Myopathy, Myofibrillar, 2

A number sign (#) is used with this entry because myofibrillar myopathy-2 (MFM2) is caused by heterozygous mutation in the alpha-B-crystallin gene (CRYAB; 123590) on chromosome 11q23.

Description

Alpha-B crystallin-related myofibrillar myopathy is an autosomal dominant muscular disorder characterized by adult onset of progressive muscle weakness affecting both the proximal and distal muscles and associated with respiratory insufficiency, cardiomyopathy, and cataracts. There is phenotypic variability both within and between families (Fardeau et al., 1978; Selcen and Engel, 2003).

A homozygous founder mutation in the CRYAB gene has been identified in Canadian aboriginal infants of Cree origin who have a severe fatal infantile hypertonic form of myofibrillar myopathy; see 613869.

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

Clinical Features

Fardeau et al. (1978) described an autosomal dominant muscle disorder with involvement of skeletal and velopharyngeal muscles, associated with hypertrophic cardiomyopathy, respiratory disturbances, and lens opacities. The proband had a history of mild muscle weakness and easy fatigability with dyspnea in childhood. At age 33 years, he was diagnosed with hypertrophic cardiomyopathy. The muscle weakness progressed during adulthood, primarily affecting proximal muscles of the upper and lower limbs. His father died at age 49 years following cataract surgery, and reportedly had progressive muscle weakness and recurrent falls. The proband's paternal uncle and paternal grandfather had a similar disorder, with onset in young adulthood. All affected individuals had a nasal voice, presumably from velopharyngeal muscle weakness, respiratory difficulties, cataracts, and cardiac involvement. A first cousin of the proband's father, who was also examined, showed a similar disorder, with the addition of distal muscle weakness and atrophy; his cardiac examination showed incomplete right heart block. None of the affected individuals had facial muscle involvement. EMG studies showed neither spontaneous activity nor myotonic discharges. Muscle biopsy of 2 patients showed dystrophic findings with 'rubbing out' of the intermyofibrillar network along with split fibers. Electron microscopy showed an intrasarcoplasmic accumulation of an electron-dense granulofilamentous material.

Vicart et al. (1996) studied 28 members from 3 families with desmin-related myopathy, 1 of whom had been reported by Fardeau et al. (1978). Sixteen affected members fulfilled the diagnostic criteria of Fardeau et al. (1978), which included proximal and distal limb muscle weakness often associated with neck, trunk, and velopharynx muscle involvement, signs of cardiomyopathy, presence of numerous desmin-reactive aggregates in the muscle fibers, and intrasarcoplasmic accumulation of dense granulofilamentous material on electron microscopy.

Vicart et al. (1998) studied 9 affected members of the family originally described by Fardeau et al. (1978), all of whom had similar clinical features with different degrees of severity. They showed symmetric, nonselective proximal and distal weakness in lower and upper limbs with velopharyngeal involvement, clinical and/or electrocardiographic signs of hypertrophic cardiomyopathy, and discrete lens opacities. Serum creatine kinase levels were moderately elevated and electromyogram showed a myopathic pattern of abnormalities. Light microscopy of muscle biopsies from all 9 affected individuals showed similar histologic features, consisting specifically of 'rubbing out' areas of the intermyofibrillar network in type I fibers on oxidative staining. Electron microscopy revealed subsarcolemmal and intermyofibrillar accumulation of dense granulofilamentous material with various degenerative changes in all biopsies.

Sacconi et al. (2012) reported a family of North African origin in which 5 members over 2 generations presented a syndrome characterized by myofibrillar myopathy, posterior polar cataracts, and dilated cardiomyopathy. Mean age of onset was 40 years. All patients presented with distal lower leg weakness, dysphagia, and dysphonia as initial complaints. Involvement of respiratory muscles was not present at the time of diagnosis, but became evident during follow-up. Posterior polar cataracts were detected in the 4 patients who underwent comprehensive ophthalmologic examination, and 2 affected individuals also had dilated cardiomyopathy on echocardiography. Patient muscle biopsies showed significant variation in muscle fiber diameter, ranging from 40 to 80 micrometers. In addition, there were atrophic fibers, an increased number of internalized nuclei, fiber splitting, core-like lesions, and 'rubbed out' fibers, with some of the latter containing aggregates visible in HE staining. Electron microscopy showed abnormal material in some areas surrounding irregularly oriented bundles of thick filaments in so-called 'sandwich' formations.

Clinical Variability

Selcen and Engel (2003) reported 2 unrelated patients with desmin-related myopathy, which they termed 'myofibrillar myopathy.' The first patient was a 52-year-old man who presented with ventilatory insufficiency associated with paresis of the diaphragm and weakness of cervical, shoulder girdle, and pelvic girdle muscles. He was also found to have scleroderma (see 181750). The second patient, a 53-year-old man, had slowly progressive leg weakness and atrophy and absent ankle reflexes. EMG and muscle biopsy were consistent with a myopathy. Seventy-five percent of abnormal muscle fiber regions reacted with desmin and alpha-B-crystallin. Ultrastructural analysis showed abnormal expanses of homogeneous material and myofibrillar disintegration involving the Z discs. Small autophagic vacuoles were also present. Unlike the patients reported by Vicart et al. (1996), neither of the patients reported by Selcen and Engel (2003) had cardiomyopathy or cataracts.

Mapping

In 3 families with MFM, Vicart et al. (1996) used linkage analysis to exclude the desmin gene as the disease defect. By genomewide screening performed on the family with DRM reported by Fardeau et al. (1978), Vicart et al. (1998) found linkage to a 26-cM interval between D11S917 and D11S925 on chromosome 11q21-q23 (maximum 2-point lod score of 3.38 at marker D11S4090).

Molecular Genetics

In affected members from the family reported by Fardeau et al. (1978), Vicart et al. (1998) identified a heterozygous mutation in the CRYAB gene (123590.0001).

In 2 adult patients with myofibrillar myopathy, Selcen and Engel (2003) identified truncating mutations in the CRYAB gene (123590.0003-123590.0004). The authors noted the phenotypic variability and suggested a dominant-negative effect of the mutations.

In all affected members of a family of North African origin with myofibrillar myopathy, posterior polar cataract, and dilated cardiomyopathy, Sacconi et al. (2012) identified heterozygosity for a missense mutation in the CRYAB gene (D109H: 123590.0011). The mutation was not found in unaffected family members or 50 ethnically matched controls.