| #608810 | ||||||||||||
| MYOPATHY, MYOFIBRILLAR, 2, MFM2 | ||||||||||||
| Alternative titles; symbols | ||||||||||||
| MYOPATHY, MYOFIBRILLAR, ALPHA-B CRYSTALLIN-RELATED MYOPATHY, DESMIN-RELATED, ASSOCIATED WITH MUTATION IN THE CRYAB GENE ALPHA-B CRYSTALLINOPATHY | ||||||||||||
| Phenotype Gene Relationships | ||||||||||||
| ||||||||||||
| Clinical Synopsis | ||||||||||||
| TEXT | ||||||||||||
| A number sign (#) is used with this entry because this form of myofibrillar myopathy (MFM) is caused by heterozygous mutation in the alpha-B-crystallin gene (CRYAB; 123590). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see desmin-related MFM (601419). | ||||||||||||
| 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). | ||||||||||||
| 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) found that the abnormal accumulations in muscle biopsies from affected patients stained with both anti-desmin and anti-alpha-B-crystallin antibodies. 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 desmin-related myopathy, 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. | ||||||||||||
| REFERENCES | ||||||||||||
| ||||||||||||
| ||||||||||||