Chapter 140 - Myofibrillar myopathies

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Abstract

Myofibrillar myopathies (MFMs) are rare, inherited or sporadic, progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. MFMs are defined morphologically by foci of myofibril dissolution that begins at the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of a large number of proteins including desmin. To date, mutations in six genes are known to cause MFMs, accounting for approximately half of the MFM patients identified. The causative genes encode mainly sarcomeric Z-disk(-related) proteins: desmin, αB-crystallin, myotilin, Z-band alternatively spliced PDZ motif containing protein (ZASP), filamin C and the antiapoptotic BCL2-associated athanogene 3 (Bag3). Although in most MFM patients the disease presents in adulthood and evolves slowly, some patients with desminopathy, αB-crystallinopathy or Bag3opathies have an infantile or juvenile disease onset. Cardiac involvement is very common in desminopathies and can sometimes be the initial or only symptom of the disease. Respiratory symptoms are noted during childhood in αB-crystallinopathies. Early severe cardiac and respiratory involvement is seen in Bag3opathies. Optical microscopic and immunohistochemical features are similar in MFMs; however, ultrastructural findings can be useful to differentiate between the distinct MFM subtypes. No curative treatment for MFMs is currently available. Careful follow-up, especially of cardiac and respiratory function, is important.

Introduction

Myofibrillar myopathies (MFMs) are rare, inherited or sporadic, progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. MFMs are defined morphologically by foci of myofibril dissolution that begins at the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of a large number of proteins including desmin, dystrophin, and ubiquitin (De Bleecker et al., 1996, Nakano et al., 1996, Olivé et al., 2004, Selcen et al., 2004, Pénisson-Besnier et al., 2006, Griggs et al., 2007, Selcen, 2008, Claeys et al., 2009; Schröder and Schoser 2009). These disorders were previously known as desmin-related myopathies or desmin storage myopathies, which is inappropriate since desmin accumulation in myofibers is not a “storage disease”. MFMs are a subgroup of the protein aggregate myopathies (PAM).

To date, mutations in six genes are known to cause MFMs, and these account for approximately half of the MFM patients identified. The causative genes encode mainly sarcomeric Z-disk proteins or Z-disk-related proteins: desmin (DES; Goldfarb et al., 1998, Muñoz-Mármol et al., 1998, Dalakas et al., 2000), αB-crystallin (CRYAB; Vicart et al., 1998, Selcen and Engel, 2003), myotilin (MYOT; Selcen and Engel, 2004, Olivé et al., 2005, Pénisson-Besnier et al., 2006, Berciano et al., 2008), Z-band alternatively spliced PDZ motif containing protein or ZASP (LDB3; Selcen and Engel, 2005, Griggs et al., 2007), filamin C (FLNC; Vorgerd et al., 2005, Kley et al., 2007; Shatunov et al., 2009) and the antiapoptotic BCL2-associated athanogene 3 or Bag3 protein (BAG3; Selcen et al., 2009). The MFM subtypes are designated according to the affected protein, such as desminopathy, αB-crystallinopathy or Bag3opathy.

The frequency of the MFM subgroups in the different cohorts studied by distinct neuromuscular centers is variable. In our cohort of 66 MFM patients belonging to 43 unrelated families followed at the Institute of Myology (Paris, France), 30% have a mutation in DES, 15% in CRYAB, 11% in ZASP and 3% harbor a mutation in MYOT. The Mayo Clinic cohort of MFM patients includes 14% with ZASP mutation, 10% MYOT, 7% DES, 3% CRYAB and 4% FLNC (Selcen et al., 2004, Goebel et al., 2008). In the remaining MFM patients the genetic defect has not yet been identified. In MFM patients with mutations in MYOT, ZASP or FLNC, and in most patients with mutations in DES or CRYAB, the disease presents in adulthood and evolves slowly. Some MFM patients, however, have an infantile or juvenile disease onset. Here, we will focus on MFMs that can be associated with early disease onset: desminopathy, αB-crystallinopathy and MFMs caused by BAG3 mutations.

Section snippets

Desminopathy

Patients with DES mutations mainly show an autosomal dominant (AD) inheritance, but de novo mutations are also frequently found. By contrast, autosomal recessive (AR) mutations have been reported in only a few cases. The earliest age of onset and the most severe disease have been observed in AR cases. In one AR family, three out of four siblings were compound heterozygous for the A360P and N393I desmin mutations and had childhood onset of the disease (Goldfarb et al., 1998). They presented with

Diagnosis

Diagnosis of MFM is based on morphological findings in muscle biopsies (Figs 140.1 and 140.2). The abnormal muscle fibers are best identified in frozen sections stained with modified Gomori trichrome (Fig. 140.1B). Affected fibers typically appear in an uneven distribution across the fascicles. Common histopathological features in MFMs are: abnormal protein aggregations, some of which stain with Congo red, internalized nuclei, fiber splitting, vacuoles, core-like lesions, mildly to severely

Therapy and follow-up

No curative treatment for MFMs is currently available. In MFM patients, cardiac screening, including electrocardiography, echocardiography and 24 hour Holter monitoring, should be performed at least once a year. However, if cardiac abnormalities are found or in patients with DES mutations, the heart should be examined at least twice a year. Since routine echocardiography can miss certain abnormalities, cardiac MRI should be preferentially undertaken when available (Strach et al., 2008). In

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