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 -