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@article{Oates:2018:10.1002/ana.25241,
author = {Oates, EC and Jones, KJ and Donkervoort, S and Charlton, A and Brammah, S and Smith, JE and Ware, JS and Yau, KS and Swanson, LC and Whiffin, N and Peduto, AJ and Bournazozs, A and Waddell, LB and Farrar, MA and Sampaio, HA and Teoh, HL and Lamont, PJ and Mowat, D and Fitzsimons, RB and Corbett, AJ and Ryan, MM and O'Grady, GL and Sandaradura, SA and Ghaoui, R and Joshi, HB and Marshall, JL and Nolan, MA and Kaur, S and Punetha, J and Topf, A and Harris, E and Bakshi, M and Genetti, CA and Marttila, M and Werlauff, U and Streichenberger, N and Pestronk, A and Mazanti, I and Pinner, JR and Vuillerot, C and Grosmann, C and Camacho, A and Mohassel, P and Leach, ME and Foley, AR and Bharucha-Goebel, D and Collins, J and Connolly, AM and Gilbreath, HR and Iannaccone, ST and Castro, D and Cummings, BB and Webster, RI and Lazaro, L and Vissing, J and Coppens, S and Deconinck, N and Luk, H and Thomas, NH and Foulds, NC and Illingworth, MA and McLean, CA and Phadke, R and Ravenscroft, G and Wit},
doi = {10.1002/ana.25241},
journal = {Annals of Neurology},
pages = {1105--1124},
title = {Congenital titinopathy: comprehensive characterisation and pathogenic insights},
url = {http://dx.doi.org/10.1002/ana.25241},
volume = {83},
year = {2018}
}

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TY  - JOUR
AB  - Objective: Comprehensive clinical characterisation 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 two pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathology and imaging features of these patients.Results: All patients had prenatal or earlyonset 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 two patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fibre size variation, internalised nuclei and cores were common histopathological abnormalities. Caplike structures, whorled or ring fibres, and mitochondrial accumulations were also observed. Muscle MRI showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a nearnormal sized titin protein in all samples.The presence of two 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 one 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/earlyonset disorder.Interpretation: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients and has provided important insights into disease pathogenesis.
AU  - Oates,EC
AU  - Jones,KJ
AU  - Donkervoort,S
AU  - Charlton,A
AU  - Brammah,S
AU  - Smith,JE
AU  - Ware,JS
AU  - Yau,KS
AU  - Swanson,LC
AU  - Whiffin,N
AU  - Peduto,AJ
AU  - Bournazozs,A
AU  - Waddell,LB
AU  - Farrar,MA
AU  - Sampaio,HA
AU  - Teoh,HL
AU  - Lamont,PJ
AU  - Mowat,D
AU  - Fitzsimons,RB
AU  - Corbett,AJ
AU  - Ryan,MM
AU  - O'Grady,GL
AU  - Sandaradura,SA
AU  - Ghaoui,R
AU  - Joshi,HB
AU  - Marshall,JL
AU  - Nolan,MA
AU  - Kaur,S
AU  - Punetha,J
AU  - Topf,A
AU  - Harris,E
AU  - Bakshi,M
AU  - Genetti,CA
AU  - Marttila,M
AU  - Werlauff,U
AU  - Streichenberger,N
AU  - Pestronk,A
AU  - Mazanti,I
AU  - Pinner,JR
AU  - Vuillerot,C
AU  - Grosmann,C
AU  - Camacho,A
AU  - Mohassel,P
AU  - Leach,ME
AU  - Foley,AR
AU  - Bharucha-Goebel,D
AU  - Collins,J
AU  - Connolly,AM
AU  - Gilbreath,HR
AU  - Iannaccone,ST
AU  - Castro,D
AU  - Cummings,BB
AU  - Webster,RI
AU  - Lazaro,L
AU  - Vissing,J
AU  - Coppens,S
AU  - Deconinck,N
AU  - Luk,H
AU  - Thomas,NH
AU  - Foulds,NC
AU  - Illingworth,MA
AU  - McLean,CA
AU  - Phadke,R
AU  - Ravenscroft,G
AU  - Witting,N
AU  - Hackman,P
AU  - Richard,I
AU  - Cooper,ST
AU  - Kamsteeg,EJ
AU  - Hoffman,EP
AU  - Bushby,K
AU  - Straub,V
AU  - Udd,B
AU  - Ferreiro,A
AU  - North,KN
AU  - Clarke,NF
AU  - Lek,M
AU  - Beggs,AH
AU  - Bonnermann,CG
AU  - MacArthur,DG
AU  - Granzier,H
AU  - Davis,MR
AU  - Laing,NG
DO  - 10.1002/ana.25241
EP  - 1124
PY  - 2018///
SN  - 0364-5134
SP  - 1105
TI  - Congenital titinopathy: comprehensive characterisation and pathogenic insights
T2  - Annals of Neurology
UR  - http://dx.doi.org/10.1002/ana.25241
UR  - http://hdl.handle.net/10044/1/60869
VL  - 83
ER  -

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