TY  - JOUR
A1  - Semmler, Anna-Lena
A1  - Sacconi, Sabrina
A1  - Bach, J. Elisa
A1  - Liebe, Claus
A1  - Bürmann, Jan
A1  - Kley, Rudolf A.
A1  - Ferbert, Andreas
A1  - Anderheiden, Roland
A1  - Van den Bergh, Peter
A1  - Martin, Jean-Jacques
A1  - De Jonghe, Peter
A1  - Neuen-Jacob, Eva
A1  - Müller, Oliver
A1  - Deschauer, Marcus
A1  - Bergmann, Markus
A1  - Schröder, J. Michael
A1  - Vorgerd, Matthias
A1  - Schulz, Jörg B.
A1  - Weis, Joachim
A1  - Kress, Wolfram
A1  - Claeys, Kristl G.
T1  - Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies
JF  - Orphanet Journal of Rare Diseases
N2  - 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.
KW  - polyneuropathy
KW  - MFM
KW  - next generation sequencing
KW  - bcl-2 associated athanogene protein 3
KW  - protein aggregation
KW  - hearing impairment
KW  - early respiratory-failure
KW  - myopathy
KW  - muscular-dystrophy
KW  - skeletal myopathy
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115623
SN  - 1750-1172
N1  - Additional files are available here: http://www.ojrd.com/content/9/1/121/additional
VL  - 9
IS  - 121
ER  -