072)
0
1 2
2 4
3 6
P a tie n ts
De
ve
lop
me
nta
l a
ge
(m
on
ths
)
0 1 0 2 0 3 0
0
1 2
2 4
3 6
A g e ( in y e a rs )
Gross motor skills (BSID III)
B= -0·04(-0·11- 0·02; p=0.17)
0
1 2
2 4
3 6
P a tie n ts
De
ve
lop
me
nta
l a
ge
(m
on
ths
)
Figure 2
E F
G
CA DB
I
KH LJ
T S H
0
5
1 0
1 5
(mU
/L)
F re e T 4
0
1 0
2 0
3 0
(pm
ol/
L)
0 5 1 0 1 5 2 0 2 5
0
2
4
6
8
1 0
1 2
A g e (y e a rs )
T3
(n
mo
l/L
)
0 5 1 0 1 5 2 0-1 0
-8
-6
-4
-2
0
2
A g e (y e a rs )
We
igh
t (z
sc
ore
)
0 5 1 0 1 5 2 0-1 0
-8
-6
-4
-2
0
2
A g e (y e a rs )
He
igh
t (z
sc
ore
)
0 5 1 0 1 5 2 0 2 5
0
5 0
1 0 0
1 5 0
p 9 0
p 5 0
p 1 0
A g e (y e a rs )
Re
sti
ng
he
art
ra
te (
bp
m)
6 0 8 0 1 0 0 1 2 0 1 4 0
H e a rt ra te
b p m
1 1 0 1 0 0 1 0 0 0 1 0 0 0 0
P V C s
P A C s
T a c h y c a rd ia
E p is o d e s / 2 4 h
D B P S B P
0
2 0
4 0
6 0
8 0
1 0 0
(Pe
rc
en
tile
)
S H B G
0
1
2
3
4
5
(re
l. t
o U
L n
orm
al)
C re a tin in e
0
1
2
3
(re
l. t
o L
L n
orm
al)
C K
0
1
2
3
(re
l. t
o U
L n
orm
al)
T o ta l T 4 (n e w b o rn )
-3
-2
-1
0
1
2
(SD
)
Figure 3
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