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Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin

Ohlsson, Monica; Hedberg, Carola; Brådvik, Björn LU ; Lindberg, Christopher; Tajsharghi, Homa; Danielsson, Olof; Melberg, Atle; Udd, Bjarne; Martinsson, Tommy and Oldfors, Anders (2012) In Brain 135(6). p.1682-1694
Abstract
Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function... (More)
Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T > C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
myopathy, respiratory failure, exome sequencing, titin, mutation
in
Brain
volume
135
issue
6
pages
1682 - 1694
publisher
Oxford University Press
external identifiers
  • wos:000304538900005
  • scopus:84861563537
ISSN
1460-2156
DOI
10.1093/brain/aws103
language
English
LU publication?
yes
id
409fdd11-bf8d-4d46-bead-662d1c8e8e33 (old id 2906473)
date added to LUP
2012-08-01 09:46:29
date last changed
2017-11-05 03:06:33
@article{409fdd11-bf8d-4d46-bead-662d1c8e8e33,
  abstract     = {Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T > C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.},
  author       = {Ohlsson, Monica and Hedberg, Carola and Brådvik, Björn and Lindberg, Christopher and Tajsharghi, Homa and Danielsson, Olof and Melberg, Atle and Udd, Bjarne and Martinsson, Tommy and Oldfors, Anders},
  issn         = {1460-2156},
  keyword      = {myopathy,respiratory failure,exome sequencing,titin,mutation},
  language     = {eng},
  number       = {6},
  pages        = {1682--1694},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin},
  url          = {http://dx.doi.org/10.1093/brain/aws103},
  volume       = {135},
  year         = {2012},
}