liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin
Lund University, Sweden .
University of Gothenburg, Sweden .
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
Uppsala University, Sweden .
Show others and affiliations
2012 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 135, 1682-1694 p.Article in journal (Refereed) Published
Abstract [en]

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 andgt; 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.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy B , 2012. Vol. 135, 1682-1694 p.
Keyword [en]
myopathy, respiratory failure, exome sequencing, titin, mutation
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-78811DOI: 10.1093/brain/aws103ISI: 000304538900005OAI: diva2:536045
Funding Agencies|Swedish Research Council|07122|Selander Foundation||Sigrid Juselius Foundation||Folkhalsan Research Funds||Available from: 2012-06-21 Created: 2012-06-21 Last updated: 2012-06-21

Open Access in DiVA

No full text

Other links

Publisher's full text
By organisation
Department of Clinical and Experimental MedicineFaculty of Health SciencesDepartment of Neurology
In the same journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 17 hits
ReferencesLink to record
Permanent link

Direct link