A 5-month-old male GSHP (dog 1) was referred to the North Carolina State University Veterinary Teaching Hospital for evaluation of poor growth, skeletal muscle atrophy, pelvic limb weakness, and episodic collapse. The owner reported that these signs had been evident since the puppy was 6 weeks old. A full-sibling male littermate of dog 1 (dog 2) lived in the same household and had similar but more severe clinical signs.
Initial physical examination at the referral hospital included neurologic evaluation, serum biochemical analysis, and a CBC. Results of physical examination of dog 1 at 5 months of age revealed severe brachygnathism with trismus, a wide-based pelvic limb stance with paws laterally rotated and tarsi held close together, and a malformed rib cage with mild concavity of the region of the ribs adjacent to the sternum. The gait was characterized by a mildly shortened stride, indicative of possible lower motor neuron disease. The puppy was reluctant to walk on a leash after only a few minutes and would lie down and resist further exercise until it was rested. There were no other abnormalities detected during the neurologic examination. The results of serum biochemical analysis revealed activities of CK (13,930 U/L) and ALT (217 U/L) above the reference ranges (CK, 28 to 97 U/L; ALT, 5 to 35 U/L). Results of the CBC revealed mild lymphocytosis (5.81 × 103 lymphocytes/μL; reference range, 1 to 5 × 103/μL). Urinalysis results were unremarkable. Differential diagnoses included porto-systemic shunt, inherited myopathies (eg, deficiencies of dystrophin or dystrophin-associated protein), metabolic myopathies (eg, electrolyte disorders), immune-mediated polymyositis, infectious myositis (eg, protozoal), nutritional myodegeneration, and, although less likely, inherited polyneuropathies.
Further evaluation of dog 1 at 5 months of age included abdominal ultrasonography and measurement of circulating preprandial and postprandial bile acids concentrations to rule out liver disease. The results of these tests were within respective reference ranges. Dog 1 was anesthetized, and EMG, motor nerve conduction tests,a and biopsy of muscle tissues were performed. During EMG, all muscles tested (appendicular, axial, and cranial muscles) had increased insertional activity, with fibrillation potentials and complex repetitive discharges. Results of nerve conduction tests were within the respective reference ranges. Biopsy samples (1 sample/muscle; size, approx 1 cm3) were obtained from the biceps femoris, cranial tibial, and triceps brachii muscles. Biopsy samples were cooled in liquid nitrogen and frozen isometrically in isopentane; frozen biopsy specimens were subsquently mounted for sectioning. Slide sections (10 μm thick) of muscle tissue were prepared by use of a cryostat and stained with H&E, periodic acid-Schiff, and oil red O stains. Microscopic analysis of the muscle samples revealed an increased number of myofibers with central nuclei, clusters of necrotic myofibers, hyaline fibers, perimysial fibrosis, and small basophilic fibers with central nuclei (Figure 1).
Photomicrographs of a muscle biopsy specimen obtained from the biceps femoris of a dystrophin-deficient male GSHP (dog 1) at 5 months of age and stained with H&E (A and B) and photomicrographs of similar sections of muscle tissue obtained from an unaffected control dog that died from natural causes not related to muscle disease (C) and from dog 1 (D); the latter sections were incubated with antibody directed against the C-terminus of canine dystrophin protein, and bound antibody was subsequently detected by use of 3,3′-diaminobenzidine tetrahydrochloride. In panel A, clusters of necrotic (black arrow) and variably sized muscle fibers are detectable in samples from dog 1. In panel B, central nuclei (arrowhead) and hyaline fibers (white arrow) are evident. In panel C, dystrophin antigen is evidenced by dark staining of the cell membrane in immunohistochemically stained muscle sections obtained from the unaffected control dog. In panel D, there is no evidence of immunoreactivity in the specimen from dog 1. Magnification = 150×.
Citation: Journal of the American Veterinary Medical Association 238, 2; 10.2460/javma.238.2.207
On the basis of the results of histologic analysis, frozen sections were immunohistochemically labeled for dystrophin protein by use of antibodies against the rod domainb and C-terminusc of the protein in accordance with the following method. Primary antibody was diluted 1:10 in PBSS containing 1% bovine serum albumin, and sections were incubated with the antibody solution for 1 hour at approximately 18°C. Sections were washed with PBSS and were incubated with peroxidase-conjugated secondary antibodyd (diluted 1:100 in PBSS with 1% bovine serum albumin) for 1 hour at 18°C. Sections then were washed with PBSS, and bound antibodies were detected with 3,3′-diaminobenzidine tetrahydrochloride.e No dystrophin immunoreactivity was detected in muscle sections from dog 1, and no revertant fibers were observed microscopically (Figure 1).
Four months after the initial examination of dog 1, dogs 1 and 2 were both evaluated at our veterinary teaching hospital for coughing. The gross musculoskeletal abnormalities, trismus, short-strided gait, and reluctance to exercise that were detected in the initial examination of dog 1 were also observed in dog 2; however, the clinical signs for dog 2 were much more severe than those detected for dog 1. The evaluation of dog 2 included most of the same tests (ie, neurologic evaluation, serum biochemical analysis, and a CBC) that had been performed on dog 1 at 5 months of age; however, muscle biopsies were not performed.
The 9-month-old dogs were considered to have stunted growth (dog 1 weighed 22 kg [48.4 lb], and dog 2 weighed 15 kg [33.0 lb]) and had severe, generalized (cranial, appendicular, and axial muscles) skeletal muscle atrophy (Figure 2). Each dog was eupneic and normothermic, but was tachycardic (heart rate, > 180 beats/min for each dog) with increased loudness (due to expanded lung fields) in breath sounds. Results of thoracic radiography were within anticipated limits for dog 1, but revealed a focal increase in opacity with an alveolar pattern in the right middle lung lobe in dog 2, consistent with aspiration pneumonia. Dog 2 also had hyperlucent lung fields, consistent with hyperinflation, and dorsal deviation of the sternum at the level of the manubrium (Figure 3). The results of echocardiographic examination of dog 1 during this visit were unremarkable; echocardiography was attempted for dog 2, but useful images were not obtained. Results of fundic examinations (performed by an ophthalmologist) and brainstem auditory-evoked potentialsa were within anticipated limits in both dogs. Serum CK and ALT activities were above the reference ranges in dog 1 (12,950 and 247 U/L, respectively) and were markedly high in dog 2 (40,200 and 660 U/L, respectively). However, results of a CBC, urinalysis, and analysis of arterial blood gases for both dogs were within the respective reference ranges. Antimicrobial treatment was initiated by the referring veterinarian, and the coughing resolved in both dogs.
Photographs depicting gross phenotypic differences readily detected in 2 male GSHP littermates with a diagnosis of MD. The dogs had been previously genotyped and were found to have a large X-chromosomal deletion that included the entire DMD sequence. A—At 9 months of age, dog 1 (left) is larger and has less severe generalized skeletal muscle atrophy than does dog 2 (right), although temporal muscle atrophy (black arrow) is apparent. B—Hyperextension of the tarsi (black arrowhead) is evident in dog 2 at 9 months of age. C—At 43 months of age, dog 2 has hypertrophic cervical musculature (white arrowhead) and its stance is frequently kyphotic, with weight shifted onto the thoracic limbs. D—At 43 months of age, hypertrophy of the cervical musculature is evident in dog 1, although less severe than the clinical signs detected in dog 2 at the same age.
Citation: Journal of the American Veterinary Medical Association 238, 2; 10.2460/javma.238.2.207
Lateral thoracic radiographic views obtained for dog 2 at 9 months of age (A) and dog 1 at 43 months of age (B). In panel A, hyperlucency of the lung fields with extension to the level of L1 dorsally and flattening of the diaphragm indicates marked hyperinflation of the lungs. Abnormal dorsal deviation of the manubrium (arrowhead) is also evident. In panel B, hyperinflation of the lungs is increased and cranioventral displacement of the sternum (arrowhead) is evident. Results of radiographic assessment of the lungs of dog 1 were unremarkable at 9 months of age, and hyperlucent lung fields were evident in both dogs at 21 months of age (views not shown). No change was detected during radiographic examination of the thorax in dog 2 at 43 months of age.
Citation: Journal of the American Veterinary Medical Association 238, 2; 10.2460/javma.238.2.207
Both dogs were reevaluated 1 and approximately 3 years later (at 21 and 43 months of age). Each had improved with respect to their exercise tolerance during the 3-year period, and although suspected aspiration pneumonia had been diagnosed several times, these episodes were mild and the dogs had responded to treatment with antimicrobial drugs. At 21 months of age, the body weight of the dogs, extent of trismus, and degree of skeletal muscle atrophy had not changed since the previous evaluation. Serum CK activities in both dogs were decreased substantially at this time (3,520 and 2,732 U/L for dogs 1 and 2, respectively), compared with concentrations measured during the previous evaluation. Results of a CBC revealed mild neutrophilia (15.4 × 103 neutrophils/μL; reference range, 3 × 103 neutrophils/μL to 11.5 × 103 neutrophils/μL) but no left shift (0 band neutrophils/μL; reference limit, ≤ 0.3 × 103 band neutrophils/μL) in dog 1; results for dog 2 were within respective reference ranges. Examination of thoracic radiographs revealed that both dogs had hyperlucent lung fields. Echocardiography and ECG were performed in both dogs; hyperechoic foci suggestive of fatty or fibrotic infiltration consistent with early Duchenne's cardiomyopathy were detected in the myocardium (particularly in the left ventricular free wall) of dog 1 (Figure 4), and fractional shortening of the cardiac muscle was subjectively assessed as low to adequate. Useful echocardiographic images of dog 2 could not be obtained because of lung hyperinflation. Analysis of the ECG revealed deep Q waves and an increase in the Q:R ratio in lead II.
Echocardiogram of a dystrophin-deficient dog (dog 1) at 21 months of age. Multiple hyperechoic foci are evident in the left ventricular free wall (arrow).
Citation: Journal of the American Veterinary Medical Association 238, 2; 10.2460/javma.238.2.207
Physical examination at 43 months of age revealed a progression in severity of most clinical signs in both dogs since the previous visit. Body weight of dog 1 had increased by 6 kg (13.2 lb; total body weight, 28 kg [61.6 lb]), and body weight of dog 2 had increased by 3 kg (6.6 lb; total body weight, 18 kg [39.6 lb]). Each had a normal respiratory rate but had hyperpnea with an increased expiratory effort. During auscultation and percussion of the thorax, increased resonance was detected over the lung fields in both dogs, but lung sounds were considered normal. The area of the lung fields assessed on the basis of percussion and auscultation was greater than expected. Generalized skeletal muscle atrophy involving the appendicular, axial, and cranial musculature was subjectively more severe at this time, compared with that observed at 21 months of age; however, both dogs had marked hypertrophy of the cervical musculature (Figure 2) and less advanced but detectable hypertrophy of the lateral head of the triceps brachii muscle. The cervical musculature in dog 2 was so hypertrophied that range of motion in the neck was severely restricted and circumference of the neck was the same as that of the much larger dog 1. No change was detected in the extent of trismus or exercise tolerance in either dog. Thoracic radiography revealed that hyperinflation of the lungs of dog 1 had increased since the previous examination; cranioventral deviation of the sternum (Figure 3) was evident, and alveolar infiltrates were detected in the right middle lung lobe, consistent with aspiration pneumonia. Evaluation of radio-graphic findings for dog 2 revealed no changes. Results of serum biochemical analysis and CBCs in both dogs revealed a marked increase in serum CK and ALT activities in dog 1 (41,340 and 222 U/L, respectively) and a moderate increase in these enzymes in dog 2 (25,260 and 163 U/L, respectively), compared with findings of the previous examination. Mild neutrophilia (cell count, 12.008 × 103 neutrophils/μL) was also detected in dog 1. Echocardiography and ECG were repeated. No further changes from those revealed during the previous examinations were detected in dog 1; however, hyperechoic foci were detected in the left ventricular free wall of dog 2, although fractional shortening of the cardiac muscle was within the reference range.
Except for intermittent episodes of mild aspiration pneumonia, clinical signs did not worsen in either dog during the next 4 years. Dogs 1 and 2 were euthanatized at 84 and 93 months of age, respectively, because of severe aspiration pneumonia. Although dog 2 had more severe diffuse neuromuscular signs, dog 1 was euthanatized first due to complications from severe pneumonia. At the time of death, dog 1 still had increased activities of CK (6,624 U/L [reference range, 48 to 380 U/L]) and ALT (369 U/L [reference range, 16 to 73 U/L]); the reference ranges for these values had changed because new equipment was obtained the same year.
Discussion
Numerous sporadic cases of MD in dogs have been reported1,2 in the past 4 decades. Although dystrophin deficiency is the most likely cause for MD in most other reports, definitive DMD mutations have been characterized only in Golden Retrievers,3 Rottweilers,4 GSHPs,5 Pembroke Welsh Corgis,f and Cavalier King Charles Spaniels.g
Dogs with dystrophin deficiency are important for use in experiments and for evaluation of treatments for Duchenne's MD and Becker's MD in humans. The X-linked human disorders Duchenne's MD and Becker's MD are typically caused by in-frame and out-of-frame DMD mutations, respectively. Human patients with Duchenne's MD have a severe phenotype and often die before they are 20 years of age, whereas patients that have Becker's MD are less severely affected, with a later onset of clinical signs and survival beyond 30 years of age. This variation in clinical phenotype has been largely attributed to the fact that in-frame mutations of Becker's MD allow translation of a truncated, partially functional protein.6 However, this does not occur in all patients,7 and the variations in clinical phenotype reported for dystrophin-deficient patients are of great interest from pathophysiologic and therapeutic perspectives.
Potential explanations for the phenotypic variation among patients with Duchenne's MD and among those with Becker's MD include increased expression of another homologous protein such as utrophin, production of revertant fibers (which are thought to be produced by alternative DMD transcripts that reestablish the open reading frame),8,9 translation reinitiation,10 influences of modifier genes,11–13 and environmental influences such as exercise and rehabilitative treatment.14 Currently, no single hypothesis fully explains the individual variation in clinical phenotypes of affected humans. The emergence of affected domestic animals, all of which exhibit different phenotypes despite analogous DMD mutations, adds to this confusion.
Several conditions in animals, including the mdx mutation in mice,15 GRMD,3 and dystrophin deficiency in other breeds of dogs and cats,16 are useful in the study of Duchenne's MD. Clinical phenotypes in dystrophin-deficient animals are extremely variable; these range from mdx mice with relatively mild clinical signs to variably, sometimes severely affected dogs with GRMD. We previously genotyped the 2 GSHPs described here and showed that each had a large X-chromosomal deletion that included the entire DMD sequence.5 There are several reports17–19 of extensive X-chromosomal deletions in humans; these patients often have a combination of disorders that include MD, retinitis pigmentosa, chronic granulomatous disease, adrenal gland insufficiency, glycerol kinase deficiency, and McLeod syndrome. The dogs of the present report did not have clinical signs of any disorders, except for MD, and on the basis of genetic test results, the RP3 retinitis pigmentosa gene was intact.5
Importantly, in most case reports4,20–23 of dystrophin-deficient dogs, the patients were euthanatized during the first few years after birth, and long-term follow-up monitoring has not been described to our knowledge. The 2 GSHP littermates of the study reported here had many of the clinical and histopathologic findings that are common among animals with conditions indicative of Duchenne's MD. These similarities include exercise intolerance, generalized muscle atrophy, elevated serum CK activity, and spontaneous EMG activity consistent with skeletal muscle dysfunction and necrosis. Other similarities included hyperechoic foci within the cardiac muscle and ECG changes considered typical of dystrophinopathy in dogs.24 Although the significance of deep Q waves (and the resulting increased Q:R ratio) is unknown, these have been associated with interventricular septal hypertrophy. Despite the myocardial changes detected echocardiographically, neither of the dogs of the present report developed dilated cardiomyopathy as has been described24 in dogs with GRMD. It is possible that if the dogs had survived longer, they would have developed clinical signs of dilated cardiomyopathy.
During a 3-year period, the dogs of this report developed hypertrophy of the cervical musculature and of the lateral head of the triceps brachii muscle. Hypertrophy of the cervical musculature associated with dystrophin deficiency has been reported20,23 in a Weimaraner and a Rat Terrier. Dogs with GRMD develop hypertrophy of the glossal musculature, gastrocnemius muscles, and cranial portion of the sartorius muscles,25,26 whereas juvenile human males with Duchenne's MD develop hypertrophy of the gastrocnemius and infraspinatus muscles.27 Muscle hypertrophy is the overriding clinical sign in dystrophin-deficient cats and can cause death as a result of massive hypertrophy of the tongue or diaphragm.16 The cause of hypertrophy of specific muscles is unclear. Hypertrophy of the gastrocnemius muscles in humans may result from the deposition of fat and the development of fibrosis within these muscles.28,29 In contrast, the hypertrophy reported in the cranial portion of the sartorius muscle of affected cats,16 mdx mice,30 and dogs with GRMD25,26 is the result of true hypertrophy of muscle fibers. It has been postulated that alterations in cell signaling result in the hypertrophy.27 Another clinical feature of the GSHPs reported here (which also has been described31 in dogs with GRMD) was hyperinflation of the lungs coupled with a pronounced expiratory effort. One possible explanation is that the bronchial smooth muscle became hypertrophic, which causes air to be trapped in the alveoli and results in an increased expiratory effort. Respiratory dysfunction is described in Duchenne's MD patients and is often the cause of death in generalized neuromuscular disorders, but this frequently results from skeletal deformity and diaphragmatic dysfunction, which causes hypoventilation. Because results of arterial blood gas analyses were within the reference ranges for the GSHPs of this report, hypoventilation was not thought to be a problem at the time of the evaluations. Ultimately, both dogs had repeated episodes of aspiration pneumonia, which was believed to be secondary to trismus and dysphagia rather than to a primary weakness of the respiratory muscles. Although it appears discordant that the less severely affected dog 1 was euthanatized 9 months before the more severely affected dog 2 was euthanatized, this was more likely associated with the random incidence of aspiration in patients with neuromuscular disorders than with a change in phenotypic severity.
Although they had many of the clinical signs commonly associated with MD in dogs, the GSHPs of this report had surprisingly mild phenotypes, given the extensive size of the reported deletion within the X chromosome. The fact that these signs were relatively mild suggests that a complete lack of dystrophin protein may be less detrimental to muscle membrane integrity than is a truncated, partially functional dystrophin protein; it may also suggest that modifier genes have a substantial influence on the severity of MD in GSHPs. Importantly, other potential mechanisms, such as translation reinitiation or alternative splicing to produce revertant muscle fibers, cannot rescue the phenotype (ie, cause reversion to the phenotype of a healthy dog) in GSHPs that have this mutation because the entire DMD sequence is deleted.
It is noteworthy that a subjective difference in clinical severity was detected between the 2 GSHP littermates described here. Although the phenotypes of these dogs were not compared by use of objective functional measurements, the disparity in clinical signs was obvious and consistent; differences were detected in the severity of neuromuscular weakness, extent of joint deformities, and amount of cervical muscle hypertrophy. The importance of phenotypic variability in GSHPs should be interpreted cautiously because evaluation of more dogs by use of objective functional measurements is necessary to reach further conclusions. However, given the phenotypic variability that has been described12,32–34 in other breeds of dogs, in cats, and in human siblings with MD, the subjectively assessed phenotypic variation was not surprising, even though only 2 littermates were evaluated.
Mechanistic causes for phenotypic variability among dogs with dystrophin deficiency are likely to be multifactorial, similar to mechanisms described8,10–13 in humans. Most dogs in which dystrophin deficiency is confirmed by use of immunohistochemical analysis have not been genotyped. Therefore, it is difficult to make meaningful phenotypic comparisons among dog breeds. However, a broad range of phenotypes have been reported,1,2 including relatively mild signs in Japanese Spitz dogs22 and Miniature Schnauzers35 and severe phenotypes in Labrador Retrievers21 and Rottweilers.4 The Rottweilers described in 1 report4 had a fulminant MD and typically died at 4 months to 1 year of age. The genetic mutation was a single G-to-T nucleotide transversion in DMD exon 58 that caused a premature stop codon and a mildly truncated dystrophin protein. Interestingly, analysis of the GRMD mutation predicts a 92% truncation of the dystrophin protein product attributable to a premature stop codon in exon 8, but objective functional studies36,37 have confirmed marked variability in clinical phenotype among affected dogs, even within a single litter. Similar variations in phenotype were reported16,38 in a colony of dystrophin-deficient cats.
From a treatment perspective, variations in clinical phenotype among individuals in a given species that have identical DMD mutations highlight another potential avenue of therapeutic intervention for Duchenne' MD. If these variations are attributable to the effects of 1 or more modifier genes that can be identified and manipulated, then this strategy ultimately might be used to ameliorate the clinical signs associated with certain mutations leading to dystrophin deficiency.
Although only 2 GSHPs were evaluated and monitored for approximately 7 years in this report, the relatively mild neuromuscular signs associated with complete DMD deletion suggest that genetic mutations are not perfectly predictive of clinical phenotype in affected dogs. In a clinical setting, the importance of phenotypic variation within and among breeds of dogs with dystrophin deficiency is that clinicians must rely on results of clinical examinations and monitor the development of clinical consequences (eg, aspiration pneumonia or dysphagia) to provide owners with a prognosis. Moreover, although supportive care (sometimes intensive) may be needed intermittently, some dystrophin-deficient dogs may live for many years with an acceptable quality of life.
ABBREVIATIONS
| ALT | Alanine aminotransferase |
| CK | Creatine kinase |
| DMD | Dystrophin gene |
| EMG | Electromyelography |
| GRMD | Golden Retriever muscular dystrophy |
| GSHP | German Shorthaired Pointer |
| MD | Muscular dystrophy |
| mdx | Murine X-linked muscular dystrophy |
| MRI | Magnetic resonance imaging |
| PBSS | Phosphate-buffered saline solution |
Nicolet Spirit, Nicolet, Ga.
Mouse anti-human DYS1, Novocastra Laboratories Ltd, Newcastle Upon Tyne, England.
Mouse anti-human DYS2, Novocastra Laboratories Ltd, Newcastle Upon Tyne, England.
Peroxidase-conjugated rabbit anti-mouse IgG, Vector Labs, Burlingame, Calif.
Vector Labs, Burlingame, Calif.
Woods P, Sharp N, Schatzberg S. Muscular dystrophy in Pembroke Corgis and other dogs (abstr), in Proceedings. 16th Annu Am Coll Vet Intern Med Forum 1998;287.
Walmsley G, Arechavala-Gomeza V, Fernandez-Fuente M, et al. Mutational analysis of dystrophin deficient muscular dystrophy in Cavalier King Charles Spaniels (abstr). J Vet Intern Med 2009;23:741.
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