Alternative titles; symbols
SNOMEDCT: 770627003; ORPHA: 98909; DO: 0080092;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q35 | Myopathy, myofibrillar, 1 | 601419 | Autosomal dominant; Autosomal recessive | 3 | DES | 125660 |
A number sign (#) is used with this entry because myofibrillar myopathy-1 (MFM1) is caused by heterozygous, homozygous, or compound heterozygous mutation in the desmin gene (DES; 125660) on chromosome 2q35.
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 MFM2 (608810), caused by mutation in the CRYAB gene (123590); MFM3 (609200), caused by mutation in the MYOT gene (604103); MFM4 (609452), caused by mutation in the ZASP gene (LDB3; 605906); MFM5 (609524), caused by mutation in the FLNC gene (102565); MFM6 (612954), caused by mutation in the BAG3 gene (603883); MFM7 (617114), caused by mutation in the KY gene (605739); MFM8 (617258), caused by mutation in the PYROXD1 gene (617220); MFM9 (603689), caused by mutation in the TTN gene (188840); MFM10 (619040), caused by mutation in the SVIL UNC45B gene (611220); MFM11 (619178), caused by mutation in the UNC45B gene (611220); and MFM12 (619424), caused by mutation in the MYL2 gene (160781).
'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), is another desmin-related myopathy. Goebel (1995) provided a review of desmin-related myopathy.
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.
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.
Messina et al. (1997) observed dilated cardiomyopathy with conduction defect and adult-onset limb-girdle muscular dystrophy in an extensively affected 4-generation family. Twenty-five members were identified as affected on the basis of the presence of cardiac conduction defects, cardiomyopathy, and/or proximal muscle weakness. The proband underwent evaluation for cardiac transplantation at the age of 37 years. Symptoms of muscle weakness had been noted as early as age 17 years. Dyspnea on exertion had been present since age 25 years. A pacemaker had been implanted at age 29 years because of syncopal episodes due to complete heart block. All 4 chambers of the heart were dilated on echocardiography. Laboratory studies showed increased serum creatine kinase, and muscle biopsies showed dystrophic changes. The proband's father died at age 49 years of congestive heart failure and arrhythmia. In follow-up of this family, Greenberg et al. (2012) stated that the proband eventually underwent cardiac transplantation. He had progressive proximal limb weakness, greater in the legs, and mildly increased serum creatine kinase at age 40 years. Endomyocardial biopsy showed fibrosis and myocyte hypertrophy. Skeletal muscle biopsy showed abundant dense cytoplasmic inclusions that occasionally stained with menadione-linked nitro blue tetrazolium, consistent with reducing bodies. There was variation in fiber size, internal nuclei, mild endomysial fibrosis, rare vacuoles, and isolated degenerating fibers. Electron microscopy showed that the inclusions were composed of fibrils and granulofilamentous material. Laser capture microdissection and mass spectrometric analysis identified desmin in the inclusions.
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.
Melberg et al. (1999) studied 12 patients from a Swedish family with myopathy and cardiomyopathy, and reviewed the medical records of 2 affected deceased members. Twelve patients, including the deceased individuals, had myopathy. The distribution of weakness was axial in mildly affected patients, axial and predominantly distal in moderately affected persons, and generalized in severely affected patients. The electromyogram showed signs of myopathy in 10 patients. Muscle biopsy specimens showed myopathic changes, rimmed vacuoles, and accumulation of desmin, dystrophin, and other proteins. Electron microscopy demonstrated granulofilamentous changes and disorganization of myofibrils. Several patients had episodes of chest pain or palpitations. Three men had arrhythmogenic right ventricular cardiomyopathy (ARVC). Nonsustained ventricular tachycardia, atrial flutter, and dilatation of the ventricles mainly affecting the right ventricle were documented. Two of the men had a pacemaker implanted because of atrial ventricular block and sick sinus syndrome (see 608567). Inheritance was autosomal dominant with variable onset and severity of skeletal muscle and cardiac involvement. Onset of muscle weakness was between the third and sixth decades. One of the deceased patients was found to have dilatation of the right ventricle, which on histologic examination, showed fibrofatty replacement of the myocardium, extending from the epicardium to the endocardium. Similar but less extensive changes were present in the left ventricle.
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.
Bergman et al. (2007) studied 2 distantly related 4-generation Dutch families segregating autosomal dominant desmin-related myopathy, in which a total of 15 patients exhibited a highly heterogeneous clinical picture, varying from isolated dilated cardiomyopathy to a more generalized skeletal myopathy and mild respiratory problems. The female proband of the first family presented at 30 years of age with myopathy and later developed cardiac arrhythmias, requiring pacemaker placement at 45 years of age. The male proband of the second family presented with arrhythmias at 31 years of age and developed slowly progressive weakness of the proximal leg muscles starting at age 52. Overall, 13 (87%) of 15 presumably affected family members presented with cardiac problems between the ages of 25 and 60 years, consisting mainly of cardiac conduction defects. Skeletal muscle weakness beginning in either proximal or distal musculature was present in 6 (40%) of the affected individuals, with onset between 30 and 58 years of age. Mild respiratory function disturbance was found in 2 patients. Causes of death, occurring between 31 and 76 years of age, were presumably heart attack in 6 patients, heart failure in 3 patients, sudden cardiac death in 1 patient, and unknown in 1 patient. Skeletal muscle biopsy showed increased variation in muscle fiber size and fatty degeneration in both probands, with endomysial fibrosis and central nuclei observed as well in the male proband. Desmin staining showed an irregular pattern in both patients. Endomyocardial biopsy in the female proband's affected sister showed hypertrophic cardiomyocytes as well as degenerating cardiomyocytes with central vacuolar changes; staining revealed dense aggregates of desmin and variable patterns of p62 (SQSTM1; 601530), ranging from fine granular staining and small dense inclusions to muscle fibers that were almost completely filled. Postmortem skeletal muscle biopsy demonstrated severe muscle pathology with vacuolar changes, and desmin staining ranged from small clumps on a normal-appearing background to fibers showing complete and intense staining. Bergman et al. (2007) noted that these families illustrated the broad intrafamilial variability of desmin-related myopathy, since 6 affected individuals exhibited isolated cardiac conduction disease or heart failure, whereas 1 family member presented with skeletal muscle weakness as the only feature.
Pica et al. (2008) reported a 39-year-old Chinese man who presented with complete heart block requiring pacemaker insertion following a syncopal episode. Examination revealed mild and symmetric weakness of both proximal and distal muscles; bilateral elbow flexion contractures of 20 degrees were also noted. Serum CK was elevated, and electromyography was consistent with myopathy. Echocardiography showed no evidence of cardiomyopathy. Family evaluation revealed a brother with a similar distribution as well as severity of muscle weakness and elevated CK levels, whereas the patient's mother and a sister had very mild proximal and distal weakness, with CK values just above the upper limits of normal. His brother also reported 2 episodes of unexplained syncope, and the affected sister reported episodes of palpitations.
Van Tintelen et al. (2009) restudied the Dutch kindred with MFM1 reported by Bergman et al. (2007) and expanded it to include 3 distantly related families. The authors described 2 more affected Dutch families whose ancestors could be traced to the same small, poorly populated region in which the common ancestral couple of the large Dutch kindred had lived. The 27 affected individuals demonstrated a fully penetrant yet variable phenotype: all had predominantly cardiac involvement characterized by high-grade atrioventricular (AV) block at young ages and significant right ventricular involvement, including right bundle branch block (RBBB) in 10 patients, sometimes as a first manifestation, and right ventricular heart failure in 6 patients. Two of the latter patients fulfilled the criteria for ARVC. Immunofluorescence analysis of patient myocardia showed normal amounts of the major desmosomal proteins, but intercalated discs were more convoluted and elongated and had a zigzag appearance compared to controls.
Otten et al. (2010) reported a Dutch family with desmin-related myopathy and ARVC. The proband, who had had palpitations since childhood, presented at 36 years of age with decreased leg strength. At age 39, he had atrial fibrillation, and 2 years later electrocardiogram showed first-degree AV block, sinus arrests, premature ventricular contractions, negative T waves in multiple leads, and an epsilon wave. At age 42, he collapsed and required resuscitation, after which a cardioverter-defibrillator was implanted. Echocardiography showed right ventricular dilation with hypokinesia and akinesia, consistent with a diagnosis of ARVC. Skeletal muscle biopsy at age 44 demonstrated desminopathy; the weakness of his leg musculature was progressive, with eventual involvement of his hand and diaphragmatic muscles. A brother of the patient also experienced loss of leg strength at age 41, and muscle biopsy at age 43 showed desminopathy; cardiac evaluation at age 46 showed first-degree AV block and slightly decreased left ventricular function, consistent with incipient cardiomyopathy. Their father had progressive loss of leg strength and was wheelchair-dependent when he died at age 59 from pneumonia; he had never undergone cardiac evaluation.
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.
Cetin et al. (2013) reported 2 Turkish sibs, born of consanguineous parents, with young-adult onset of what the authors described as progressive limb-girdle muscular dystrophy, formerly designated as LGMD2R. The 39-year-old proband had developed progressive proximal muscle weakness of the arms and legs at age 15 years. He had mild facial muscle weakness and mild scapular winging but severe limb weakness and was wheelchair-bound since age 33 years. He had no subjective cardiac complaints or cardiomyopathy, but studies showed incomplete right bundle branch block and rare ventricular extrasystoles. Cognition was normal and he had no bulbar symptoms. Muscle biopsy showed dystrophic features with variation in fiber size, internal nuclei, and fibrosis, but no evidence of myofibrillar disruption or aggregation of abnormal proteins. There was a predominance of type 2 fibers. His 45-year-old sister had similar muscle complaints with proximal muscle weakness starting at age 27 years. She became wheelchair-bound most of the time at age 43, and could only walk a few steps at age 46. She had rare ventricular extrasystoles and echocardiography showed normal left ventricular function with mild tricuspid insufficiency; there was no evidence of cardiomyopathy.
Gudkova et al. (2013) reported a 27-year-old man with a splicing mutation in the DES gene who developed cardiomyopathy that transitioned from an initial hypertrophic appearance to a restrictive form, and later to a dilated phenotype. He also had cardiac arrhythmias and AV block, and electroneuromyography confirmed a myopathic pattern with predominantly proximal muscle involvement.
Ojrzynska et al. (2017) studied a 62-year-old woman with progressive skeletal weakness, primarily of the lower extremities, who had a splicing mutation in the DES gene. She was pacemaker-dependent due to cardiac arrhythmias, and echocardiography was consistent with restrictive cardiomyopathy. She died at age 65 at home. Her son was also diagnosed with restrictive cardiomyopathy, and died after cardiac transplantation at 23 years of age.
Riley et al. (2019) reported 2 Italian sisters who presented in their mid to late 20s with a limb-girdle pattern of muscle weakness and elevated serum creatine kinase. The weakness was slowly progressive and associated with cardiomyopathy and respiratory weakness. In the younger sister, echocardiogram showed severe systolic dysfunction requiring defibrillator insertion, with an ejection fraction of 15% and dilated left ventricle, and electrocardiogram showed prolonged QRS. A skeletal muscle biopsy at age 27 showed dystrophic changes, with variation in fiber size, scattered necrotic fibers, and an increase in central nuclei; oxidative stains were normal. Electron microscopy showed extensive myofibrillar disarray and reduplication of basal lamina, but no inclusions or granulofilamentous aggregates. By age 34, she developed respiratory weakness requiring continuous positive airway pressure, and by age 43, she became wheelchair dependent. Her older sister showed a somewhat less severe clinical course, presenting with progressive limb-girdle weakness with cardiac involvement at the age of 29 years, and requiring use of a wheelchair at age 45. In addition, the older sister did not have insertion of a defibrillator or any respiratory support at the time of evaluation.
By linkage analysis of the large family with autosomal dominant myopathy 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.
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 6 patients from 4 unrelated families with desmin-related myopathy, Bar et al. (2007) identified mutations in the DES gene (see, e.g., 125660.0015).
In affected members of 2 distantly related Dutch families segregating autosomal dominant desmin-related myopathy with a highly heterogeneous clinical picture, varying from isolated dilated cardiomyopathy to more generalized skeletal myopathy and mild respiratory problems, Bergman et al. (2007) identified heterozygosity for a missense mutation in the DES gene (S13F; 125660.0019) that was not found in unaffected family members or in 216 ethnically matched controls.
In 4 affected members of a 2-generation Chinese family with desmin-related myopathy, Pica et al. (2008) identified heterozygosity for the S13F mutation in the DES gene.
Van Tintelen et al. (2009) restudied the Dutch kindred with MFM1 previously reported by Bergman et al. (2007), now expanded to 3 distantly related families. The authors described 2 more affected Dutch families whose ancestors could be traced to the same small, poorly populated region in which the common ancestral couple of the large Dutch kindred had lived. All 27 affected individuals were heterozygous for the S13F mutation, and demonstrated a fully penetrant yet variable predominantly cardiologic phenotype, characterized by conduction disease at an early age and right ventricular involvement, including RBBB and/or right ventricular tachycardias and ARVC phenocopies. Based on haplotype analysis, the mutation was estimated to be between 220 and 495 years old.
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.
In a Dutch patient with desmin-related myopathy and arrhythmogenic right ventricular cardiomyopathy (ARVC), Otten et al. (2010) identified heterozygosity for a missense mutation in the DES gene (N342D; 125660.0020).
In affected members of a large family with autosomal dominant limb-girdle muscular dystrophy and cardiomyopathy (Messina et al., 1997), Greenberg et al. (2012) identified a heterozygous mutation in the desmin gene (125660.0008). The mutation was found after laser capture microdissection of skeletal muscle and mass spectrometry-based proteomics identified desmin as the major constituent of cytoplasmic inclusions. Initial mapping studies on this family by Messina et al. (1997) had found linkage to chromosome 6q23, and the locus was designated 'LGMD1D.' Subsequent mapping by Greenberg et al. (2012) excluded 6q23 due to absence of cosegregation of this locus with the phenotype in affected family members.
By exome sequencing in the Swedish family with myofibrillar myopathy and ARVC reported by Melberg et al. (1999), Hedberg et al. (2012) identified a heterozygous mutation in the DES gene (P419S; 125660.0017) in affected members.
In 2 sibs with MFM1 who were diagnosed with a form of limb-girdle muscular dystrophy, Cetin et al. (2013) identified a homozygous splice site mutation in the DES gene (125660.0018). The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder and was not found in several control databases. The mutant protein was expressed in patient skeletal muscle, which had normal myofibrillar organization, but confocal laser scanning microscopy showed a disruption in binding between desmin and lamin B (LMNB1; 150340), which is a component of the nuclear lamina.
In 2 Italian sisters with limb-girdle weakness and cardiomyopathy, who were negative for mutation in 5 known muscular dystrophy-associated genes, Riley et al. (2019) performed whole-genome sequencing and identified compound heterozygosity for a missense mutation and a deep intronic variant in the DES gene. The mutations segregated with disease in the family, and neither variant was found in the gnomAD database. Noting the previously reported severe infantile presentation associated with homozygous loss-of-function DES variants (Pinol-Ripoll et al., 2009), Riley et al. (2019) considered these affected sisters, with expression of diminished levels of mutant desmin, to have extended the phenotypic spectrum of recessive desminopathy, with onset in late teens to early 20s. In addition, muscle biopsy showed extensive myofibrillar disarray, but did not show the aggregates typical of DES myofibrillar myopathy, which the authors noted were also not present in the sibs described by Cetin et al. (2013).
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.
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 had previously been referred to in OMIM as IBM1 to distinguish it in particular from autosomal recessive IBM2 (see 605820), 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.
The symbol 'LGMD1D' had previously been used in OMIM for a form of limb-girdle muscular dystrophy mapping to chromosome 7q; however, according to the report of the 105th ENMC workshop, the form of LGMD mapping to chromosome 7q has been designated 'LGMD1E' (603511) (Bushby and Beckmann, 2003). The symbol 'LGMD1D' was later used for a form of LGMD and cardiomyopathy mapped to 6q23 in 1 family (Messina et al., 1997); however, the disorder in that family was later mapped to 2q35 and found to be caused by mutation in the desmin gene (Greenberg et al., 2012).
Limb-girdle muscular dystrophy-2R (LGMD2R) was reclassified as a form of myofibrillar myopathy caused by mutation in the DES gene by Straub et al. (2018).
The symbol 'ARVD7' was initially used for a form of myofibrillar myopathy with arrhythmogenic right ventricular dysplasia identified in a large Swedish family and mapped to chromosome 10q22 by Melberg et al. (1999) and Kuhl et al. (2008). Reevaluation of that family by Hedberg et al. (2012) found that affected individuals carried a heterozygous mutation in the DES gene (P419S; 125660.0017) on chromosome 2, indicating that this family has myofibrillar myopathy-1.
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.
Abe, K., Kobayashi, K., Chida, K., Kimura, N., Kogure, K. Dominantly inherited cytoplasmic body myopathy in a Japanese kindred. Tohoku J. Exp. Med. 170: 261-272, 1993. [PubMed: 8122252] [Full Text: https://doi.org/10.1620/tjem.170.261]
Ariza, A., Coll, J., Fernandez-Figueras, M. T., Lopez, M. D., Mate, J. L., Garcia, O., Fernandez-Vasalo, A., Navas-Palacios, J. J. Desmin myopathy: a multisystem disorder involving skeletal, cardiac, and smooth muscle. Hum. Path. 26: 1032-1037, 1995. [PubMed: 7672786] [Full Text: https://doi.org/10.1016/0046-8177(95)90095-0]
Bar, H., Goudeau, B., Walde, S., Casteras-Simon, M., Mucke, N., Shatunov, A., Goldberg, Y. P., Clarke, C., Holton, J. L., Eymard, B., Katus, H. A., Fardeau, M., Goldfarb, L., Vicart, P., Herrmann, H. Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies. Hum. Mutat. 28: 374-386, 2007. [PubMed: 17221859] [Full Text: https://doi.org/10.1002/humu.20459]
Barohn, R. J., Amato, J. J., Griggs, R. C. Overview of distal myopathies: from the clinical to the molecular. Neuromusc. Disord. 8: 309-316, 1998. [PubMed: 9673984] [Full Text: https://doi.org/10.1016/s0960-8966(98)00030-3]
Bergman, J. E. H., Veenstra-Knol, H. E., van Essen, A. J., van Ravenswaaij, C. M. A., den Dunnen, W. F. A., van den Wijngaard, A., van Tintelen, J. P. Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene. Europ. J. Med. Genet. 50: 355-366, 2007. [PubMed: 17720647] [Full Text: https://doi.org/10.1016/j.ejmg.2007.06.003]
Bushby, K. M., Beckmann, J. S. The 105th ENMC sponsored workshop: pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies, Naarden, April 12-14, 2002. Neuromusc. Disord. 13: 80-90, 2003. [PubMed: 12467737] [Full Text: https://doi.org/10.1016/s0960-8966(02)00183-9]
Cetin, N., Balci-Hayta, B., Gundesli, H., Korkusuz, P., Purali, N., Talim, B., Tan, E., Selcen, D., Erdem-Ozdamar, S., Dincer, P. A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies. J. Med. Genet. 50: 437-443, 2013. [PubMed: 23687351] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101487]
Chapon, F., Viader, F., Fardeau, M., Tome, F., Daluzeau, N., Berthelin, C., Thenint, J. P., Lechevalier, B. Myopathie familiale avec inclusions de type corps cytoplasmiques (ou spheroides) revelee par une insuffisance respiratoire. Rev. Neurol. 145: 460-465, 1989. [PubMed: 2552561]
Clark, J. R., D'Agostino, A. N., Wilson, J., Brooks, R. R., Cole, G. C. Autosomal dominant myofibrillar inclusion body myopathy: clinical, histologic, histochemical, and ultrastructural characteristics. (Abstract) Neurology 28: 399 only, 1978.
Ferreiro, A., Ceuterick-de Groote, C., Marks, J. J., Goemans, N., Schreiber, G., Hanefeld, F., Fardeau, M., Martin, J.-J., Goebel, H. H., Richard, P., Guicheney, P., Bonnemann, C. G. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann. Neurol. 55: 676-686, 2004. [PubMed: 15122708] [Full Text: https://doi.org/10.1002/ana.20077]
Goebel, H. H. Desmin-related neuromuscular disorders. Muscle Nerve 18: 1306-1320, 1995. [PubMed: 7565929] [Full Text: https://doi.org/10.1002/mus.880181114]
Goldfarb, L. G., Park, K.-Y., Cervenakova, L., Gorokhova, S., Lee, H.-S., Vasconcelos, O., Nagle, J. W., Semino-Mora, C., Sivakumar, K., Dalakas, M. C. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nature Genet. 19: 402-403, 1998. [PubMed: 9697706] [Full Text: https://doi.org/10.1038/1300]
Greenberg, S. A., Salajegheh, M., Judge, D. P., Feldman, M. W., Kuncl, R. W., Waldon, Z., Steen, H., Wagner, K. R. Etiology of limb girdle muscular dystrophy 1D/1E determined by laser capture microdissection proteomics. Ann. Neurol. 71: 141-145, 2012. [PubMed: 22275259] [Full Text: https://doi.org/10.1002/ana.22649]
Gudkova, A., Kostareva, A., Sjoberg, G., Smolina, N., Turalchuk, M., Kuznetsova, I., Rybakova, M., Edstrom, L., Shlyakhto, E., Sejersen, T. Diagnostic challenge in desmin cardiomyopathy with transformation of clinical phenotypes. Pediat. Cardiol. 34: 467-470, 2013. [PubMed: 22484823] [Full Text: https://doi.org/10.1007/s00246-012-0312-x]
Hedberg, C., Melberg, A., Kuhl, A., Jenne, D., Oldfors, A. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation. Europ. J. Hum. Genet. 20: 984-985, 2012. [PubMed: 22395865] [Full Text: https://doi.org/10.1038/ejhg.2012.39]
Horowitz, S. H., Schmalbruch, H. Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship. Muscle Nerve 17: 151-160, 1994. [PubMed: 8114783] [Full Text: https://doi.org/10.1002/mus.880170204]
Kaminska, A., Strelkov, S. V., Goudeau, B., Olive, M., Dagvadorj, A., Fidzianska, A., Simon-Cateras, M., Shatunov, A., Dalakas, M. C., Ferrer, I., Kwiecinski, H., Vicart, P., Goldfarb, L. G. Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy. Hum. Genet. 114: 306-313, 2004. [PubMed: 14648196] [Full Text: https://doi.org/10.1007/s00439-003-1057-7]
Kuhl, A., Melberg, A., Meinl, E., Nurnberg, G., Nurnberg, P., Kehrer-Sawatzki, H., Jenne, D. E. Myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7: corroboration and narrowing of the critical region on 10q22.3. Europ. J. Hum. Genet. 16: 367-373, 2008. [PubMed: 18197198] [Full Text: https://doi.org/10.1038/sj.ejhg.5201980]
Melberg, A., Oldfors, A., Blomstrom-Lundqvist, C., Stalberg, E., Carlsson, B., Larsson, E., Lidell, C., Eeg-Olofsson, K. E., Wikstrom, G., Henriksson, K. G., Dahl, N. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann. Neurol. 46: 684-692, 1999. [PubMed: 10970245] [Full Text: https://doi.org/10.1002/1531-8249(199911)46:5<684::aid-ana2>3.0.co;2-#]
Messina, D. N., Speer, M. C., Pericak-Vance, M. A., McNally, E. M. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am. J. Hum. Genet. 61: 909-917, 1997. [PubMed: 9382102] [Full Text: https://doi.org/10.1086/514896]
Milhorat, A. T., Wolff, H. G. Studies in diseases of muscle. XIII. Progressive muscular dystrophy of atrophic distal type: report on a family: report of autopsy. Arch. Neurol. Psychiat. 49: 655-664, 1943.
Munoz-Marmol, A. M., Strasser, G., Isamat, M., Coulombe, P. A., Yang, Y., Roca, X., Vela, E., Mate, J. L., Coll, J., Fernandez-Figueras, M. T., Navas-Palacios, J. J., Ariza, A., Fuchs, E. A dysfunctional desmin mutation in a patient with severe generalized myopathy. Proc. Nat. Acad. Sci. 95: 11312-11317, 1998. [PubMed: 9736733] [Full Text: https://doi.org/10.1073/pnas.95.19.11312]
Ojrzynska, N., Bilinska, Z. T., Franaszczyk, M., Ploski, R., Grzybowski, J. Restrictive cardiomyopathy due to novel desmin gene mutation. Kardiol. Pol. 75: 723, 2017. Note: Electronic Article. [PubMed: 28703267] [Full Text: https://doi.org/10.5603/KP.2017.0129]
Otten, E., Asimaki, A., Maass, A., van Langen, I. M., van der Wal, A., de Jonge, N., van den Berg, M. P., Saffitz, J. E., Wilde, A. A. M., Jongbloed, J. D. H., van Tintelen, J. P. Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks. Heart Rhythm 7: 1058-1064, 2010. [PubMed: 20423733] [Full Text: https://doi.org/10.1016/j.hrthm.2010.04.023]
Park, K.-Y., Dalakas, M. C., Goebel, H. H., Ferrans, V. J., Semino-Mora, C., Litvak, S., Takeda, K., Goldfarb, L. G. Desmin splice variants causing cardiac and skeletal myopathy. J. Med. Genet. 37: 851-857, 2000. [PubMed: 11073539] [Full Text: https://doi.org/10.1136/jmg.37.11.851]
Pica, E. C., Kathirvel, P., Pramono, Z. A. D., Lai, P.-S., Yee, W.-C. Characterization of a novel S13F desmin mutation associated with desmin myopathy and heart block in a Chinese family. Neuromusc. Disord. 18: 178-182, 2008. [PubMed: 18061454] [Full Text: https://doi.org/10.1016/j.nmd.2007.09.011]
Pinol-Ripoll, G., Shatunov, A., Cabello, A., Larrode, P., de la Puerta, I., Pelegrin, J., Ramos, F. J., Olive, M., Goldfarb, L. G. Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin. Neuromusc. Disord. 19: 418-422, 2009. [PubMed: 19433360] [Full Text: https://doi.org/10.1016/j.nmd.2009.04.004]
Porte, A., Stoeckel, M.-E., Sacrez, A., Batzenschlager, A. Unusual familial cardiomyopathy with storage of intermediate filaments in the cardiac muscular cells. Virchows Arch. A Path. Anat. Histol. 386: 43-58, 1980. [PubMed: 7405006] [Full Text: https://doi.org/10.1007/BF00432643]
Riley, L. G., Waddell, L. B., Ghaoui, R., Evesson, F. J., Cummings, B. B., Bryen, S. J., Joshi, H., Wang, M.-X., Brammah, S., Kirtharides, L., Corbett, A., MacArthur, D. G., Cooper, S. T. Recessive DES cardio/myopathy without myofibrillar aggregates: intronic splice variant silences one allele leaving only missense L190P-desmin. Europ. J. Hum. Genet. 27: 1267-1273, 2019. [PubMed: 31024060] [Full Text: https://doi.org/10.1038/s41431-019-0393-6]
Saavedra-Matiz, C. A., Chapman, N. H., Wijsman, E. M., Horowitz, S. H., Rosen, D. R. Linkage of hereditary distal myopathy with desmin accumulation to 2q. Hum. Hered. 50: 166-170, 2000. [PubMed: 10686494] [Full Text: https://doi.org/10.1159/000022908]
Selcen, D., Ohno, K., Engel, A. G. Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain 127: 439-451, 2004. [PubMed: 14711882] [Full Text: https://doi.org/10.1093/brain/awh052]
Shelton, G. D., Sammut, V., Homma, S., Takayama, S., Mizisin, A. P. Myofibrillar myopathy with desmin accumulation in a young Australian Shepherd dog. Neuromusc. Disord. 14: 399-404, 2004. [PubMed: 15210162] [Full Text: https://doi.org/10.1016/j.nmd.2004.03.010]
Sjoberg, G., Saavedra-Matiz, C. A., Rosen, D. R., Wijsman, E. M., Borg, K., Horowitz, S. H., Sejersen, T. A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation. Hum. Molec. Genet. 8: 2191-2198, 1999. [PubMed: 10545598] [Full Text: https://doi.org/10.1093/hmg/8.12.2191]
Stoeckel, M.-E., Osborn, M., Porte, A., Sacrez, A., Batzenschlager, A., Weber, K. An unusual familial cardiomyopathy characterized by aberrant accumulations of desmin-type intermediate filaments. Virchows Arch. A Path. Anat. Histol. 393: 53-60, 1981. [PubMed: 6889780] [Full Text: https://doi.org/10.1007/BF00430870]
Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862] [Full Text: https://doi.org/10.1016/j.nmd.2018.05.007]
Vajsar, J., Becker, L. E., Freedom, R. M., Murphy, E. G. Familial desminopathy: myopathy with accumulation of desmin-type intermediate filaments. J. Neurol. Neurosurg. Psychiat. 56: 644-648, 1993. [PubMed: 8509778] [Full Text: https://doi.org/10.1136/jnnp.56.6.644]
van Spaendonck-Zwarts, K. Y., van Hessem, L., Jongbloed, J. D. H., de Walle, H. E. K., Capetanaki, Y., van der Kooi, A. J., van Langen, I. M., van den Berg, M. P., van Tintelen, J. P. Desmin-related myopathy. Clin. Genet. 80: 354-366, 2011. [PubMed: 20718792] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01512.x]
van Tintelen, J. P., Van Gelder, I. C., Asimaki, A., Suurmeijer, A. J. H., Wiesfeld, A. C. P., Jongbloed, J. D. H., van den Wijngaard, A., Kuks, J. B. M., van Spaendonck-Zwarts, K. Y., Notermans, N., Boven, L., van den Heuvel, F., Veenstra-Knol, H. E., Saffitz, J. E., Hofstra, R. M. W., van den Berg, M. P. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm 6: 1574-1583, 2009. [PubMed: 19879535] [Full Text: https://doi.org/10.1016/j.hrthm.2009.07.041]
Wolburg, H., Schlote, W., Langohr, H. D., Peiffer, J., Reiher, K. H., Heckl, R. W. Slowly progressive congenital myopathy with cytoplasmic bodies: report of two cases and a review of the literature. Clin. Neuropath. 1: 55-66, 1982. [PubMed: 6301720]