Hereditary myopathy with early respiratory failure: occurrence in various populations.
OBJECTIVE
Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort.


METHODS
DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations.


RESULTS
All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin.


CONCLUSIONS
We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.
['Palmio|Johanna|J|', 'Evilä|Anni|A|', 'Chapon|Françoise|F|', 'Tasca|Giorgio|G|', 'Xiang|Fengqing|F|', 'Brådvik|Björn|B|', 'Eymard|Bruno|B|', 'Echaniz-Laguna|Andoni|A|', 'Laporte|Jocelyn|J|', 'Kärppä|Mikko|M|', 'Mahjneh|Ibrahim|I|', 'Quinlivan|Rosaline|R|', 'Laforêt|Pascal|P|', 'Damian|Maxwell|M|', 'Berardo|Andres|A|', 'Taratuto|Ana Lia|AL|', 'Bueri|Jose Antonio|JA|', 'Tommiska|Johanna|J|', 'Raivio|Taneli|T|', 'Tuerk|Matthias|M|', 'Gölitz|Philipp|P|', 'Chevessier|Frederic|F|', 'Sewry|Caroline|C|', 'Norwood|Fiona|F|', 'Hedberg|Carola|C|', 'Schröder|Rolf|R|', 'Edström|Lars|L|', 'Oldfors|Anders|A|', 'Hackman|Peter|P|', 'Udd|Bjarne|B|']
D000328:Adult D000368:Aged D064211:Connectin D059472:Exome D005260:Female D030342:Genetic Diseases, Inborn D008040:Genetic Linkage D020022:Genetic Predisposition to Disease D006801:Humans D008279:Magnetic Resonance Imaging D008297:Male D008875:Middle Aged D018482:Muscle, Skeletal D009135:Muscular Diseases D009154:Mutation D010375:Pedigree D010641:Phenotype D012131:Respiratory Insufficiency
MYOPATHY GENETICS EPIDEMIOLOGY