title: Hereditary myopathy with early respiratory failure: occurrence in various populations.
abstract: 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.
authors.affiliation: Department of Neurology, Neuromuscular Research Unit, Tampere University and University Hospital, , Tampere, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Palmio
authors.forename: Anni
authors.initials: A
authors.lastname: Evilä
authors.forename: Françoise
authors.initials: F
authors.lastname: Chapon
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tasca
authors.forename: Fengqing
authors.initials: F
authors.lastname: Xiang
authors.forename: Björn
authors.initials: B
authors.lastname: Brådvik
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.forename: Mikko
authors.initials: M
authors.lastname: Kärppä
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Mahjneh
authors.forename: Rosaline
authors.initials: R
authors.lastname: Quinlivan
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforêt
authors.forename: Maxwell
authors.initials: M
authors.lastname: Damian
authors.forename: Andres
authors.initials: A
authors.lastname: Berardo
authors.forename: Ana Lia
authors.initials: AL
authors.lastname: Taratuto
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Bueri
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.forename: Taneli
authors.initials: T
authors.lastname: Raivio
authors.forename: Matthias
authors.initials: M
authors.lastname: Tuerk
authors.forename: Philipp
authors.initials: P
authors.lastname: Gölitz
authors.forename: Frederic
authors.initials: F
authors.lastname: Chevessier
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Fiona
authors.initials: F
authors.lastname: Norwood
authors.forename: Carola
authors.initials: C
authors.lastname: Hedberg
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.forename: Lars
authors.initials: L
authors.lastname: Edström
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
mesh_terms: D000328:Adult; D000368:Aged; D064211:Connectin / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D030342:Genetic Diseases, Inborn / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012131:Respiratory Insufficiency / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology
chemical_list: D064211:Connectin; C577285:TTN protein, human
keywords: EPIDEMIOLOGY; GENETICS; MYOPATHY