Myofibrillar Myopathies and Other Myopathies with Rimmed Vacuoles

Introduction

A vacuole is a membrane-bound area of a muscle fibre that may contain various cellular components or enzymes. The type and function of a vacuole vary, and the properties of a vacuole can be a useful pathological indicator. The membrane may be revealed with antibodies to sarcolemmal proteins, or may only be visible with electron microscopy. The nature of the contents of a vacuole may also only be seen with electron microscopy, although some stains (e.g. PAS and acid phosphatase) and some antibodies (e.g. to markers of autophagy or proteins related to ubiquitinylation) can give an indication of the material within a vacuole. It is important to distinguish vacuoles from unstained areas in histologically stained sections (e.g. with haematoxylin and eosin (H&E) and Gomori trichrome), which relate to lipid droplets or ice crystal damage. In some muscle biopsies vacuoles may only be a minor feature, whereas in others they are numerous. In the past, the type of vacuole surrounded by basophilic material that stains red with the Gomori trichrome stain (commonly known as rimmed vacuoles), in particular, was thought to be restricted to disorders such as inclusion body myositis, but it is now apparent that this type of vacuole can occur in a wide variety of disorders, including myopathies, muscular dystrophies and neuropathies. They probably relate to common pathological pathways such as misfolding of proteins, the proteasome and autophagic pathways and various chaperone and co-chaperone proteins ( ). In this chapter we discuss disorders in which vacuoles, together with additional pathological features and the clinical phenotype, can be useful diagnostic clues. In particular, we cover the pathology of myofibrillar myopathies and other disorders with an accumulation of proteins, and some distal myopathies, including those described as hereditary inclusion body myopathies. The pathology and associated phenotype of other disorders where vacuoles of various types are a feature are described in other chapters: glycogenoses (see Ch. 17 ), ion channel disorders (see Ch. 20 ), inclusion body myositis (see Ch. 22 ), myosin 2A myopathy (see Ch. 15 ), oculopharyngeal muscular dystrophy (see Ch. 14 ), LGMD2G (TCAP; see Ch. 11 ) and toxic myopathies (see Ch. 23 ).

Myofibrillar Myopathies

Over the years a number of disorders with various types of inclusions have been described, such as spheroid bodies ( ), sarcoplasmic bodies ( ), cytoplasmic bodies ( ) and granulofilamentous material ( ). More recently, it has been appreciated that these disorders share similar histopathological features, in particular accumulation of several proteins, especially desmin. This led to the use of terms such as ‘desminopathies’, ‘desmin-related myopathies’ and ‘protein aggregate myopathies’ ( ). Several other proteins in addition to desmin also accumulate, several of which are also seen in inclusion body myositis (see Ch. 22 ) and neurodegenerative disorders. The terms ‘hereditary inclusion body myopathy’ or ‘protein surplus myopathies’ have also been suggested ( ), as well as the more general term of ‘myofibrillar myopathies’ ( ). The molecular basis of several of these conditions has now been determined. Although it is now known that defects in several proteins associated with the sarcomere can cause a neuromuscular disorder (see Fig. 8.2 ), the term ‘myofibrillar myopathy’ is usually restricted to conditions in which proteins of the Z line, or associated with it, are implicated. These share some similar pathological features, which include deposition of amorphous or granular aggregates consisting of ectopic proteins, such as desmin, αB-crystallin, myotilin, dystrophin and others, presence of rimmed or non-rimmed vacuoles and focal loss of oxidative enzyme activity ( ). The genes and proteins considered in this section are listed in Table 16.1 .

Defects in the proteins that are included in this group of disorders were historically desmin, αB-crystallin, myotilin, Z-line alternatively spliced PDZ motif-containing protein (ZASP), filamin C and bcl-2-associated athanogene 3 (BAG3). More recently, the definition has been broadened to include more protein defects ( ). Four-and-a-half-LIM domain 1 protein (FHL1) is often included, although this is not a protein of the Z line but localizes to the myofibrils and sarcolemma ( ) and also titin, skeletal muscle α-actin, heat-shock 22-kd protein 8 (HSPB8) and DNAJ/HSP40 homolog subfamily B member 6 (DNAJB6) and plectin. Plectin is closely associated with desmin and the Z line, and desmin accumulation occurs when there is a mutation in the gene in common with myofibrillar myopathies. Although vacuoles are not a frequent pathological feature of plectinopathy, it may be grouped among the myofibrillar myopathies because of several other important pathological features ( ). Telethonin is also a protein of the Z line and biopsies can have vacuoles but this is discussed with limb-girdle muscular dystrophies (LGMD2G, ; see Ch. 11 ).

Many cases are sporadic, but when inheritance can be determined, the majority of cases show autosomal dominant inheritance, although rare recessive mutations in the genes encoding desmin, αB-crystallin and myotilin have been identified ( ), and disorders associated with FHL1 are X-linked with mainly dominant inheritance. Myopathies caused by mutations in PLEC are inherited in an autosomal recessive manner.