Clinical Diagnosis

The term myofibrillar myopathy refers to a group of genetically distinct disorders linked by common morphologic features observed on muscle histology.

The diagnosis of myofibrillar myopathy rests on the following:

• History of slowly progressive weakness accompanied in a smaller proportion of individuals by paresthesias, muscle atrophy, stiffness or aching, cramps, dyspnea, and dysphagia. Physical examination reveals proximal and distal weakness in the majority of individuals; in about one-third, the weakness is greater proximally than distally, and in another third, it is greater distally than proximally. Facial weakness is uncommon but can occur. Tendon reflexes are normal or diminished.

• Electromyography (EMG) that reveals abnormal electrical irritability (fibrillation potentials, positive sharp waves, complex repetitive discharges, and myotonic discharges) in most individuals. The motor unit potentials show either myopathic features or both myopathic and neurogenic features. Abnormal nerve conduction studies are detected in about 20% of individuals.

• Muscle histology that reveals: (1) characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers; (2) sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions; (3) intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and (4) small vacuoles in a variable number of fibers. The combination of these findings points to the diagnosis of myofibrillar myopathy (see Figure 1).

• Immunocytochemical studies of muscle that show abnormal ectopic expression of myotilin (90% of abnormal fibers), desmin (75%), α-B crystallin (75%), dystrophin (70%), and β-amyloid precursor protein (70%) on immunocytochemical studies

• Electron microscopy of muscle showing progressive myofibrillar degeneration commencing at the Z-disk, disintegration of the sarcomeres, accumulation of degraded filamentous material in pleomorphic hyaline inclusions, and dislocation of membranous organelles and their degradation in autophagic vacuoles [Selcen et al 2004]

• Other tissues. Peripheral nerve biopsies, in a few descriptions, show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids; myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis. Peripheral nerve pathology [Sabatelli et al 1992] and myocardial pathology [Abraham et al 1998, Arbustini et al 1998, Lobrinus et al 1998] have been described briefly in a small number of individuals with myofibrillar myopathy.

• Serum creatine kinase concentration can be normal or elevated to no greater than seven times the upper limit of normal.

Figure

Figure 1. Muscle histology observed in myofibrillar myopathy

Molecular Genetic Testing

Genes. So far, the genetic basis of myofibrillar myopathy (MFM) has been elucidated in only a minority of cases. In 54% of the Mayo Clinic's cohort of 80 unrelated individuals with myofibrillar myopathy, the genetic basis was not established. Mutations have been identified in the following genes:

• DES, encoding desmin [Goldfarb et al 1998, Munoz-Marmol et al 1998, Dalakas et al 2000]

• CRYAB, encoding α-B crystallin [Vicart et al 1998, Selcen & Engel 2003]

• MYOT (known previously as TTID), encoding myotilin [Selcen & Engel 2004]

• LDB3 (known previously as ZASP), encoding LIM domain-binding protein 3 [Selcen & Engel 2005]

• FLNC, encoding filamin C [Vorgerd et al 2005]

• BAG3, encoding Bag3 [Selcen et al 2009]

Clinical testing

• Sequence analysis

  • DES. Sequence analysis of DES is expected to identify approximately 99% of mutations in exons 1-9.

  • CRYAB. Mutation detection frequency is unknown.

  • MYOT. Mutation detection frequency is unknown.

  • LDB3. Mutation detection frequency is unknown.

  • FLNC. Mutation detection frequency is unknown.

  • BAG3. Mutation detection frequency is unknown.

Table 1. Summary of Molecular Genetic Testing Used in Myofibrillar Myopathy

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Gene Symbol	Proportion of MFM Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 2	Test Availability
DES	8%	Sequence analysis	Sequence variants 3	99%	Clinical
CRYAB	3%	Sequence analysis	Sequence variants 3	Unknown	Clinical
MYOT	13%	Sequence analysis	Sequence variants 3	Unknown	Clinical
LDB3	14%	Sequence analysis	Sequence variants 3	Unknown	Clinical
FLNC	4%	Sequence analysis	Sequence variants 3	Unknown	Clinical
BAG3	4%	Sequence analysis	Sequence variants 3	Unknown	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Frequencies based on Mayo Clinic MFM cohort

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Testing Strategy

To confirm/establish the diagnosis in a proband

• Generic basis of an MFM can be made on clinical and histologic grounds.

• The diagnosis of a specific MFM is based on molecular genetic testing.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Cardiomyopathy can occur with each genetically defined type of MFM.

Mutations in CRYAB can also cause cataracts without causing myofibrillar myopathy.

Mutations in MYOT can also present with a limb girdle-like phenotype that has been designated as LGMD1A [Hauser et al 2000] and also as a distal myopathy [Fischer et al 2006, Penisson-Besnier et al 2006] (see Limb-Girdle Muscular Dystrophy Overview).

Natural History

In the Mayo Clinic series of 80 individuals with myofibrillar myopathy (MFM), the age of onset varied from two to 77 years. The age at diagnosis ranged from 11 to 82 years. BAG3-related myofibrillar myopathy (Bag3opathy) characteristically presents in the first or second decade of life and is highly fatal. Desminopathies may also present in the first decade of life, usually with cardiomyopathy. However, the majority of MFM presents after age 40 years.

The predominant presenting symptom is slowly progressive weakness; a minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. The weakness can involve both proximal and distal muscles; however, distal muscle weakness is 25% more common than proximal weakness.

Objective clinical signs or EMG findings of peripheral neuropathy are present in approximately 20% of affected individuals, but muscle biopsy studies suggest an even higher frequency of peripheral nerve involvement.

Overt cardiomyopathy can be a presenting manifestation or can appear during the evolution of myofibrillar myopathy in 15%-30% of affected individuals.

A restrictive ventilatory defect can result from respiratory muscle weakness.

Variable expressivity has been observed in kinships with mutations in DES, with some family members showing signs of cardiomyopathy only, some showing signs of both myopathy and cardiomyopathy, and some with reduced penetrance who have signs of neither myopathy nor cardiomyopathy.

Genotype-Phenotype Correlations

The only genotype-phenotype correlations detected to date:

• Cataracts were present in affected members of one of the three reported kinships with mutations in CRYAB, the gene encoding alpha crystallin B chain (also known as α-B crystallin) [Vicart et al 1998].

• Neuropathy and cardiomyopathy were observed in families with mutations in MYOT [Selcen & Engel 2004] and BAG3 [Selcen et al 2009].

• Rigid spine has been observed in Bag3opathy [Selcen et al 2009].

• Neuropathy and cardiomyopathy also occur in individuals in whom the genetic basis of myofibrillar myopathy has not been established.

• No morphologic features consistently or reliably predict mutation in a given gene.

• The p.Ala147Val mutation in LDB3 presents as a distal myopathy [Selcen & Engel 2004, Griggs et al 2007].

Penetrance

Data are insufficient to draw conclusions about penetrance.

Anticipation

No convincing evidence of anticipation has been documented.

Nomenclature

"… The light microscopic features of myofibrillar myopathy were described in the 1970s and 1980s under such names as 'myopathy with inclusion bodies' [Nakashima et al 1970], 'atypical myopathy with myofibrillar aggregates' [Kinoshita et al 1975], 'autosomal dominant cardiomyopathy with inclusions' [Clark et al 1978], 'cardioskeletal myopathy with intrasarcoplasmic dense granulofilamentous material' [Fardeau et al 1978], 'autosomal dominant spheroid body myopathy' [Goebel et al 1978], ‘myopathy with sarcoplasmic bodies and desmin filaments’ [Edstrom et al 1980], 'congenital myopathy with cytoplasmic bodies' [Wolburg et al 1982], 'congenital myopathy with Mallory body-like inclusions' [Fidzianska et al 1983], and 'familial cardiomyopathy with subsarcolemmal vermiform deposits' [Calderon et al 1987]. Later, however, it became apparent that some authors described the same pathologic reaction under different names; that more than one pathologic alteration thought to be specific for a single disorder could be present in the same muscle specimen, or even in the same muscle fiber; and that in each instance the pathologic changes involve the Z-disks of the myofibril. Edstrom et al [1980] noted that some inclusions or material around them reacted for desmin. This generated the names of 'desmin storage myopathy' [Horowitz & Schmalbruch 1994] and later 'desmin-related myopathies' [Goebel 1997]. In 1996 and 1997, detailed immunocytochemical studies revealed that many proteins, not just desmin, accumulate in the abnormal fibers, and prompted the use of the noncommittal term myofibrillar myopathy [De Bleecker et al 1996, Nakano et al 1997]…"

[Selcen et al 2004; republished with permission of Oxford University Press]

Myofibrillar myopathy has also been referred to as desmin storage myopathy, desmin-related myopathy, or protein surplus myopathy. Because myofibrillar myopathy is genetically heterogeneous and the disease-causing protein or gene is known only in a minority of cases, because multiple other proteins besides desmin are also overexpressed in muscle, and because myotilin is not related to desmin, the noncommittal term "myofibrillar myopathy" is the preferred designation until the gene in which mutation is causative is determined. When the disease-associated protein is identified, designations such as desminopathy, α-B crystallinopathy, myotilinopathy, zaspopathy, filaminopathy, or Bag3opathy are appropriate.

Prevalence

The prevalence of myofibrillar myopathy cannot be estimated at this time.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with myofibrillar myopathy (MFM), the following evaluations are recommended:

• EMG

• Routine ECG to identify arrhythmias and cardiac conduction defects; Holter monitoring if symptoms suggest an intermittent arrhythmia; echocardiogram if cardiac symptoms are present

• Respiratory function tests if respiratory symptoms are present

Treatment of Manifestations

Pacemaker and implantable cardioverter defibrillator (ICD) should be considered in individuals with arrhythmia and/or cardiac conduction defects. Individuals with progressive or life-threatening cardiomyopathy are candidates for cardiac transplantation.

Respiratory support, consisting of continuous or bilevel positive airway pressure (CPAP and BIPAP), initially at night and later in the daytime, is indicated in individuals with hypercapnea and other signs of incipient ventilatory failure.

Range of motion physical therapy and assistive devices are appropriate for those with advanced muscle weakness. Treatment of scoliosis by spinal fusion is appropriate. Orthoses are indicated for treatment of foot drop.

Surveillance

The following are appropriate:

• Physical examination to monitor disease progression yearly or less often depending on rate of progression

• Electrocardiogram and/or echocardiogram yearly for early detection of cardiomyopathy

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

The role of strengthening exercises has not been defined.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Myofibrillar myopathy (MFM) is inherited in an autosomal dominant manner. The inheritance pattern in some families cannot be determined because of the late onset of the disease in many affected individuals and because parents who are mildly affected heterozygotes may have deceased before becoming symptomatic for MFM.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Approximately 25% of individuals diagnosed with myofibrillar myopathy have an affected parent.

• A proband with myofibrillar myopathy may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical examination looking for weakness, EMG, and possible muscle biopsy. Molecular genetic testing may also be appropriate if a disease-causing mutation has been identified in the proband.

Note: Twenty-five percent of individuals diagnosed with myofibrillar myopathy have an affected parent; in other individuals, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband cannot be determined with confidence.

• Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. In most kinships, each child of an individual with myofibrillar myopathy has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder and/or the disease-causing mutation, the proband likely has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption or maternity (e.g., with assisted reproduction) could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for some forms of myofibrillar myopathy is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

No laboratories offering molecular genetic testing for prenatal diagnosis for other forms of myofibrillar myopathy are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified.

Note: When no laboratories offering prenatal testing are listed in the GeneTests Laboratory Directory, such testing may still be available (1) through a laboratory not listed in GeneTests or (2) through laboratories offering custom prenatal testing (see ).

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Because myofibrillar myopathy is caused by mutation of different genes and each disease-associated gene may have different mutations, the molecular pathogenesis may vary from case to case. However, in all myofibrillar myopathies, the initial pathologic change involves disintegration of the Z-disk, and all disease proteins identified to date are involved in maintaining the structural integrity of the Z-disk. Because the Z-disks are sites of tension transmission between sarcomeres, the myofibrils fall apart when the Z-disks disintegrate.

Animal models. Desmin knockout mice show normal development of cardiac and skeletal muscle but subsequently show myofiber necrosis and phagocytosis [Capetanaki et al 1997]. This model is not comparable with human cases of desminopathy in which missense mutations weaken sarcomere structure and are associated with abnormal accumulation of desmin and other proteins. Transgenic mice carrying deleted human desmin (p.Arg173_Glu179del) show desmin immunoreactive aggregates in myocardium [Munoz-Marmol et al 1998]. Transgenic mice expressing an α-B crystallin mutation p.Arg120Gly develop a severe cardiomyopathy with abnormal accumulation of desmin and α-B crystallin in the heart. Muscle pathology is not mentioned in this report [Wang et al 2001].

DES

Normal allelic variants. DES consists of nine exons.

Pathologic allelic variants. Twenty-one mutations, including missense, frameshifting nucleotide insertion, small in-frame deletion, and splice-site mutations, have been reported [Goldfarb et al 2004]. See Table 2.

Normal gene product. Desmin is a constituent of intermediate filaments in cardiac and skeletal muscle linking Z-disks with each other and to the subsarcolemmal cytoskeleton.

Abnormal gene product. Expression data suggest abnormal aggregation of mutant desmin molecules in heterologous systems. Mutations may interfere with desmin assembly and filament formation [Bar et al 2006].

CRYAB

Normal allelic variants. CRYAB consists of three exons.

Pathologic allelic variants. A nonsense mutation, a missense mutation, and a small frameshifting deletion have been reported [Vicart et al 1998, Selcen & Engel 2003]. See Table 3.

Normal gene product. Alpha crystallin B chain (α-B crystallin) is a small heat-shock chaperone protein required for maintaining the structural integrity of desmin.

Abnormal gene product. Mutant alpha crystallin B chain molecules form smaller molecular-weight polymers than wild type in human muscle. In heterologous cells that constitutively express desmin, misfolded desmin molecules appear in aggregates.

MYOT (TTID)

Normal allelic variants. MYOT consists of ten exons.

Pathologic allelic variants. Five missense mutations have been reported; all are in exon 2 [Hauser et al 2000, Hauser et al 2002, Selcen & Engel 2004]. See Table 4.

Normal gene product. Myotilin is a key Z-disk protein that interacts with α-actinin, filamin-C, and actin.

Abnormal gene product. Mutant myotilin is predicted to weaken the linkage of Z-disk filaments to thin filaments. Transgenic mice with the p.Thr57Ile mutation and muscle disease similar to LGMD1A have been described [Garvey et al 2006].

LDB3 (ZASP)

Normal allelic variants. LDB3 consists of 16 exons. It is alternatively spliced.

Pathologic allelic variants. Three missense mutations have been reported [Selcen & Engel 2005]. See Table 5.

Normal gene product. LIM domain-binding protein 3 (Zasp) is a key Z-disk protein that interacts with α-actinin and protein kinase C.

Abnormal gene product. Mutant LIM domain-binding protein 3 (Zasp) is predicted to weaken the linkage of Z-disk filaments to thin filaments.

FLNC

Normal allelic variants. FLNC consists of 48 exons. No splice variants have been identified.

Pathologic allelic variants. One nonsense mutation and one in-frame deletion have been reported [Vorgerd et al 2005, Shatunov et al 2009].

Normal gene product. Filamin-C is a Z-disk protein that interacts with actin and myotilin.

Abnormal gene product. Mutant filamin-C has a disturbed secondary structure that prevents normal dimerization.

BAG3

Normal allelic variants. BAG3 consists of four exons. No splice variants have been identified.

Pathologic allelic variants. The mutation p.Pro209Leu has been reported [Selcen et al 2009]. See Table 6.

Normal gene product. Bag3 is a co-chaperone for the Z-disk and has anti-apoptotic properties.

Abnormal gene product. Mutant Bag3 may alter the folding of Bag3 or may allosterically affect the binding properties of the canonical Bag3 domains.

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Suggested Reading

1. Olivé M. Extralysosomal protein degradation in myofibrillar myopathies. Brain Pathol. 2009;19:507–15. [PubMed: 19563542]
2. Piñol-Ripoll G, Shatunov A, Cabello A, Larrodé P, de la Puerta I, Pelegrín J, Ramos FJ, Olivé M, Goldfarb LG. Neuromuscul Disord. 2009;19:418–22. [PMC free article: PMC2695848] [PubMed: 19433360]
3. Schroder R, Schoser B. Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol. 2009;19:483–92. [PubMed: 19563540]
4. Selcen D. Myofibrillar myopathies. Curr Opin Neurol. 2008;21:585–9. [PubMed: 18769253]
5. Shalaby S, Mitsuhashi H, Matsuda C, Minami N, Noguchi S, Nonaka I, Nishino I, Hayashi YK. J Neuropathol Exp Neurol. 2009;68:701–7. [PubMed: 19458539]

Revision History

• 27 July 2010 (cd) Revision: sequence analysis for BAG3 mutations available clinically

• 2 February 2010 (me) Comprehensive update posted live

• 10 March 2008 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for zaspopathy (LDB3 mutations)

• 1 March 2007 (me) Comprehensive update posted to live Web site

• 9 January 2006 (ds) Revision: included disorders added (zaspopathy, filaminopathy)

• 1 July 2005 (ds) Revision: DES testing clinically available

• 28 January 2005 (me) Review posted to live Web site

• 2 August 2004 (ds) Original submission