Chapter 130 Disorders of Muscle and Neuromuscular Junction
Neuromuscular disorders of dogs and cats are disorders of the motor unit. The motor unit is the morphologic and functional unit of skeletal muscle and includes the following:
This chapter focuses on disorders of muscle and the neuromuscular junction. Disorders of peripheral nerves are discussed in Chapter 129.
ETIOLOGY
Underlying causes of disorders of muscle and neuromuscular transmission are listed in Table 130-1 and include hereditary or suspected hereditary disorders and acquired disorders with autoimmune, metabolic, endocrine, neoplastic or paraneoplastic, infectious, toxic or drug-induced, and ischemic etiologies.
Table 130-1 CAUSES OF NEUROMUSCULAR DISEASES AND BREED PREDISPOSITION
Hereditary Disorders
Glycogen Storage Disorders (Glycogenoses)
Acid Maltase Deficiency (Glycogenosis Type II)
Branching Enzyme Deficiency (Glycogenosis Type IV)
Debranching Enzyme Deficiency (Glycogenosis Type III)
Phosphofructokinase Deficiency (Glycogenosis Type VII)
Hereditary Disorders
Several neuromuscular diseases have a known or suspected genetic basis.
Canine Dystrophin-Deficient Muscular Dystrophy
• Canine X-linked muscular dystrophy has striking phenotypic and genotypic similarities to Duchenne muscular dystrophy (DMD) in humans. While this disorder occurs most commonly in males, females may be affected if a carrier female is bred to an affected male. Although this form of muscular dystrophy has been most extensively studied in the golden retriever, several breeds may be affected, including Irish terriers, Samoyeds, rottweilers, Japanese spitz, and Labrador retrievers. Onset is about 10 to 12 weeks of age. As in humans with DMD, affected dogs lack the Duchenne gene transcript and its protein product, dystrophin.
• Clinical signs include stunted growth, weakness, gait abnormalities, and muscle atrophy, with hypertrophy of selected muscles in some cases.
Feline Dystrophin-Deficient Muscular Dystrophy
• A lethal muscle hypertrophy has been described in young male cats associated with dystrophin deficiency.
• Clinically the cats have generalized skeletal muscle hypertrophy, glossal hypertrophy and dysfunction, and excessive salivation. Progressive hypertrophy of the diaphragmatic muscles may result in occlusion of the esophagus.
Muscular Dystrophy with Merosin (Laminin Alpha-2) Deficiency in Dogs and Cats
• Congenital muscular dystrophies (CMDs) with deficiency of laminin alpha-2 make up a large group of autosomal recessive muscle diseases in humans. Recently, muscular dystrophy associated with absence of laminin alpha-2 was described in a young female Brittany-springer spaniel mixed-breed dog, and in domestic shorthaired, flame point Siamese, and Maine coon cats. Onset is less than 6 months of age.
• Clinical signs may vary from muscle weakness and atrophy to progressive spasticity and contractions.
Muscular Dystrophy with Sarcoglycan Deficiency
• The limb-girdle muscular dystrophies (LGMDs) make up a diverse group of myopathies in humans. Mutations of sarcoglycans (SGs), which span the muscle membrane, typically cause the most severe forms of LGMD. Recently, SG deficiencies have been identified in Chihuahua, Boston terrier, and Cocker Spaniel breeds.
Hereditary Myopathy of Labrador Retrievers
• Although hereditary myopathy of Labrador retrievers (HMLR) is commonly referred to as “type II fiber deficiency” or “muscular dystrophy,” the precise underlying abnormality is still unknown. A disorder in young Labrador dogs, clinically indistinguishable from HMLR and termed centronuclear myopathy, has recently been described in a French pedigree. Linkage analysis has shown that the gene for the disorder in the French pedigree is localized on canine chromosome 2.
• Both disorders present clinically with progressive muscle weakness, exercise intolerance, and abnormalities of gait and posture. There is, however, a wide variation in clinical presentations and pathologic findings in HMLR.
• Within muscle biopsy specimens, variable morphologic features have been reported; some biopsies show changes typical of neuropathic disease, whereas others show myopathic changes. The fiber type proportions are also variable. To date, pathologic changes in the spinal cord and peripheral nerves have not been found, even in cases in which histologic changes within the muscle biopsy suggest an underlying neuropathic disorder.
“Central Core-Like” Myopathy
• Myopathy with pathologic changes in the central region of muscle fibers has been reported in several young Great Danes from the United Kingdom showing clinical signs of progressive exercise intolerance, muscle atrophy, and tremors. Recently, an affected dog was confirmed from North America (Shelton, unpublished), suggesting that this myopathy may be more widespread. Excitement associated with feeding or exercise precipitates episodes of general body tremors and collapse. This condition is not pathologically analogous to the human disorder with this name.
Nemaline Rod Myopathy
• Five related cats were described with an early onset of mild weakness with progression to tremors, reluctance to move, and a crouched, hypermetric gait. Muscle atrophy was progressive. A similar myopathy has been seen in a young Border collie.
Familial Canine Dermatomyositis
• Familial canine dermatomyositis is well documented in young collies and less well characterized in Shetland sheepdogs. In collies, the inheritance pattern appears to be autosomal dominant with variable expression.
• Initially there is a variably severe dermatitis on the skin of the face, ears, distal extremities over bony prominences, and tail tip that may be followed by an inflammatory myopathy of the masticatory muscles and muscles distal to the elbow and stifle.
Glycogen Storage Disorders (Glycogenoses)
• Although rare in companion animals, disorders of lysosomal glycogenosis (acid maltase deficiency, an alpha-glucosidase that releases glucose from maltose, oligosaccharides, and glycogen) and non-lysosomal glycogenosis (branching enzyme deficiency, debranching enzyme deficiency, and phosphofructokinase (PFK) deficiency affecting glycogenolysis, glycolysis, or glycogen synthesis) have been described.
• In dogs, clinical presentations for the non-lysosomal glycogenoses are not usually specific to the neuromuscular system since glycolysis plays a relatively minor role in canine muscle energetics.
Myotonia Congenita
• An inherited myotonic myopathy has been described in the chow chow and miniature schnauzer breeds in which clinical signs of difficulty rising after a period of rest, muscle stiffness, and a stilted or bunny-hopping gait are visible when puppies are first able to walk. An autosomal recessive mode of inheritance is suspected in the chow chow and has been confirmed in the miniature schnauzer. A missense mutation in both alleles of the gene encoding the skeletal muscle voltage-dependent chloride channel C1C-1 has been identified in the miniature schnauzer.
• A DNA-based test capable of detecting the mutant allele in affected and carrier miniature schnauzers has been developed and is available at the Josephine Deubler Genetic Disease Testing Laboratory at the University of Pennsylvania (www.vet.upenn.edu/penngen).
Mitochondrial Myopathy
• Although there has been an explosion of information related to mitochondrial-associated diseases in humans in the past 10 years, only a few case reports are in the veterinary literature regarding this potentially important group of disorders.
• Marked exercise intolerance associated with metabolic acidosis and excessive elevations in lactate and pyruvate support a mitochondrial myopathy. In Clumber and Sussex spaniels, a deficiency of pyruvate dehydrogenase has been described. A similar exertional lactic acidosis has been reported in Old English sheepdog littermates associated with altered cytochrome-c oxidase activity and reduced mitochondrial mRNA.
Hypertonicity Syndromes
• Hypertonicity syndromes (paroxysmal movement disorders) are being identified in several breeds of dogs, including the cavalier King Charles spaniel (CKCS), springer spaniel, Wheaton terrier, and Border terrier. With the exception of the CKCS, these disorders are poorly characterized.
• In the CKCS, clinical signs are apparent between 3 and 7 months of age. Variable periods of exercise or excitement precipitate pelvic and thoracic limb hypertonicity that may result in complete incapacitation.
Acquired Neuromuscular Disorders
Autoimmune Disorders
Acquired Myasthenia Gravis
• Acquired MG is common in dogs and occasionally found in cats. Feline MG is associated with an increased incidence of thymoma. Acquired MG probably is the best defined of all the neuromuscular disorders with respect to mechanisms of injury and pathogenesis. It is now well documented that acquired MG is associated with autoantibodies directed against the nicotinic AChRs on the postsynaptic membrane of the neuromuscular junction. As a consequence of autoantibody binding, there is loss of AChRs resulting in impaired neuromuscular transmission and marked muscle weakness. AChR loss is a result of the following:
Masticatory Muscle Myositis
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