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Myopathology pp 103–130Cite as

Muscular Dystrophies

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Abstract

The term dystrophy is derived from the Greek word “dus” meaning “bad” and “trophia” meaning “nourishment” as it was initially thought of muscle disease due to disordered nutritional factors. Muscular dystrophies are a group of heterogeneous genetic disorders that have in common irreversible loss of muscle fibers resulting from repetitive cycles of degeneration, necrosis, regeneration, and eventually fibrosis and fat replacement [1]. The worldwide prevalence of muscular dystrophies is 16.14 per 100,000 [2]. The most common muscular dystrophy is the Duchenne muscular dystrophy (DMD), first described by Edward Meryon in 1851 at the Royal Medical and Chirurgical Society meeting. The same was published a year later [3, 4]. In the ensuing years 1861 and 1868, Guillaume-Benjamin-Amand Duchenne described the same disease in greater detail [5]. The term “muscular dystrophy”, however, was first coined by Erb in 1891 [6]. Over the years, scientists gradually realized that muscular dystrophies were inherited and most had a characteristic pattern of muscle involvement. The myopathological features common to most muscular dystrophies are variation in muscle fiber size and shape, myonecrosis, myophagocytosis and eventually replacement of myoarchitecture by fibroadipose connective tissue. The first clinical classification for muscular dystrophies was proposed by Walton and Nattrass based on the pattern of muscle involvement [7]. The clinical classification although simple has many limitations because of considerable overlap between the subgroups and at times between nondystrophic myopathies. For example, limb-girdle muscular dystrophy 2A (LGMD2A) can clinically mimic facioscapulohumeral muscular dystrophy (FSHD). Dysferlinopathy (LGMD2B), LGMD2A, and FSHD are common mimics of inflammatory myopathy [8]. Histopathological features in such cases may at times provide a clue to the subtype of muscular dystrophy under question. FSHD and LGMD2B may have endomysial mononuclear infiltrate as the dominant finding. In oculopharyngeal muscular dystrophy (OPMD), rimmed vacuoles and nuclear tubulofilamentous inclusions are quite characteristic. Lobulated fibers and eosinophils are commonly encountered in LGMD2A. However, these findings can be a double-edged sword and misleading at times. In LGMD2B, infiltration of the endomysium by mononuclear cells associated with MHC-I upregulation and elevated serum CK levels may mimic inflammatory myopathy. Lobulated fibers are known to occur in a variety of conditions such as normal myotendinous junctions, LGMD2A, α-sarcoglycanopathy, dysferlinopathy, carriers of dystrophin gene mutation, Bethlem myopathy, LGMD2G, scapuloperoneal muscular dystrophy, nemaline myopathy, etc. [9–15]. Similarly, rimmed inclusions can be observed in Becker muscular dystrophy, Miyoshi myopathy, LGMD2I, LGMD2G, FSHD, titinopathy, oculopharyngeal muscular dystrophy, scapuloperoneal muscular dystrophy, congenital muscular dystrophy with merosin deficiency, GNE myopathy, etc. [9, 11, 16–23]. One of the most significant breakthroughs in the history of myopathology is the discovery of DMD gene locus by Monaco et al. [24]. Thereafter, the amassing wealth of molecular genetic data with respect to the muscle diseases has been phenomenal. Recent classifications have focused on the molecular genetic mechanisms that underlie muscular dystrophies especially the genes encoding proteins directly or indirectly associated with muscle contraction and repair. The data is likely to increase exponentially as new state-of-the-art techniques evolve in the future. In this chapter, we will follow the molecular pathology-based classification with emphasis on clinical and myopathological features. Although there is an interplay of other factors, this classification is being adopted because of its lucidity. The onset of dystrophies may be at birth or may be delayed until late adulthood. The key aspect in the assessment of a suspected muscular dystrophy is defining the pattern of muscle weakness. Most of the adult muscular dystrophies have a “limb-girdle” pattern of weakness with proximal limb muscles being weaker than distal muscle groups. It is important to look for additional features such as facial weakness, scapular winging, calf hypertrophy/atrophy, asymmetry in strength, and rippling of muscles to narrow down the list of differential diagnosis. Dystrophies affect not only skeletal muscles. Cardiomyopathy may be the presenting feature. The primary reason for demise in most cases of dystrophy can be attributed to respiratory muscle failure. Smooth muscles may also be affected, leading to abnormal gastrointestinal motility. Serum creatine kinase (CK) levels are usually raised (sometimes up to 20 times normal or greater) in most of the dystrophies. However, this is not always true especially in some of the more indolent disorders and in end-stage muscle disease where the muscle does not have enough CK. Levels of other enzymes, including aldolase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), may be elevated as well. Electromyography (EMG) may be helpful in sporadic cases and in patients with normal or modest elevation CK levels. Muscle imaging, especially the magnetic resonance imaging (MRI), is helpful to assess selective muscle involvement and to guide biopsy sites. In most patients with muscular dystrophy, genetic studies are the first line of investigations to circumvent the need for a muscle biopsy. However, muscle biopsy may be indicated under special circumstances such as ambiguous clinical manifestations, non-contributory genetic testing, and unknown prevalence of the suspected dystrophy. Diagnostic accuracy increases when light microscopic morphology is complemented by ancillary techniques. Development of diagnostic antibodies against proteins implicated in dystrophy permits us in drafting appropriate protocols to guide genetic testing.

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  1. Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Balan Louis Gaspar & Rakesh Kumar Vasishta

  2. Division of Neuropathology, Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Bishan Dass Radotra

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Gaspar, B.L., Vasishta, R.K., Radotra, B.D. (2019). Muscular Dystrophies. In: Myopathology. Springer, Singapore. https://doi.org/10.1007/978-981-13-1462-9_8

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