This article includes discussion of desmin body myofibrillar myopathy, chronic noninflammatory myopathy, and cytoplasmic body myopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Myofibrillar myopathies refer to a heterogeneous group of disorders associated with disintegration of myofibrils and accumulation of Z-disk related proteins. Typically, patients present with lower limb muscle weakness, which slowly spreads to involve truncal, neck-flexor, facial, bulbar, and respiratory muscles. Distribution of the weakness may be distal or both proximal and distal. Skeletal myopathy may be combined with or preceded by cardiomyopathy, conduction blocks, and arrhythmias resulting in premature sudden death. Respiratory muscle weakness can also be a major complication in some patients. The age of disease onset and the rate of progression vary depending on the mode of inheritance as well as the specific mutations. In this updated article, the author highlights advances in the diagnosis and treatment of myofibrillar myopathies.
• Myofibrillar myopathies are a subgroup of hereditary protein aggregate myopathies.
• Muscle biopsy reveals characteristic amorphous or granular material, with focal areas of myofibrillar disintegration, reduced oxidative enzyme activity, and vacuolar changes.
• The clinical phenotype is highly variable; most commonly it presents as a distal myopathy involving the hands and feet, with progressive muscle weakness, respiratory dysfunction, and cardiomyopathy.
• Treatment remains primarily supportive; those with significant cardiac complications may require pacemaker implantation or cardiac transplant.
Historical note and terminology
Myofibrillar myopathies refer to a heterogeneous group of rare primary chronic noninflammatory myopathies characterized by pathological abnormal accumulation of cytoplasmic inclusion bodies and myofibrillar disarray in skeletal or cardiac muscles (Goebel 2011; Béhin et al 2015). The disease was originally described more than 30 years ago based on common muscle histopathological features (Goebel 1995). The onset usually occurs in adult life (between the second and fourth decade) but may be congenital or present in early childhood. A combination of distal and proximal weakness, cardiomyopathy, peripheral neuropathy, and autosomal dominant inheritance should suggest this disorder (Nakano et al 1996). However, these symptoms may be sporadic, and autosomal recessive or X-linked inheritance has also been described (Feldkirschner et al 2013; Schessl et al 2014).
The first description of cytoplasmic body as a structural anomaly of the Z-disc was in 1969 (MacDonald and Engel 1969). Cytoplasmic bodies occur in a number of unrelated neuromuscular disorders, but their relationship to desmin-related neuromuscular diseases was only recognized in the 1980s (Edstrom et al 1980; Stoeckel et al 1981; Osborn and Goebel 1983).
A report of a sporadic adult-onset myopathy describing spheroid inclusions on the basis of the ultrastructural findings and the formation of the inclusions in muscle fibers was postulated (Nakashima et al 1970). Other early reports of sporadic cases include postmortem findings of cytoplasmic bodies and myofibrillar aggregates (Kinoshita et al 1975; Jerusalem et al 1979). Autosomal dominant inheritance was described in 4 successive generations with a benign proximal myopathy of adolescent onset with spheroid bodies (Goebel et al 1978) or granulofilamentous inclusions (Fardeau et al 1978). Similarly, a late-onset myopathy showed myofibrillar inclusions in all 3 symptomatic and in 4 of the 7 asymptomatic family members (Clark et al 1978). Intermediate filaments were identified in association with sarcoplasmic bodies in a severe progressive late-onset autosomal dominant distal myopathy, with patients becoming wheelchair-bound within 10 years (Edstrom et al 1980). Sixteen patients representing 7 different pedigrees with an adult-onset limb-girdle myopathy (Edstrom et al 1990) and 16 family members with a distal myopathy were described (Horowitz and Schmalbruch 1994). A cardiomyopathy found in 3 brothers showed large proteinaceous inclusions in the cardiac muscle consisting of intermediate filaments (Porte et al 1980) that were immunofluorescent desmin-positive (Stoeckel et al 1981). Desmin body myofibrillar myopathy can also present as a congenital myopathy (Goebel et al 1981; Wolburg et al 1982) with or without a cardiomyopathy (Calderon et al 1987). The cardiomyopathy can precede the myopathy (Calderon et al 1987; Goebel et al 1994).
Myopathic manifestations caused by desmin (DES) or alpha-B-crystallin (CRYAB) mutations are identical but are termed “desminopathy” when desmin is involved and “alpha-B-crystallinopathy” when alpha-B-crystallin is involved (Vicart et al 1998; Dalakas et al 2000; Selcen and Engel 2003; Selcen 2008; Selcen 2011). Similarly, mutations involving myotilin (MYOT), Z-band alternately spliced PDZ motif-containing protein (ZASP), filamin C (FLNC), or bcl-2-associated athanogene 3 (Bag3) result in myotilinopathy, zaspopathy, filaminopathy, or Bag3opathy, respectively (Selcen and Engel 2004; Selcen and Engel 2005; Vorgerd et al 2005; Ruparelia et al 2012; Tasca et al 2012; Selcen et al 2009; Jaffer et al 2012). The term myofibrillar myopathies (MFM) has been proposed to cover a broad spectrum of pathologic changes found in muscle, including focal myofibrillar destruction, mitochondrial dysfunction, and accumulation of multiple proteins in addition to desmin (De Bleecker et al 1996; Nakano et al 1996; Selcen 2008; Selcen 2011; Selcen and Engel 2011). Approximately half of the myofibrillar myopathies are caused by mutations in genes encoding sarcomeric and extra-sarcomeric proteins, including desmin, filamin C, plectin, valosin-containing protein (VCP), ZO-2 associated speckle protein (ZASP), myotilin, alpha-B-crystallin, Bcl2-associated athanogene 3 (BAG3), and DnaJ homolog subfamily B member 6 (DNAJB6) (Winter and Goldman 2015; Sandell et al 2016). In addition, mutations involving four and a half LIM domain 1 (FHL1) and titin (TTN) were found to be responsible for a subgroup of patients with MFM, which lead to reducing body myopathy and hereditary myopathy with early respiratory failure (Schessl et al 2008; Ohlsson et al 2012; Feldkirchner et al 2013; Pfeffer et al 2014). Myofibrillar myopathies are considered a subgroup of protein aggregate myopathies (Goebel 2011; Béhin et al 2015).
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