Myopathy, Myofibrillar, 5

A number sign (#) is used with this entry because myofibrillar myopathy-5 (MFM5) is caused by heterozygous mutation in the FLNC gene (102565) on chromosome 7q32.

For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (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.

Chevessier et al. (2015) found that, in addition to protein aggregates, Z-disc lesions similar to those observed in a mouse model of MFM5 (see ANIMAL MODEL) were present in biopsy specimens from patients with different MFM5-associated FLNC mutations.

Molecular Genetics

In affected members of a German family with autosomal dominant 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 rare.

Animal Model

Chevessier et al. (2015) created knockin mice harboring a W2711X mutation in Flnc corresponding to the W2710X mutation (102565.0001) in human patients with MFM5. Heterozygous knockin mice expressed both wildtype and mutant Flnc alleles at comparable levels. No kyphosis or focal muscle atrophy was observed in mutant mice at any age, but reduced grip strength or muscle weakness was evident beginning at 4 months of age. Histologic analysis of skeletal muscle from sedentary heterozygous knockin mice showed no overt defects up to 8 months of age. However, ultrastructural analysis revealed abnormalities, such as enlarged mitochondria and autophagic vacuoles, in 3-month-old mutant mice. Myofibrillar degeneration in mutant mice started at Z-discs, and myofibrillar lesions were observed. These lesions appeared as electron-dense material between adjacent Z-discs and spanned as little as a single sarcomere or extended across multiple sarcomeres and included several neighboring myofibrils. Similar pathology was also detected in diaphragm and was exacerbated by eccentric exercise.