What causes myofibrillar myopathies?

Updated: Aug 15, 2019
  • Author: Monica Saini, MD, MBBS, MRCP(UK); Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Many patients with a clinical and histologic phenotype of myofibrillar myopathy have no known mutation. Myofibrillar myopathy syndromes related to know genetic mutations are described below.

Most mutations are in proteins of the Z-disk or with attachments to the Z-disk. Most are proposed to cause disease by means of a dominant negative effect due to combined wild-type and mutant protein. The pathogenesis of disease is likely due to disrupted Z-disk function, which includes: (1) an attachment site and mechanical link of actin and titin filaments, (2) transmission of force along the myofibril, and (3) an attachment site for intermediate filaments (desmin) that link adjacent sarcomeres with each other and with other cellular organelles.

The common morphologic features of myofibrillar myopathies includes myobrillar disorganization at the Z-disk (Z-disk streaming) followed by accumulation of myofibrillar degradation products and aggregation of many proteins. These proteins include not only cytoskeletal and myofibrillar proteins and intermediate filaments, but also proteins of the ubiquitin-proteasome system, nuclear proteins, chaperones, Alzheimer disease-related proteins, oxidative stress proteins, kinases, and neuronal proteins. [63] A proposed molecular pathogenesis includes aggregation of mutant proteins followed by aggregation of other proteins including those of the ubiquitin-proteasome system, which is the main pathway for nonlysosomal protein degradation. Abnormal proteasome function results and may then lead to autophagocytosis, hyaline inclusion body formation, and inflammation, all pathologic hallmarks of the disease.

Desminopathy (MFM1) is caused by mutations on chromosome 2 in the desmin gene and can be either autosomal dominant or autosomal recessive. More than 20 mutations (most nonsense or missense and autosomal dominant) have been identified. Most mutations are located in the α-helical rod domain, which is critically important for filament assembly. Different mutations cause variable phenotypes and also disrupt desmin filaments at various stages of assembly. Pathogenesis is likely due to loss of desmin function or a dominant negative effect related to the accumulation of mutant desmin into toxic aggregates that disrupt cell function and eventually cause cell death.

  • Desmin protein is an intermediate filament (IF) protein. In muscle, it is located at the periphery of the Z-disk, under the sarcolemma, and at myotendinous junctions. In cardiac muscle, it is at intercalated disks and Purkinje fibers. Two desmin molecules align head to tail to form a dimer, 2 dimers form a tetramer, 2 tetramers form a protofilament, 2 protofilaments form a protofibril, and 2-6 protofibrils form an IF. IFs can heterodimerize with other IFs or IF-associated proteins. Desmin binds to ankyrin, spectrin, synemin, syncoilin, plectin, and nebulin. IFs form a heteropolymeric lattice to organize the myofibrils and link them to nuclei, mitochondria, and the sarcolemma.

  • αβ-crystallinopathy (MFM2) is caused by a mutation on chromosome 11 on the αβ-crystallin gene. Mutations have all been autosomal dominant.

    • αβ-crystallin protein is a small heat-shock protein that forms homo-oligomeric or hetero-oligomeric complexes with αβ-crystallin or other heat-shock proteins. Expression in skeletal and cardiac muscles and in the lens is high. In muscle, the protein is localized to the Z-disk. It binds to unfolded and denatured proteins to suppress nonspecific aggregation, and it protects actin, desmin, tubulin, and a variety of soluble enzymes from stress-induced damage. Mutant proteins are expressed and likely impair this chaperone function by means of dominant negative effect.

Myotilinopathy (MFM3) is caused by mutations on chromosome 5 in the myotilin gene (see LGMD1A). More than 15 families have been described with autosomal dominant or sporadic mutations. The serine-rich exon 2 is a hot spot for mutations. Myotilin protein is expressed in skeletal and cardiac muscle and in peripheral nerves. In muscle, it is expressed at the Z-disk. The protein binds to α-actinin, F-actin and filamin C and likely plays a role in cross-linking actin filaments and is in control of sarcomere assembly.

ZASP (Z-band alternatively spliced PDZ-containing protein) myopathy (MFM4) is caused by mutations on chromosome 10 in the ZASP gene, and is allelic with Markesbery distal myopathy and a form of hereditary dilated cardiomyopathy. In the largest series to date, 3 mutations have been identified in 11 patients with autosomal dominant or sporadic inheritance. ZASP may be a common cause of myofibrillar myopathy (about 15% of patients). ZASP protein is expressed in cardiac and skeletal muscle, binds to α-actinin in the Z-disk, and supports Z-disk structure during contraction.

Filamin C myopathy (MFM5) has been described in 1 German family with an autosomal dominant truncating mutation on chromosome 7 in the filamin C gene. Filamin C protein is expressed in skeletal and cardiac muscle. It is a Z-disk protein that binds actin, sarcoglycans, myotilin, myozenin, and many other proteins. It functions in actin reorganization, signal transduction, and maintenance of membrane integrity during force application.

BCL2-associated athanogene 3 myopathy (MFM6) is caused by a mutation on the BAG3 gene and has been described in a few patients. [51, 52] The BAG family of proteins bind to HSP70/HSC70 (heat shock proteins that act as chaperones to assist with protein folding and prevent protein aggregation) and are thought to inhibit the activity of these HSPs, thereby promoting protein release. Bag-3 localizes to and co-chaperones the Z disk in skeletal and cardiac muscle. Muscle pathology showed abnormal aggregation of desmin and Bag-3, Z-disc disintegration, and nuclear apoptosis.

Selenoprotein N related myopathy is caused by mutations on chromosome 1 in the selenoprotein N gene. These patients were originally described as having Mallory-body desmin-related myopathy. The term selenoprotein-related myopathy has been proposed to encompass patients with Mallory-body desmin-related myopathy, rigid spine syndrome, and minimulticore disease who have mutations in selenoprotein N. Selenoprotein N is a ubiquitously expressed glycoprotein that localizes to the endoplasmic reticulum and has an unknown function. Increased levels are present in myoblasts, with lower levels in myotubes or mature muscle fibers suggesting a role in early muscle development or in muscle cell proliferation or regeneration.

Laminopathy: Mutations in lamin A/C cause a wide variety of neuromuscular and more complex phenotypes. The pathogenesis is unknown (see LGMD1B).

Muscle biopsy of myofibrillar myopathies

See the list below.

  • Light microscopy: Trichrome-stained tissue shows single or multiple areas of blue-red amorphous material described as hyaline structures, cytoplasmic bodies, or inclusions. Abnormal hyaline structures are congophilic and contain many degraded proteins. Oxidative enzymes and ATPase activity is absent in the areas containing inclusions. Rimmed or nonrimmed vacuoles are present in most biopsies. Focal muscle fiber degeneration or inflammation can occur.

  • Electron microscopy: Z-disk streaming is an early feature. The main ultrastructural feature of all myofibrillar myopathies is disintegration of the Z disk and replacement of normal structures by homogenous irregular masses of electron dense material and granulofilamentous material. The normal myofibrillar architecture is replaced by fragments of thick and thin filaments and Z-disk material. Autophagic vacuoles contain abnormal sarcomeric proteins and other organelles.

  • Immunohistochemical staining: Many proteins can be localized to over 50% of abnormal fibers noted on light microscopy: desmin, αβ-crystallin, myotilin, dystrophin, β-amyloid precursor protein, neural cell adhesion molecule, actin, cell division cycle kinase 2, plectin, and prion protein. Several other proteins are noted in less than 50% of abnormal fibers including α1-antichymotrypsin, gelsolin, ubiquitin, synemin, and nestin.

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