title: Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies.
abstract: BACKGROUND
  Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement.
  
  
  METHODS
  We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms.
  
  
  RESULTS
  We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%).
  
  
  CONCLUSIONS
  We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany. anna.semmler@rwth-aachen.de.|Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. anna.semmler@rwth-aachen.de.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Semmler
authors.affiliation: Centre de Référence des Maladies Neuromusculaires, Nice Hospital and UMR CNRS6543, Nice University, Nice, France. Sacconi.S@chu-nice.fr.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany. elisa.bach@uni-wuerzburg.de.
authors.forename: J Elisa
authors.initials: JE
authors.lastname: Bach
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany. claus.liebe@rwth-aachen.de.|Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. claus.liebe@rwth-aachen.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Liebe
authors.affiliation: Department of Neurology, Saarland University, Homburg/Saar, Germany. jan.buermann@uks.eu.
authors.forename: Jan
authors.initials: J
authors.lastname: Bürmann
authors.affiliation: Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany. rudolf.kley@rub.de.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Kley
authors.affiliation: Department of Neurology, Klinikum Kassel, Kassel, Germany. ferbert@klinikum-kassel.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.affiliation: Department of Neurology, Klinikum Merzig, Merzig, Germany. r.anderheiden@mzg.shg-kliniken.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Anderheiden
authors.affiliation: Department of Neurology, Neuromuscular Reference Center, University Hospital Saint-Luc, Brussel, Belgium. Peter.Vandenbergh@uclouvain.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Van den Bergh
authors.affiliation: Institute Born-Bunge, University of Antwerpen, Antwerpen, Belgium. jean-jacques.martin@ua.ac.be.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: Institute Born-Bunge, University of Antwerpen, Antwerpen, Belgium. peter.dejonghe@molgen.vib-ua.be.|Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerpen, Antwerpen, Belgium. peter.dejonghe@molgen.vib-ua.be.|Department of Neurology, University Hospital of Antwerpen, Antwerpen, Belgium. peter.dejonghe@molgen.vib-ua.be.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Institute of Neuropathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. Neuen-Jacob@med.uni-duesseldorf.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Neuen-Jacob
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany. Oliver.Mueller@med.uni-heidelberg.de.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg, Heidelberg, Germany. Oliver.Mueller@med.uni-heidelberg.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Müller
authors.affiliation: Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle, Germany. marcus.deschauer@uk-halle.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Deschauer
authors.affiliation: Institute of Neuropathology, Klinikum Bremen-Mitte, Bremen, Germany. Markus.Bergmann@Klinikum-Bremen-Mitte.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Bergmann
authors.affiliation: Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. jmschroder@ukaachen.de.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Schröder
authors.affiliation: Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany. Matthias.vorgerd@ruhr-uni-bochum.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany. jschulz@ukaachen.de.|JARA - Translational Brain Medicine, Jülich and Aachen, Germany. jschulz@ukaachen.de.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.affiliation: Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. jweis@ukaachen.de.|JARA - Translational Brain Medicine, Jülich and Aachen, Germany. jweis@ukaachen.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany. wkress@biozentrum.uni-wuerzburg.de.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany. kclaeys@ukaachen.de.|Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. kclaeys@ukaachen.de.|JARA - Translational Brain Medicine, Jülich and Aachen, Germany. kclaeys@ukaachen.de.
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000150:complications / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human