Quoted from OMIM#609524
Alternative titles; symbols
Phenotype Gene Relationships
Location Phenotype Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
7q32.1 Myopathy, myofibrillar, 5 609524 FLNC 102565
Clinical Synopsis
A number sign (#) is used with this entry because filamin C-related myofibrillar myopathy is caused by heterozygous mutation in the FLNC gene (102565).For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see desmin-related MFM (601419).

Mutation in the FLNC gene can also cause distal myopathy-4 (MPD4; 614065), which shows a different pattern of muscle involvement and different histologic changes.

Clinical Features
Vorgerd et al. (2005) reported a German family in which 17 members had adult-onset of slowly progressive skeletal muscle weakness with autosomal dominant inheritance. Although most patients had proximal involvement of the lower limbs with lesser involvement of the upper extremities, 1 patient had distal weakness of the calf muscles only. Initial symptoms included weakness when climbing stairs, waddling gait, and lower back pain. Several patients also had respiratory insufficiency, and 3 patients had evidence of peripheral nerve involvement. Only 1 patient had evidence of cardiac involvement. All patients showed increased serum creatine kinase. Skeletal muscle biopsy showed MFM with amorphous, granular, or hyaline deposits and occasional vacuoles. Other features included internal nuclei, fiber splitting, and necrotic fibers. Oxidative enzymes were decreased. Immunohistochemical analysis showed accumulation of desmin (DES; 125660) and filamin C. Electron microscopy of skeletal muscle biopsy from 1 patient showed Z disc streaming, nemaline rod formation, and intermyofibrillar and subsarcolemmal granulofilamentous protein aggregates. Vorgerd et al. (2005) noted that the features in their family were distinct from those reported by Gamez et al. (2001) (see LGMD1F; 608423).Shatunov et al. (2009) reported a German mother and daughter with adult onset of slowly progressive muscle weakness at ages 60 and 34 years, respectively. Symptoms in the mother began with difficulty climbing stairs and paresis of the pelvic muscles, with proximal upper extremity muscles becoming involved 4 years later. She later had paresis of the neck muscles, muscles surrounding the knees, and distal leg muscles, with hypo- or areflexia. She could not stand or walk on heels or toes, and used a walking frame. The daughter first developed muscle pain increasing with exercise and difficulty climbing stairs. Two years later, she had limb-girdle paresis and hypotrophy of the proximal muscles of the upper limb. Both patients had winging of the scapula and involvement of the paraspinal and abdominal muscles; neither patient had evidence of cardiac or respiratory muscle involvement. Family history indicated that a maternal grandmother, maternal uncle, and a brother had slowly progressive muscle weakness. Skeletal muscle biopsy from the daughter showed marked variation in fiber size and some fibers with internal nuclei. There was type 1 fiber predominance. Several fibers showed polymorphous hyaline and nonhyaline myofibrillary FLNC-positive inclusions with a convoluted, serpentine appearance. Ultrastructural examination showed major myofibrillar abnormalities, with accumulation of Z disc debris, granulofilamentous material, and nemaline rods. There were also mitochondrial aggregates.
Molecular Genetics
In affected members of a German family with autosomal dominant filamin C-related MFM, Vorgerd et al. (2005) identified a heterozygous mutation in the FLNC gene (102565.0001).In a German mother and daughter with adult-onset limb-girdle muscle weakness, Shatunov et al. (2009) identified a heterozygous deletion in the FLNC gene (102565.0002). This family was the only 1 of 127 families with a myopathy examined that was found to have an FLNC mutation, indicating that this subtype of myofibrillar myopathy is very rare.
1. Gamez, J., Navarro, C., Andreu, A. L., Fernandez, J. M., Palenzuela, L., Tejeira, S., Fernandez-Hojas, R., Schwartz, S., Karadimas, C., DiMauro, S., Hirano, M., Cervera, C. Autosomal dominant limb-girdle muscular dystrophy: a large kindred with evidence for anticipation. Neurology 56: 450-454, 2001. [PubMed: 11222786, related citations] [Full Text: HighWire Press, Pubget]
2. Shatunov, A., Olive, M., Odgerel, Z., Stadelmann-Nessler, C., Irlbacher, K., van Landeghem, F., Bayarsaikhan, M., Lee, H.-S., Goudeau, B., Chinnery, P. F., Straub, V., Hilton-Jones, D., and 9 others. In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy. Europ. J. Hum. Genet. 17: 656-663, 2009. [PubMed: 19050726, related citations] [Full Text: Nature Publishing Group, Pubget]
3. Vorgerd, M., van der Ven, P. F. M., Bruchertseifer, V., Lowe, T., Kley, R. A., Schroder, R., Lochmuller, H., Himmel, M., Koehler, K., Furst, D. O., Huebner, A. A mutation in the dimerization domain of filamin C causes a novel type of autosomal dominant myofibrillar myopathy. Am. J. Hum. Genet. 77: 297-304, 2005. [PubMed: 15929027, related citations] [Full Text: Elsevier Science, Pubget]
Contributors: Cassandra L. Kniffin – updated : 11/2/2010
Creation Date: Cassandra L. Kniffin : 8/9/2005
▸ Edit History: alopez : 02/03/2012
wwang : 7/1/2011
ckniffin : 6/29/2011
terry : 6/3/2011
wwang : 12/7/2010
ckniffin : 11/2/2010
terry : 7/30/2008
wwang : 8/12/2005
ckniffin : 8/9/2005

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