Congenital Titinopathy: Comprehensive characterization and pathogenic insights
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Congenital Titinopathy : Comprehensive characterization and pathogenic insights. / Oates, Emily C.; Jones, Kristi J.; Donkervoort, Sandra; Charlton, Amanda; Brammah, Susan; Smith, John E.; Ware, James S.; Yau, Kyle S.; Swanson, Lindsay C.; Whiffin, Nicola; Peduto, Anthony J.; Bournazos, Adam; Waddell, Leigh B.; Farrar, Michelle A.; Sampaio, Hugo A.; Teoh, Hooi Ling; Lamont, Phillipa J.; Mowat, David; Fitzsimons, Robin B.; Corbett, Alastair J.; Ryan, Monique M.; O'Grady, Gina L.; Sandaradura, Sarah A.; Ghaoui, Roula; Joshi, Himanshu; Marshall, Jamie L.; Nolan, Melinda A.; Kaur, Simranpreet; Punetha, Jaya; Töpf, Ana; Harris, Elizabeth; Bakshi, Madhura; Genetti, Casie A.; Marttila, Minttu; Werlauff, Ulla; Streichenberger, Nathalie; Pestronk, Alan; Mazanti, Ingrid; Pinner, Jason R.; Vuillerot, Carole; Grosmann, Carla; Camacho, Ana; Mohassel, Payam; Leach, Meganne E.; Foley, A. Reghan; Bharucha-Goebel, Diana; Collins, James; Connolly, Anne M.; Gilbreath, Heather R.; Iannaccone, Susan T.; Castro, Diana; Cummings, Beryl B.; Webster, Richard I.; Lazaro, Leïla; Vissing, John; Coppens, Sandra; Deconinck, Nicolas; Luk, Ho Ming; Thomas, Neil H.; Foulds, Nicola C.; Illingworth, Marjorie A.; Ellard, Sian; McLean, Catriona A.; Phadke, Rahul; Ravenscroft, Gianina; Witting, Nanna; Hackman, Peter; Richard, Isabelle; Cooper, Sandra T.; Kamsteeg, Erik Jan; Hoffman, Eric P.; Bushby, Kate; Straub, Volker; Udd, Bjarne; Ferreiro, Ana; North, Kathryn N.; Clarke, Nigel F.; Lek, Monkol; Beggs, Alan H.; Bönnemann, Carsten G.; MacArthur, Daniel G.; Granzier, Henk; Davis, Mark R.; Laing, Nigel G.
I: Annals of Neurology, Bind 83, Nr. 6, 2018, s. 1105-1124.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Congenital Titinopathy
T2 - Comprehensive characterization and pathogenic insights
AU - Oates, Emily C.
AU - Jones, Kristi J.
AU - Donkervoort, Sandra
AU - Charlton, Amanda
AU - Brammah, Susan
AU - Smith, John E.
AU - Ware, James S.
AU - Yau, Kyle S.
AU - Swanson, Lindsay C.
AU - Whiffin, Nicola
AU - Peduto, Anthony J.
AU - Bournazos, Adam
AU - Waddell, Leigh B.
AU - Farrar, Michelle A.
AU - Sampaio, Hugo A.
AU - Teoh, Hooi Ling
AU - Lamont, Phillipa J.
AU - Mowat, David
AU - Fitzsimons, Robin B.
AU - Corbett, Alastair J.
AU - Ryan, Monique M.
AU - O'Grady, Gina L.
AU - Sandaradura, Sarah A.
AU - Ghaoui, Roula
AU - Joshi, Himanshu
AU - Marshall, Jamie L.
AU - Nolan, Melinda A.
AU - Kaur, Simranpreet
AU - Punetha, Jaya
AU - Töpf, Ana
AU - Harris, Elizabeth
AU - Bakshi, Madhura
AU - Genetti, Casie A.
AU - Marttila, Minttu
AU - Werlauff, Ulla
AU - Streichenberger, Nathalie
AU - Pestronk, Alan
AU - Mazanti, Ingrid
AU - Pinner, Jason R.
AU - Vuillerot, Carole
AU - Grosmann, Carla
AU - Camacho, Ana
AU - Mohassel, Payam
AU - Leach, Meganne E.
AU - Foley, A. Reghan
AU - Bharucha-Goebel, Diana
AU - Collins, James
AU - Connolly, Anne M.
AU - Gilbreath, Heather R.
AU - Iannaccone, Susan T.
AU - Castro, Diana
AU - Cummings, Beryl B.
AU - Webster, Richard I.
AU - Lazaro, Leïla
AU - Vissing, John
AU - Coppens, Sandra
AU - Deconinck, Nicolas
AU - Luk, Ho Ming
AU - Thomas, Neil H.
AU - Foulds, Nicola C.
AU - Illingworth, Marjorie A.
AU - Ellard, Sian
AU - McLean, Catriona A.
AU - Phadke, Rahul
AU - Ravenscroft, Gianina
AU - Witting, Nanna
AU - Hackman, Peter
AU - Richard, Isabelle
AU - Cooper, Sandra T.
AU - Kamsteeg, Erik Jan
AU - Hoffman, Eric P.
AU - Bushby, Kate
AU - Straub, Volker
AU - Udd, Bjarne
AU - Ferreiro, Ana
AU - North, Kathryn N.
AU - Clarke, Nigel F.
AU - Lek, Monkol
AU - Beggs, Alan H.
AU - Bönnemann, Carsten G.
AU - MacArthur, Daniel G.
AU - Granzier, Henk
AU - Davis, Mark R.
AU - Laing, Nigel G.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1002/ana.25241
DO - 10.1002/ana.25241
M3 - Journal article
C2 - 29691892
AN - SCOPUS:85048683016
VL - 83
SP - 1105
EP - 1124
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 6
ER -
ID: 201514721