A number sign (#) is used with this entry because of evidence that 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.

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.

Lee et al. (2020) reported 34 individuals from 9 apparently unrelated Chinese families segregating MFM5. Eight of the individuals, aged 26 to 47 years, were asymptomatic at the time of molecular analysis. The other 26 individuals presented with clinical manifestations between ages 45 and 62 years. Four of the 26 patients had died from pulmonary causes (pneumonia or respiratory failure). Twenty-three initially had muscle weakness with lower limb predominance, one had only an elevation of creatine kinase, and another had lower back pain with gait disturbance. On initial physical examination, 10 patients had lower back pain, 4 had scapular winging, and 13 had gait disturbances. Respiratory manifestations were reported in 11 patients; one of them was ventilation dependent and another required BiPAP. Six of 17 patients evaluated had cardiac abnormalities, including valvular regurgitation, ventricular hypertrophy, atrial fibrillation, or sick sinus syndrome and Mobitz II heart block. Two patients required pacemaker implantation. In 15 of 17 patients tested, electromyography showed myopathic changes. Of 14 muscle biopsies examined, evidence of mitochondrial abnormalities were seen in 9.

The transmission pattern of MFM5 in the family reported by Vorgerd et al. (2005) was consistent with autosomal dominant inheritance.

In affected members of a German family with autosomal dominant MFM, Vorgerd et al. (2005) identified a heterozygous mutation in the FLNC gene (W2710X; 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.

In 34 Chinese individuals with MFM5 from 9 apparently unrelated families in Hong Kong, Lee et al. (2020) identified a heterozygous c.8129G-A transition in the FLNC gene, resulting in a trp2710-to-ter (W2710X; 102565.0010) substitution. This mutation has the same amino acid substitution that occurred in a German family with MFM5 with a different basepair change (c.8130G-A; 102565.0001) in the same codon. Polymorphic marker analysis on the 9 probands identified a distinct haplotype that was not detected among 20 ethnic-matched control chromosomes. The mutation was estimated to have occurred 42 to 71 generations previously, dating it to 844 to 1,315 years earlier.

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.