Aetiology

Muscular dystrophies are progressive generalised muscle diseases most often caused by defective or specifically absent glycoproteins in muscle membranes, although some are due to mutations in other proteins. Each type of muscular dystrophy is caused by a different gene deletion or mutation. Mutations related to muscular dystrophies have been identified in over 40 genes.[1]

DMD and Becker muscular dystrophy are caused by mutations of the dystrophin gene (the largest in the human genome, with 79 exons): these are most often exon deletions, but duplications and smaller-sized variants within the dystrophin gene also occur.[17]​ Spontaneous mutation results in one third of DMD cases, whereas maternal-fetal transmission results in the remaining two-thirds.[11]​ Emery-Dreifuss and limb-girdle muscular dystrophies can be confused with DMD.

  • Emery-Dreifuss muscular dystrophy is caused by mutations in genes for nuclear envelope proteins, including emerin and lamin A/C. The mutation in emerin shows an X-linked recessive inheritance pattern. Mutations in the LMNA gene usually have an autosomal dominant pattern of inheritance, but an autosomal recessive pattern may also rarely be observed.[1]

  • Limb-girdle muscular dystrophies are a heterogeneous group, caused by mutations in or deletions of various genes, e.g., lamin A/C, caveolin 3, calpain, dysferlin, telethonin, TRIM 32, or fukutin.​[1][14]

  • Facioscapulohumeral muscular dystrophy (FSHD) is associated with a small deletion on chromosome 4 affecting the D4Z4 region in FSHD1 (95% of cases) and the SMCHD1 region in FSHD2.[13]​ It is an autosomal dominant disorder, but up to 30% of cases arise from spontaneous mutations.

  • Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK, which encodes the DM protein kinase.[12]​ DM2 results from expansion of a CCTG repeat in the first intron of the ZNF9 gene. Patients with small expansions generally have mild symptoms, but repeat size does not always correlate with disease severity.[18]

  • Congenital muscular dystrophies can be caused by deficiencies or mutations in a number of genes, such as those encoding laminin-alpha 2, collagen type VI, dystroglycan, or integrin-alpha 7. Not all causative genes have been identified.[15]

  • Spinal muscular atrophy is caused by the homozygous deletion of exons 7 and 8 (or sometimes just exon 7) of the survival motor neuron 1 (SMN1) gene. The number of copies of the SMN2 gene predicts disease severity (classified from type 1 [most severe] to type 4).[3]​​​[4][17]

Pathophysiology

The Xp21 defect or deletion in Duchenne/Becker muscular dystrophies results in the absence of the sarcolemma-associated protein dystrophin. This protein provides structural stability to the dystroglycan complex in cell membranes. Although most of the cell membranes in the body contain dystrophin, the tissue most affected by its absence is skeletal muscle. The absence of dystrophin results in ongoing cell membrane depolarisation due to calcium entering the cell. This in turn causes ongoing degeneration and regeneration of muscle fibres. Degeneration is faster than regeneration, and muscle fibres undergo necrosis. Muscle fibres are replaced by adipose and connective tissue, causing the muscles to progressively weaken. In some people with DMD, the absence of dystrophin also causes effects in other cells in the body as follows.

  • Brain cells: increased information-processing time and apparently lower intelligence quotient (mean 89 to 90). Learning difficulties and autistic spectrum disorders are well recognised.

  • Smooth muscle cells: cardiomyopathy and prolonged intestinal transit times.

A wide variety of proteins are affected in other muscular dystrophies; these include other sarcolemma-associated proteins, enzymes, nuclear membrane proteins, sarcomeric proteins, and endoplasmic reticulum proteins. All lead to muscle weakness, with presentations varying in location, severity, and time of onset.[1]

Spinal muscular atrophy (SMA) is a motor neuronopathy rather than a muscular dystrophy, although symptoms are similar. The pathophysiology of SMA is not yet fully understood. The survival motor neuron (SMN) protein is involved in a number of cell mechanisms, including assembly of the spliceosomal machinery, endocytosis, and protein translation. Lack of SMN affects the motor neurons, leading to muscle degeneration and atrophy.[19]

Classification

Types of muscular dystrophy[1]

X-linked muscular dystrophies

  • Duchenne

  • Becker

  • Emery-Dreifuss

Limb-girdle muscular dystrophies[2]

Other types of muscular dystrophy

  • Facioscapulohumeral muscular dystrophy

  • Myotonic dystrophy

  • Congenital muscular dystrophies.

Spinal muscular atrophy (SMA)[3][4]

  • Type 1: patient unable to sit unsupported; manifests after birth but before age 6 months

  • Type 2: non-ambulant patient able to sit independently; usually manifests between 6 and 18 months

  • Type 3: can walk independently in childhood, but with muscle weakness; usually manifests after age 18 months

  • Type 4: adult onset; usually presents with muscle weakness in the second or third decade.

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