Duchenne muscular dystrophy

From Dog
Characteristic loss of myofibres associated with Duchenne muscular dystrophy[1]
A male canine with X-linked muscular dystrophy (CXMDJ) at 6 months of age. The atrophy of muscles throughout the body (including temporal muscle) is observed, with characteristic kyphosis, abnormal sitting posture and contracture of hindlimb joints[2]

Duchenne muscular dystrophy is a rare fatal, X-linked recessive genetic disease of dogs caused by dystrophin deficiency, resulting in generalized skeletal and cardiac muscular weakness[3].

Mutations in the causative gene result in a lack of dystrophin at the muscle fiber membrane. Dystrophin is the essential link between the subsarcolemmal cytoskeleton and the extracellular matrix[4]. Disruption of this link results in fiber necrosis and progressive muscle weakness. The muscle is progressively replaced by fibrous or fatty tissue.

Dystrophin-deficient dogs have been reported in many breeds, including the Golden Retriever, Labrador Retriever, German Short-Haired Pointer, Grand Basset Griffon Vendéen[5], Weimaraner[6] and Corgi. Gene mutations have been determined in several cases[7].

As with polymyositis, there is characteristic muscular atrophy observed with Duchenne muscular dystrophy, opposite to what is observed with cats where muscular hypertrophy is usually observed[8].

Clinically affected dogs commonly present with generalized weakness, bradycardia, anorexia, episodic coughing, poor growth, skeletal muscle atrophy and pelvic limb weakness[9]. Brachygnathism, trismus and dysbasia may be observed in some dogs.

Less than half of affected dogs survive beyond 6 weeks of age[10], and aspiration pneumonia is a common clinical complication.

Most dogs invariably die from degenerative cardiomyopathy[11], with concurrent nitrous oxide-mediated vascular endothelial dysfunction[12], yet paradoxically with no significant decrease in cardiac function[13].

Diagnosis is based on muscle biopsy, which shows characteristic dystrophic muscle pathology with prominent muscle degeneration, necrosis, myofiber size variation and inflammation[14]. Immunohistochemical analysis usually reveals a lack of dystrophin protein. Blood tests are usually unrewarding, although creatinine kinase levels are usually elevated.

A differential diagnosis would include polymyositis, nemaline myopathy, Golden Retriever Muscular Dystrophy[15], Toxoplasma gondii, Hepatozoon americanum, Sarcocystis neurona[16], Neospora spp[17], Hammondia hammondi, masticatory muscle myositis, tetanus, myasthenia gravis[18], thymoma[19] and dermatomyositis.

The use of prednisolone may benefit affected dogs in the short-term, but has been shown to promote disease progression[20]. Adjunct therapy such as hematopoietic stem cell transplantation does not appear to improve clinical progress[21].

Although there is no remedial treatment for this disease, adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment[22].

References

  1. Yang HT et al (2012) Dystrophin deficiency compromises force production of the extensor carpi ulnaris muscle in the canine model of Duchenne muscular dystrophy. PLoS One 7(9):e44438
  2. Nakamura A & Takeda S (2011) Mammalian models of Duchenne Muscular Dystrophy: pathological characteristics and therapeutic applications. J Biomed Biotechnol 2011:184393
  3. de la Fuente C et al (2012) Pathology in practice. Dystrophin-deficient muscular dystrophy. J Am Vet Med Assoc 240(12):1423-1425
  4. Hoffman EP et al (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919–928
  5. Klarenbeek S et al (2007) Canine X-linked muscular dystrophy in a family of Grand Basset Griffon Vendéen dogs. J Comp Pathol 137(4):249-252
  6. Baltzer WI et al (2007) Dystrophin-deficient muscular dystrophy in a Weimaraner. J Am Anim Hosp Assoc 43(4):227-232
  7. Shelton GD & Engvall E (2005) Canine and feline models of human inherited muscle diseases. Neuromuscul Disord 15:127–138
  8. Kornegay JN et al (2012) The paradox of muscle hypertrophy in muscular dystrophy. Phys Med Rehabil Clin N Am 23(1):149-172
  9. Olby NJ et al (2011) Clinical progression of X-linked muscular dystrophy in two German Shorthaired Pointers. J Am Vet Med Assoc 238(2):207-212
  10. Fine DM et al (2011) Age-matched comparison reveals early electrocardiography and echocardiography changes in dystrophin-deficient dogs. Neuromuscul Disord 21(7):453-461
  11. Su JB et al (2012) Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy. Cardiovasc Res 95(1):86-96
  12. Dabiré H et al (2012) Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS. Basic Res Cardiol 107(1):240
  13. Kerwin WS et al (2012) Mapping contrast agent uptake and retention in MRI studies of myocardial perfusion: case control study of dogs with Duchenne muscular dystrophy. Int J Cardiovasc Imaging Oct 17
  14. McDonnell JJ et al (2001) Neurologic conditions causing lameness in companion animals. Vet Clin North Am Small Anim Pract 31(1):17-38
  15. Thibaud JL et al (2012) Comprehensive longitudinal characterization of canine muscular dystrophy by serial NMR imaging of GRMD dogs. Neuromuscul Disord 22(2):S85-S99
  16. Vashisht K et al (2005) Naturally occurring Sarcocystis neurona-like infection in a dog with myositis. Vet Parasitol 133(1):19-25
  17. Reichel MP et al (2007) Neosporosis and hammondiosis in dogs. J Small Anim Pract 48(6):308-312
  18. Clooten JK et al (2003) Myasthenia gravis and masticatory muscle myositis in a dog. Can Vet J 44(6):480-483
  19. Hackett TB et al (1995) Third degree atrioventricular block and acquired myasthenia gravis in four dogs. J Am Vet Med Assoc 206:1173–1176
  20. Liu JM et al (2004) Effects of prednisone in canine muscular dystrophy. Muscle Nerve 30(6):767-773
  21. Dell'Agnola C et al (2004) Hematopoietic stem cell transplantation does not restore dystrophin expression in Duchenne muscular dystrophy dogs. Blood 104(13):4311-4318
  22. Wang Z et al (2012) Successful regional delivery and long-term expression of a dystrophin gene in canine muscular dystrophy: a preclinical model for human therapies. Mol Ther 20(8):1501-1507