Myopathy, Myofibrillar, 6

A number sign (#) is used with this entry because of evidence that myofibrillar myopathy-6 (MFM6) is caused by heterozygous mutation in the BAG3 gene (603883) on chromosome 10q26.

Description

Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by Jaffer et al., 2012).

For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419).

Clinical Features

Selcen et al. (2009) reported 3 unrelated children, 2 boys and a girl, with early-onset rapidly progressive myofibrillar myopathy. The first patients had been a toe walker since early childhood. In his early teens, he experienced a restrictive cardiomyopathy and received a heart transplant at age 13 years. Two years later, he had severe diffuse muscle weakness and atrophy, contractures at the knees and ankles, bilateral diaphragm paralysis, and respiratory insufficiency. The second patient presented at age 13 years with scoliosis, rigid spine, and easy fatigability. By the age of 14 years, she had restrictive respiratory insufficiency, and at age 15, she had hypernasal speech, and axial and progressively severe distal, more than proximal, muscle weakness. EMG conduction studies demonstrated myopathic motor unit potentials, and nerve conduction studies showed axonal and demyelinating peripheral neuropathy. EKG showed a hypertrophic cardiomyopathy. The third patient walked on his toes since toddler age. From 7 years of age, he had progressive leg weakness, fatigability, and a valgus ankle deformity. At the age of 11 years, he had moderate proximal muscle weakness, thoracic scoliosis, and a rigid spine predominantly affecting the cervical region. EKG showed a restrictive cardiomyopathy with trivial pulmonary and mitral regurgitation. His symptoms progressed rapidly, and by age 12, he had marked weakness of axial and proximal limb muscles, scapular winging, and reduced forced vital capacity. He died from respiratory insufficiency and a chest infection at age 13. Selcen et al. (2009) noted that serum creatine kinase was significantly increased in all 3 patients. Skeletal muscle biopsy showed dystrophic changes with fiber size variation, fiber splitting, necrotic fibers, internal nuclei, and structural alterations consisting of replacement of the normal myofibrillar markings by small, dense granules, or larger hyaline masses, or amorphous material. Numerous abnormal fibers displayed intense congophilia, consistent with the presence of beta-pleated sheets. The abnormal fibers displayed strong ectopic immunoreactivity for Bag3. Electron microscopy studies showed that minimally affected myofibers displayed Z disc streaming and accumulation of small pleomorphic dense structures between the myofibrils, More severely affected fibers had large lakes of small, pleomorphic, dense structures surrounded by myofibrillar remnants. Apoptotic nuclei were also observed.

Odgerel et al. (2010) reported 4 patients from 3 unrelated families with MFM6. One of the patients was an Italian girl who had previously been reported by Sabatelli et al. (1992). Between ages 5 and 12 years, all developed a skeletal myopathy with severe generalized and proximal muscle weakness and atrophy and respiratory insufficiency, as well as cardiomyopathy. Muscle biopsy showed abnormal desmin (DES; 125660)-positive inclusions and myofibrillar breakdown with loss of Z-line streaming. All patients also had peripheral neuropathy with axonal loss, thin myelin sheaths, and giant axons on nerve biopsy. Two patients underwent cardiac transplant in their teens and were ventilator-dependent; the other 2 patients died at ages 9 and 20 years.

Lee et al. (2012) reported a Chinese girl with myofibrillar myopathy. At age 6 years, she developed difficulty walking due to proximal muscle weakness, although she remained ambulatory at age 12. Both upper and lower extremities were affected. She developed rapidly progressive contractures of the Achilles tendons and limited spine movement due to scoliosis. Other features included hypertrophic cardiomyopathy, prolonged QT interval, and mild restrictive lung disease. Nerve conduction studies and electromyography suggested a neurogenic axonal disease. Skeletal muscle biopsy showed atrophic fibers, focal myofibrillar disorganization, and type 1 fiber predominance. Electron microscopy showed sarcoplasmic accumulation of electron-dense granulofilamentous material and myofibrillar degeneration with minicores. Sural nerve biopsy showed axonopathy in some large myelinated fibers and occasional giant axons with thin myelin sheaths.

Jaffer et al. (2012) reported 5 patients with MFM6, including 1 boy previously described by Selcen et al. (2009) and 2 affected sisters. The patients had onset of rapidly progressive cardiomyopathy and generalized skeletal muscle weakness in late childhood or early adolescence. Patients showed toe walking due to steppage gait in early childhood, although early motor development was normal. There were skeletal abnormalities due to muscle weakness, such as large and small joint contractures, scoliosis, and pes cavus. Signs of a peripheral neuropathy included distal sensory impairment and hyporeflexia, mainly of the lower limbs. Respiratory compromise was severe, usually requiring nocturnal ventilation. EMG indicated chronic neurogenic changes, and sural nerve biopsy of 2 patients showed axonal loss and thinly myelinated giant axons. Muscle biopsy showed fiber-type grouping, small atrophic fibers, internal nuclei, accumulation of granulomatous material, myofibrillar loss, and Z-line streaming.

Semmler et al. (2014) reported a man with a relatively mild form of MFM6. He developed distal lower limb weakness at age 34 years, which progressed to proximal muscle weakness affecting the upper and lower limbs. Muscle biopsy showed vacuoles, core-like lesions, and some necrotic fibers; ultrastructural examination showed tubulofilamentous accumulations, Z-disc streaming, and the accumulation of granulofilamentous material. The patient also had an axonal sensorimotor polyneuropathy manifest as decreased vibration sense and ataxic gait, but sural nerve biopsy did not show giant axons. He did not have cardiac or respiratory muscle involvement.

Inheritance

Selcen et al. (2009) determined that MFM6 is an autosomal dominant disorder. The mutation occurs de novo in most affected patients, but transmission from an unaffected parent who is somatic mosaic has been reported (Odgerel et al., 2010).

Molecular Genetics

In 3 unrelated patients with childhood-onset of rapidly progressive myofibrillar myopathy, Selcen et al. (2009) identified the same heterozygous mutation in the BAG3 gene (P209L; 603883.0001). The mutation was absent in both parents of 2 of the patients, indicating de novo occurrence; parental DNA from the third patient was not available.

In 4 patients from 3 unrelated families with MFM6, Odgerel et al. (2010) identified a heterozygous P209L mutation. The mutation occurred de novo in 2 patients. Two brothers inherited the mutation from their unaffected father, who was somatic mosaic for the mutation, with an expression level of 17% in the peripheral blood lymphocytes.

Lee et al. (2012) identified a de novo heterozygous P209L mutation in the BAG3 gene in a Chinese girl with myofibrillar myopathy.

In 4 patients with MFM6, Jaffer et al. (2012) identified a heterozygous P209L mutation. One of the patients had a sister who was similarly affected, but DNA was not available. Their father had died of a similar but milder disorder at age 30 years, suggesting that he may have been somatic mosaic for the mutation.

In a man with adult-onset MFM6, Semmler et al. (2014) identified a de novo heterozygous missense mutation in the BAG3 gene (P209Q; 603883.0010).

Animal Model

Homma et al. (2006) showed that Bag3 is prominently expressed in striated muscle and colocalizes with Z discs. Mice with homozygous disruption of the Bag3 gene developed normally, but deteriorated postnatally with stunted growth evident by 1 to 2 weeks of age and death by 4 weeks. Bag3-deficient mice developed a fulminant myopathy characterized by noninflammatory myofibrillar degeneration with apoptotic features. Knockdown of Bag3 expression in cultured myoblasts increased apoptosis on induction of differentiation, suggesting that Bag3 is needed for maintenance of myotube survival and confirming a cell autonomous role for Bag3 in muscle. Homma et al. (2006) concluded that, although BAG3 is not required for muscle development, it appears to be critically important for maintenance of mature skeletal muscle.