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Titel: Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies
VerfasserIn: Semmler, Anna-Lena
Sacconi, Sabrina
Bach, J Elisa
Liebe, Claus
Bürmann, Jan
Kley, Rudolf A
Ferbert, Andreas
Anderheiden, Roland
Van den Bergh, Peter
Martin, Jean-Jacques
De Jonghe, Peter
Neuen-Jacob, Eva
Müller, Oliver
Deschauer, Marcus
Bergmann, Markus
Schröder, J Michael
Vorgerd, Matthias
Schulz, Jörg B
Weis, Joachim
Kress, Wolfram
Claeys, Kristl G
Sprache: Englisch
Titel: Orphanet journal of rare diseases
Bandnummer: 9
Seiten: 1-13
Verlag/Plattform: BMC
Erscheinungsjahr: 2014
Freie Schlagwörter: MFM
Next generation sequencing,
bcl-2 associated athanogene protein 3
Protein aggregation
Hearing impairment
Polyneuropathy
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: 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.
DOI der Erstveröffentlichung: 10.1186/s13023-014-0121-9
URL der Erstveröffentlichung: https://ojrd.biomedcentral.com/articles/10.1186/s13023-014-0121-9
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-382323
hdl:20.500.11880/34509
http://dx.doi.org/10.22028/D291-38232
ISSN: 1750-1172
Datum des Eintrags: 25-Nov-2022
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Innere Medizin
Professur: M - Prof. Dr. Michael Böhm
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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