| #601419 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MYOPATHY, MYOFIBRILLAR, 1; MFM1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MYOPATHY, MYOFIBRILLAR, DESMIN-RELATED DESMINOPATHY, PRIMARY DESMIN-RELATED MYOPATHY; DRM INCLUSION BODY MYOPATHY 1, AUTOSOMAL DOMINANT, FORMERLY; IBM1, FORMERLY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because myofibrillar myopathy-1 (MFM1) can be caused by heterozygous, homozygous, or compound heterozygous mutation in the desmin gene (DES; 125660). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Myofibrillar myopathy (MFM) is a noncommittal term that refers to a group of morphologically homogeneous, but genetically heterogeneous chronic neuromuscular disorders. The morphologic changes in skeletal muscle in MFM result from disintegration of the sarcomeric Z disc and the myofibrils, followed by abnormal ectopic accumulation of multiple proteins involved in the structure of the Z disc, including desmin, alpha-B-crystallin (CRYAB; 123590), dystrophin (300377), and myotilin (TTID; 604103). Genetic Heterogeneity of Myofibrillar Myopathy Other forms of MFM include alpha-B crystallinopathy (608810), caused by mutation in the CRYAB gene; myotilinopathy (609200) and spheroid body myopathy (182920), both caused by mutation in the myotilin gene; ZASP-related MFM (609452), caused by mutation in the ZASP gene (LDB3; 605906); FLNC-related MFM (609524), caused by mutation in the FLNC gene (102565); and BAG3-related MFM (612954), caused by mutation in the BAG3 gene (603883). 'Desmin-related myopathy' is another term referring to MFM in which there are intrasarcoplasmic aggregates of desmin, usually in addition to other sarcomeric proteins. Rigid spine syndrome (602771), caused by mutation in the SEPN1 gene (606210), and arrhythmogenic right ventricular dysplasia-7 (ARVD7; 609160), which maps to chromosome 10q22.3, are other desmin-related myopathies. Goebel (1995) provided a review of desmin-related myopathy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nomenclature | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Selcen et al. (2004) noted that the pathologic findings in myofibrillar myopathy have been described in the past in various ways, including 'inclusion bodies,' 'intrasarcoplasmic dense granulofilamentous material,' 'spheroid bodies,' 'sarcoplasmic bodies,' 'cytoplasmic bodies,' 'Mallory body-like inclusions,' and 'subsarcolemmal vermiform deposits.' Autosomal dominant inclusion body myopathy has previously been referred to in OMIM as IBM1 to distinguish it in particular from autosomal recessive IBM2 (600737), which is caused by mutation in the GNE gene (603824) on chromosome 9p13.3. Since then, autosomal dominant inclusion body myopathy has been found to be a genetically heterogeneous condition and is referred to as myofibrillar myopathy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Desmin-related MFM is characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias, and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. Autosomal dominant and autosomal recessive forms have been reported. Approximately one-third of DRMs are thought to be caused by mutations in the desmin gene (Ferreiro et al., 2004). Clark et al. (1978) described a large kindred with an autosomal dominant benign myopathy of late-adult onset (average age 53 years) characterized by mild weakness of the pelvic and shoulder girdles. Light microscopy identified myofibrillar cytoplasmic inclusions in type 1 muscle fibers in all 3 symptomatic and in 4 of 7 asymptomatic members. Ultrastructural characteristics showed Z band material and aggregates of actin (ACTA1; 102610) and myosin (MYH1; 160730). Porte et al. (1980) and Stoeckel et al. (1981) reported 3 brothers with a familial cardiomyopathy characterized by aberrant accumulation of desmin-type intermediate filaments within cardiac muscle cells. The 3 brothers were admitted to hospital at ages 23, 29, and 24, respectively, with complete AV block requiring implantation of a pacemaker. Concentric and obstructive ventricular hypertrophy was demonstrated. The parents and a fourth brother had no signs of cardiomyopathy. Wolburg et al. (1982) reported 2 unrelated patients with a slowly progressive myopathy characterized by dense granular inclusions in skeletal muscle and subsarcolemmal filamentous bodies as well as streaming and disintegration of the Z discs. Among the offspring of second-cousin parents, Vajsar et al. (1993) described a brother and sister who developed symptoms of cardiomyopathy at the age of 2 and 5 years, respectively, and slowly progressive muscle weakness a few years later. Skeletal muscle biopsy specimens showed subsarcolemmal crescents of dark eosinophilic material in both type 1 and type 2 fibers that stained positively for desmin and ubiquitin (191339). Ultrastructurally, the subsarcolemmal deposits consisted of aggregates of granular and filamentous material arising from Z bands. Horowitz and Schmalbruch (1994) provided follow-up of an Ashkenazi Jewish family with autosomal dominant myopathy originally described by Milhorat and Wolff (1943). The 6-generation family had early- to mid-adult onset of gait disturbances due to symmetric weakness in distal leg muscles, which progressed over 5 to 10 years to involve all extremities and bulbar, respiratory, and facial muscles. There was loss of leg reflexes with preservation of arm reflexes until late in the disorder. Laboratory examination showed a 3- to 5-fold increase in serum creatine kinase levels. There was frequent cardiac involvement with arrhythmias, conduction block, and congestive heart failure, resulting in a shortened life span. In addition to typical myopathic features and rimmed vacuoles on muscle biopsy, desmin was present as abundant granulofilamentous deposits in the form of reticular meshworks between individual myofibrils or adjacent to the sarcolemma. Abe et al. (1993) described a family in which 12 members of 4 successive generations suffered from weakness and atrophy of muscles in the distal extremities, neck, thorax, and shoulder girdle. Male-to-male transmission was observed. The mean age at onset was 42 years, and the patients became disabled after 5 to 10 years due to chronic respiratory failure. The level of serum creatine kinase was normal or slightly elevated. Electromyogram showed a predominant myopathic change with a slight neurogenic change. Autopsy, performed in 2 cases, revealed numerous cytoplasmic bodies in skeletal muscles; smooth and cardiac muscles were also affected. Cytoplasmic bodies were present predominantly in type 1 fibers in skeletal muscle. Electron microscopic examination showed dense central cores of myofilaments surrounded by radiating filaments. Goldfarb et al. (1998) reported 2 unrelated families with a cardiac and skeletal myopathy. In 1 family, 2 of 3 sibs developed proximal muscle weakness and wasting in their twenties or thirties. Weakness slowly progressed to involve the entirety of the limbs and eventually spread to the neck, bulbar, and facial muscles. Electrocardiograms of each patient showed right bundle branch block. In both affected sibs, an accumulation of amorphous material immunoreactive for desmin, dystrophin (300377), and vimentin (193060) was observed in the cytoplasm of the skeletal muscle cells. An uncle and the father of the patients had an identical condition. In the second family, 3 of 4 sibs developed complete atrioventricular conduction block requiring a permanent pacemaker at 2, 9, and 10 years of age. Between 20 and 24 years of age, all 3 sibs developed progressive muscle weakness and atrophy with swelling and breathing difficulties. The 2 older sibs died of progressive fibrosis of the cardiac conduction system and cardiomyopathy at 28 and 30 years of age. The surviving sib developed congestive heart failure secondary to restrictive cardiomyopathy. Examination of tissue from all 3 patients showed intracytoplasmic accumulation of amorphous desmin- and dystrophin-immunoreactive material with a characteristic subsarcolemmal distribution. There was no case of a similar disease in the extended family. Inheritance appeared to be autosomal dominant in the first family and autosomal recessive in the second family. Ariza et al. (1995) described a patient with severe generalized myopathy affecting skeletal, cardiac, and smooth muscle. At age 19 years, the patient exhibited generalized muscle weakness; at 28 years, respiratory failure and intestinal pseudoobstruction led to death. Biopsies from skeletal muscle, myocardium, and intestinal muscle revealed numerous atrophic fibers and frequent misplacement of nuclei to the interior of the cells with subsarcolemmal eosinophilic masses. Immunohistochemistry was positive for desmin and negative for vimentin; antidesmin staining was patchy with extensive areas lacking staining and immunoreactive aggregates in other regions. Electron microscopy revealed classic features of desminopathies and abnormalities similar to those observed in desmin-null mutant mice. In the mice, myofibrils are fragile upon mechanical stress, and muscle weakness develops with age. Park et al. (2000) reported a patient who presented at age 24 years with difficulty climbing steps due to weakness in the legs. A year later, she experienced dizziness and syncopal episodes and was found to have atrioventricular conduction block requiring a permanent pacemaker. At age 29 years, distal and proximal muscle weakness in the arms and legs and mild neck and facial weakness were found. No other family members were affected. A homozygous mutation in the DES gene (125660.0007) was identified. Kaminska et al. (2004) reported 2 Polish families with skeletal myopathy without cardiac involvement. In the first family, a mother, her daughter, niece, and nephew had onset of gait disturbance and bilateral weakness in the legs between 39 and 45 years of age. A brother and sister in the second family presented with difficulty climbing stairs and raising their arms between 31 and 33 years of age. Progression was slower than that in the first family. Both families had the same deletion in the DES gene (125660.0012). Bar et al. (2007) reported a French family in which at least 6 members spanning 3 generations had desmin-related myopathy inherited in an autosomal dominant pattern. The proband had onset of proximal and distal lower limb weakness and dyspnea on exertion at age 35 years, followed by proximal upper limb weakness a year later. He had increased serum creatine kinase and became wheelchair-bound at age 44 years. He underwent tracheostomy for nocturnal ventilatory assistance at age 46 years. A year later, he had a pacemaker implanted for bradyarrhythmia. Of note, the patient had repetitive episodes of diarrhea and constipation during the disease course, indicating smooth muscle involvement. His mother and 2 maternal aunts died of heart failure. Genetic analysis identified a heterozygous mutation in the DES gene in 3 affected family members (125660.0015). Van Spaendonck-Zwarts et al. (2011) performed a metaanalysis of 159 patients with 40 different DES mutations reported in the literature. Familial disease was documented in 54%. Neurologic signs were present in 74%, cardiac signs in 74%, and both neurologic and cardiac signs in 49%. Isolated neurologic signs were found in 22%, and isolated cardiac signs in 22%. More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy, mostly dilated cardiomyopathy, and about 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Respiratory insufficiency was suggested in 26%. Symptoms generally started during the thirties. A quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in 2 patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The findings emphasized the importance of cardiac monitoring in these patients. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By linkage analysis of the large family reported by Horowitz and Schmalbruch (1994), Saavedra-Matiz et al. (2000) mapped the disease locus to a 17-cM region on chromosome 2q bounded by DNA markers D2S2248 and D2S401. The region colocalized on the radiation hybrid map with the desmin gene. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a family with autosomal dominant inheritance of a desmin-related cardioskeletal myopathy, Goldfarb et al. (1998) identified a heterozygous mutation in the desmin gene (125660.0001). In 3 affected members of a second family with apparent autosomal recessive inheritance of a more severe disorder, Goldfarb et al. (1998) identified compound heterozygosity for 2 mutations in the desmin gene (125660.0002; 125660.0003). Several older unaffected family members carried 1 of the mutations. Park et al. (2000) reported splice site mutations in the desmin gene causing deletion of exon 3 (125660.0008; 125660.0009) in 2 individuals with cardiac and skeletal myopathy. In the patient reported by Ariza et al. (1995), Munoz-Marmol et al. (1998) identified a homozygous 21-bp deletion in the DES gene (125660.0004). In affected members of the large, 6-generation Ashkenazi Jewish family with desmin-related myopathy reported by Horowitz and Schmalbruch (1994), Sjoberg et al. (1999) identified a heterozygous mutation in the desmin gene (125660.0006). In a female patient who had recurrent episodes of syncope from infancy and an aggressive course leading to the devastation of cardiac, skeletal, and smooth musculature, and death from cardiac failure at age 20 years, Pinol-Ripoll et al. (2009) identified homozygosity for the same 21-bp deletion in the DES gene that was previously found by Munoz-Marmol et al. (1998) in the patient reported by Ariza et al. (1995). Pinol-Ripoll et al. (2009) stated that this was the youngest known molecularly identified patient with desminopathy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Van Spaendonck-Zwarts et al. (2011) performed a metaanalysis of 159 patients with 40 different DES mutations reported in the literature. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurologic phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiac phenotype. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Shelton et al. (2004) reported myofibrillar myopathy with accumulations of desmin and other proteins in an Australian shepherd dog. The dog presented at age 1 year with chronic lameness, contractures, exercise intolerance, cardiomyopathy, and increased serum creatine kinase. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Barohn et al. (1998); Chapon et al. (1989); Edstrom et al. (1980); Edstrom et al. (1980) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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