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Orphanet J Rare Dis. 2014 Aug 1;9:121. doi: 10.1186/s13023-014-0121-9.

Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies.

Author information

1
Department of Neurology, RWTH Aachen University, Aachen, Germany. anna.semmler@rwth-aachen.de.
2
Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. anna.semmler@rwth-aachen.de.
3
Centre de Référence des Maladies Neuromusculaires, Nice Hospital and UMR CNRS6543, Nice University, Nice, France. Sacconi.S@chu-nice.fr.
4
Department of Human Genetics, University of Würzburg, Würzburg, Germany. elisa.bach@uni-wuerzburg.de.
5
Department of Neurology, RWTH Aachen University, Aachen, Germany. claus.liebe@rwth-aachen.de.
6
Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. claus.liebe@rwth-aachen.de.
7
Department of Neurology, Saarland University, Homburg/Saar, Germany. jan.buermann@uks.eu.
8
Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany. rudolf.kley@rub.de.
9
Department of Neurology, Klinikum Kassel, Kassel, Germany. ferbert@klinikum-kassel.de.
10
Department of Neurology, Klinikum Merzig, Merzig, Germany. r.anderheiden@mzg.shg-kliniken.de.
11
Department of Neurology, Neuromuscular Reference Center, University Hospital Saint-Luc, Brussel, Belgium. Peter.Vandenbergh@uclouvain.be.
12
Institute Born-Bunge, University of Antwerpen, Antwerpen, Belgium. jean-jacques.martin@ua.ac.be.
13
Institute Born-Bunge, University of Antwerpen, Antwerpen, Belgium. peter.dejonghe@molgen.vib-ua.be.
14
Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerpen, Antwerpen, Belgium. peter.dejonghe@molgen.vib-ua.be.
15
Department of Neurology, University Hospital of Antwerpen, Antwerpen, Belgium. peter.dejonghe@molgen.vib-ua.be.
16
Institute of Neuropathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. Neuen-Jacob@med.uni-duesseldorf.de.
17
Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany. Oliver.Mueller@med.uni-heidelberg.de.
18
DZHK (German Centre for Cardiovascular Research), partner site Heidelberg, Heidelberg, Germany. Oliver.Mueller@med.uni-heidelberg.de.
19
Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle, Germany. marcus.deschauer@uk-halle.de.
20
Institute of Neuropathology, Klinikum Bremen-Mitte, Bremen, Germany. Markus.Bergmann@Klinikum-Bremen-Mitte.de.
21
Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. jmschroder@ukaachen.de.
22
Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany. Matthias.vorgerd@ruhr-uni-bochum.de.
23
Department of Neurology, RWTH Aachen University, Aachen, Germany. jschulz@ukaachen.de.
24
JARA - Translational Brain Medicine, Jülich and Aachen, Germany. jschulz@ukaachen.de.
25
Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. jweis@ukaachen.de.
26
JARA - Translational Brain Medicine, Jülich and Aachen, Germany. jweis@ukaachen.de.
27
Department of Human Genetics, University of Würzburg, Würzburg, Germany. wkress@biozentrum.uni-wuerzburg.de.
28
Department of Neurology, RWTH Aachen University, Aachen, Germany. kclaeys@ukaachen.de.
29
Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. kclaeys@ukaachen.de.
30
JARA - Translational Brain Medicine, Jülich and Aachen, Germany. kclaeys@ukaachen.de.

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.

PMID:
25208129
PMCID:
PMC4347565
DOI:
10.1186/s13023-014-0121-9
[Indexed for MEDLINE]
Free PMC Article

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