Clinical characteristics.

Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%.

Diagnosis/testing.

The diagnosis of myofibrillar myopathy is based on clinical findings, electromyography (EMG), nerve conduction studies, and, most importantly, muscle histology. To date, the genetic basis of myofibrillar myopathy has been elucidated in only about 50% of cases. Pathogenic variants have been identified in DES, the gene encoding desmin; CRYAB, encoding alpha-crystallin B chain; MYOT, encoding myotilin; LDB3 (ZASP), encoding LIM domain-binding protein 3; FLNC, encoding filamin-C, and BAG3, encoding BAG family molecular chaperone regulator 3. Recently, pathogenic variants in FHL1, encoding four and a half LIM domains protein 1, and DNAJB6, encoding DnaJ homolog subfamily B member 6 were also identified.

Management.

Treatment of manifestations: Consider pacemaker and implantable cardioverter defibrillator (ICD) in individuals with arrhythmia and/or cardiac conduction defects; consider cardiac transplantation in individuals with progressive or life-threatening cardiomyopathy; respiratory support (continuous or bilevel positive airway pressure), initially at night and later in the daytime, in individuals with hypercapnea and other signs of incipient respiratory failure; range-of-motion physical therapy and assistive devices for those with advanced muscle weakness.

Other: The role of strengthening exercises has not been defined.

Genetic counseling.

Myofibrillar myopathy is most commonly inherited in an autosomal dominant manner. Exceptions include: X-linked inheritance of FHL1 pathogenic variants and autosomal recessive inheritance of CRYAB pathogenic frameshift variants that lead to premature termination of the translational chain resulting in non-transcription of the mutated protein. The inheritance in some families cannot be determined with confidence. When the pathogenic variant(s) in the family are known, carrier testing and prenatal testing for pregnancies at increased risk is possible.

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; 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 the following combination of findings (see Figure 1):
  • Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers;
  • Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions;
  • Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics; and
  • Small vacuoles in a variable number of fibers
• 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%)
• 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 1.

Muscle histology observed in myofibrillar myopathy

Molecular Genetic Testing

Genes. To date, the genetic basis of myofibrillar myopathy (MFM) has been elucidated in about 50% of kinships. Pathogenic variants have been identified in the following genes:

• DES, encoding desmin [Goldfarb et al 1998, Muñoz-Mármol et al 1998, Dalakas et al 2000]
• CRYAB, encoding α-crystallin B chain [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 BAG family molecular chaperone regulator 3 (Bag3) [Selcen et al 2009]
• FHL1, encoding four and a half LIM containing protein 1 [Selcen et al 2011]
• DNAJB6, encoding DnaJ homolog subfamily B member 6 (heat shock protein 40) [Harms et al 2012; Sarparanta et al 2012; Author, personal observation]

Testing Strategy

To confirm/establish the diagnosis in a proband

• Generic diagnosis of an MFM can be made on clinical and histologic grounds.
• The diagnosis of a specific MFM is based on molecular genetic testing:
  • If the proband's symptoms suggest a candidate gene (see Genotype-Phenotype Correlations), perform sequence analysis of that gene first.
  • If no pathogenic variant is identified, perform sequence analysis for the remaining genes (Table 1).
  • At present no clear criteria for testing for deletions/duplications exist.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant(s) in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant(s) in the family.

Clinical Description

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 typically 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 in MFM 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 pathogenic variants 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

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

The only genotype-phenotype correlations detected to date are:

• Cataracts were present in affected members of one of the three reported kinships with pathogenic variants 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 pathogenic variants in MYOT [Selcen & Engel 2004] and BAG3 [Selcen et al 2009].
• Rigid spine has been observed in Bag3opathy [Selcen et al 2009] and FHL1-related MFM [Selcen et al 2011].
• Neuropathy and cardiomyopathy also occur in individuals in whom the genetic basis of myofibrillar myopathy has not been established.

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" [Edström 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. Edström 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 involved 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 generic term "myofibrillar myopathy" is the preferred designation until the gene(s) in which pathogenic variants occur are determined. When the disease-associated gene or protein is identified, designations such as desminopathy, α-B crystallinopathy, myotilinopathy, zaspopathy (Markesbery-Griggs late-onset distal myopathy), filaminopathy, or BAG3-related myofibrillar myopathy 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
• Consultation with a clinical geneticist and/or genetic counselor

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 or 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.

Prevention of Secondary Complications

Pacemaker or implantable cardioverter defibrillator placement for individuals with arrhythmogenic cardiomyopathy.

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
• Pulmonary function tests for individuals with exertional or nocturnal dyspnea.

Evaluation of Relatives at Risk

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Pregnancy Management

Affected pregnant women may need assistance during delivery if they have significant weakness of their abdominal muscles.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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.

Mode of Inheritance

Myofibrillar myopathy (MFM) is most commonly inherited in an autosomal dominant manner. Exceptions include:

• Autosomal recessive inheritance of CRYAB pathogenic frameshift variants that predict premature termination of the protein (see Molecular Genetics).
• X-linked inheritance of FHL1 pathogenic variants

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

• Approximately 25% of individuals diagnosed with autosomal dominant (AD) myofibrillar myopathy have an affected parent.
• A proband with AD myofibrillar myopathy may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include clinical examination looking for weakness, EMG, and possible muscle biopsy. Molecular genetic testing may also be appropriate if a pathogenic variant 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. Each child of an individual with AD myofibrillar myopathy has a 50% chance of inheriting the pathogenic variant.

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 affected or has a pathogenic variant, his or her family members are at risk.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Unless an individual with MFM has children with an affected individual or a carrier of a CRYAB pathogenic variant, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic frameshift variant in CRYAB.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the CRYAB pathogenic variants in the family have been identified.

Risk to Family Members – X-Linked Inheritance

Parents of a proband

• The father of an affected male will not have MFM nor will he be a carrier of the FHL1 pathogenic variant.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo pathogenic variant and, thus, the mother is not a carrier. The percent of simplex cases representing de novo pathogenic variants is not known.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a FHL1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and may be severely affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males pass the FHL1 pathogenic variant to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts' offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Carrier testing for at-risk female relatives is possible if the FHL1 pathogenic variant in the family has been identified.

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being affected or carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Molecular Genetic Pathogenesis

Because myofibrillar myopathy is caused by pathogenic variants in any of eight different genes and each disease-associated gene may have different types of pathogenic variants, 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 pathogenic missense variants weaken sarcomere structure and are associated with abnormal accumulation of desmin and other proteins. Transgenic mice that produce an inactivated form of human desmin (p.Arg173_Glu179del) show desmin immunoreactive aggregates in myocardium [Muñoz-Mármol et al 1998]. Transgenic mice expressing an α-B crystallin mutated protein (p.Arg120Gly) develop a severe cardiomyopathy with abnormal accumulation of desmin and α-B crystallin in the heart; muscle pathology was not mentioned in this report [Wang et al 2001].

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Suggested Reading

• Olivé M. Extralysosomal protein degradation in myofibrillar myopathies. Brain Pathol. 2009;19:507–15. [PMC free article: PMC8094729] [PubMed: 19563542]
• 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]
• Schröder R, Schoser B. Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol. 2009;19:483–92. [PMC free article: PMC8094720] [PubMed: 19563540]
• Selcen D. Myofibrillar myopathies. Curr Opin Neurol. 2008;21:585–9. [PMC free article: PMC4151125] [PubMed: 18769253]
• 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

• 9 May 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 29 October 2012 (me) Comprehensive update posted live
• 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 live
• 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 live
• 2 August 2004 (ds) Original submission