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Ann Neurol. 2018 Jun;83(6):1105-1124. doi: 10.1002/ana.25241.

Congenital Titinopathy: Comprehensive characterization and pathogenic insights.

Author information

1
Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
2
Institute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
3
Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
4
School of Biotechnology and Biomolecular Sciences, Faculty of Science, The University of New South Wales, Sydney, New South Wales, Australia.
5
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
6
Department of Histopathology, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
7
Electron Microscope Unit, Department of Anatomical Pathology, Concord Repatriation General Hospital, Concord, Sydney, New South Wales, Australia.
8
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
9
National Heart and Lung Institute and MRC London Institute of Medical Science, Imperial College London, London, United Kingdom.
10
Royal Brompton and Harefield Hospitals NHS Trust, London, United Kingdom.
11
Institute for Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
12
Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
13
Department of Radiology, Westmead Hospital, Sydney, New South Wales, Australia.
14
University of Sydney Western Clinical School, Sydney, New South Wales, Australia.
15
Department of Neurology, Sydney Children's Hospital, Sydney, New South Wales, Australia.
16
School of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
17
Neurogenetic Unit, Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia.
18
Department of Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia.
19
Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
20
Department of Neurology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
21
Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
22
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
23
University of Melbourne, Parkville, Victoria, Australia.
24
Paediatric Neuroservices, Starship Child Health, Auckland, New Zealand.
25
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
26
Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.
27
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC.
28
Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC.
29
John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
30
Department of Clinical Genetics, Liverpool Hospital, Sydney, New South Wales, Australia.
31
Danish National Rehabilitation Center for Neuromuscular Diseases, Aarhus, Denmark.
32
Neuropathology Department, Hospices Civils Lyon, Claude Bernard University, Lyon1, France.
33
NeuroMyogene Institute, CNRS UMR 5310, INSERM U1217, Lyon, France.
34
Department of Neurology, Washington University School of Medicine, Saint Louis, MO.
35
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO.
36
Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
37
Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia.
38
Woman-Mother-Child Hospital, Hospices Civils Lyon, Bron, France.
39
Claude Bernard University Lyon1, France.
40
University of California, San Diego/Rady Children's Hospital, San Diego, CA.
41
Child Neurology Unit, Department of Neurology, October 12 University Hospital, Faculty of Medicine, Complutense University, Madrid, Spain.
42
Division of Neurology, Children's National Health System, Washington, DC.
43
Mercy Clinic Pediatric Neurology, Springfield, MO.
44
Neuromuscular Division, Departments of Neurology and Pediatrics, Washington University School of Medicine, Saint Louis, MO.
45
Department of Advanced Practice, Children's Medical Center of Dallas, Dallas, TX.
46
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
47
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX.
48
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
49
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA.
50
T. Y. Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
51
Pediatric Service, Basque Coast Hospital Center, Bayonne, France.
52
Neuromuscular Clinic and Research Unit, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
53
Department of Pediatric Neurology, Neuromuscular Reference Center, Erasmus Hospital, Free University of Brussels, Brussels, Belgium.
54
Department of Pediatric Neurology, Neuromuscular Reference Center, Queen Fabiola Children's University Hospital, Free University of Brussels, Brussels, Belgium.
55
Clinical Genetic Service, Department of Health, Hong Kong, China.
56
Department of Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
57
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
58
University of Exeter Medical School, Exeter, United Kingdom.
59
Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
60
Department of Anatomical Pathology, Alfred Hospital, Melbourne, Victoria, Australia.
61
Faculty of Medicine, Nursing, and Health Sciences, Monash University, Melbourne, Victoria, Australia.
62
National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, United Kingdom.
63
Harry Perkins Institute, University of Western Australia, Nedlands, Western Australia, Australia.
64
Copenhagen Neuromuscular Unit and Department of Neurology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark.
65
Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Helsinki, Finland.
66
Généthon, INSERM U951, INTEGRARE Research Unit, Évry, France.
67
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
68
Neuromuscular Research Center, Tampere University and University Hospital, Neurology, Tampere, Finland.
69
Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
70
Vaasa Central Hospital, Department of Neurology, Vaasa, Finland.
71
Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptative Biology, BFA, Paris Diderot University/CNRS, Sorbonne Paris Cité, Paris, France.
72
Public Hospital Network of Paris, Paris-East Reference Center Neuromuscular Diseases, Pitié-Salpêtrière Hospital Group, Paris, France.
73
Department of Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia.

Abstract

OBJECTIVE:

Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

METHODS:

Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.

RESULTS:

All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.

INTERPRETATION:

This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

PMID:
29691892
PMCID:
PMC6105519
[Available on 2019-06-01]
DOI:
10.1002/ana.25241

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