Juvenile-Onset Distal Myopathy in Rottweiler Dogs

In this report we describe a myopathy involving predominantly distal muscles in 4 young Rottweiler pups, 2 of which were siblings. All of the dogs were bred in southern California. These dogs had distal appendicular weakness evidenced by postural abnormalities ranging from a splay of the digits and hyperflexion of the hocks to a plantigrade and palmigrade stance. Histopathologic changes in the muscles consisted mainly of atrophy, myofiber necrosis, and replacement of muscle with fibrous and fatty connective tissue. An underlying etiology for these changes could not be identified. This condition resembles the distal myopathies reported in humans in the distribution of lesions and familial occurrence. A variety of distal myopathies are recognized in humans, including a late adult onset autosomal dominant myopathy beginning in the hands (Welander myopathy), a late adult onset autosomal dominant myopathy beginning in the feet, an early adult onset autosomal recessive or sporadic myopathy beginning in the hands or feet, and various infantile and juvenile onset distal myopathies.1 No specific treatment for these conditions has been found. These conditions are grouped under the human muscular dystrophies. Congenital myopathies described previously in dogs include myotonic myopathies, myopathy associated with type II fiber deficiency in Labrador Retrievers, and X-linked muscular dystrophies, associated with lack of the muscle protein dystrophin.

 Materials and Methods

 Muscle biopsies were fresh frozen in isopentane precooled in liquid nitrogen and processed by a standard panel of stains and reactions, including hematoxylin and eosin, modified trichrome, periodic acid-Schiff, and oil red O. Sections also were incubated and stained for the histochemical localization of nicotinamide adenine dinucleotide tetrazolium reductase, myofibrillar adenosine triphosphatase (pH = 9.8 and 4.3), acid and alkaline phosphatases, esterase, and staphylococcal pro tein A-horseradish peroxidase.2 Frozen sections of peripheral nerve samples were evaluated with the modified Gomori trichrome stain. Urinary organic acids were quantified by gas chromatography- mass spectrometry as described by Hoffman et al.3 Amino acids were quantified in plasma and urine by the method of Spackman et al.4 Carnitine was quantified in the plasma, urine, and muscle by the method of Bieber and Lewin.5 Muscle carnitine concentration was expressed as nmol/mg muscle protein. Muscle protein was determined using a standard Lowry assay.

 Case Reports

 Two Rottweiler siblings were presented to the Colorado State University Veterinary Teaching Hospital with the chief complaint of abnormal posture. The pups were from a litter of 15 with a high early mortality rate. Four pups were born dead or died within the first few hours of life; I of these was reported to be underdeveloped, whereas the others appeared to be normal. Another pup was reported to be underdeveloped and weak and lived only a few days, whereas 3 apparently normal pups were assumed to have been inadvertently smothered by the dam within days of birth. Seven pups survived early life. One of the authors (GDS) was presented with muscle samples from 2 additional pups from 2 different litters with signs similar to the first 2 pups presented. Sufficient pedigree information was not available to determine whether the 3 litters were related.

 Dog 1

 The 1st pup was a male examined at 5 months of age. From the time the dog was obtained at approximately 8 weeks of age, the owners noticed that he stood and walked plantigrade and palmigrade (Fig. 1). The owners reported no other historical problems. Physical examination revealed markedly flaccid limbs with moderately decreased muscle mass. Conscious proprioception was normal in all limbs, and reflexes were judged to be within normal limits. No joint laxity was found on orthopedic evaluation and the remainder of the physical examination was also normal. Serum biochemical abnormalities included a mild decrease in blood urea nitrogen (6 mg/dL, reference range = 7-28 mg/dL) and a mild increase in cholesterol (333 mg/dL, reference range = 130-300 mg/dL) concentrations; creatine kinase (CK) activity was normal. A mild normocytic, normochromic anemia (PCV = 33%, reference range = 37-55%) was present; the CBC was otherwise normal A urinalysis also was normal. A tentative diagnosis of a primary myopathy was made based on the presence of abnormal gait and posture with normal conscious proprioception and spinal reflexes. To support the diagnosis of a myopathy, electromyography (EMG) was performed, and it revealed rare fibrillation potentials and positive sharp waves within the thigh musculature. A biopsy was taken from the biceps femoris muscle and histopathologic examination showed vari ability in myofiber size, and atrophic fibers of both fiber types.

 The pup was brought back to the hospital approximately 2 weeks later with an open, poorly healing biopsy site and bilateral hock hygromas. An EMG revealed isolated complex repetitive discharges in the quadriceps femoris and triceps brachii muscles. Rare fibrillation potentials also were present in the latter. Motor nerve conduction velocity was normal (tibial nerve velocity = 50 m/see, reference range for sciatic-tibial nerve conduction velocity for dogs 3-6 months old = 53.0 ± 5.6 m/second),6 although amplitudes of the interosseus compound muscle action potential were decreased (8.0 mV with stimulation at the hock, normal = 22.7 ± 2.7 mV; 4.3 mV with stimulation at the stifle, normal = 22.0 ± 2.9 mV).7 Compound muscle action potential durations were within normal limits.7 Because of the severity of the pup's clinical condition he was euthanized.

 Gross and histopathologic postmortem examination showed that the sciatic nerve (sampled at mid-thigh) and radial nerve (sampled at midbrachium) were normal. The spinal cord (sampled at the 2nd cervical segment, 2nd thoracic segment, and in the lumbar region) and brain, as well as the thoracic and abdominal viscera and thyroid glands, were normal. Samples from the vastus lateralis, triceps brachii, gastrocnemius, and extensor carpi radialis muscles were processed as described above. The vastus lateralis and triceps brachii muscles were normal. Within the gastrocnemius muscle, however, there was marked replacement of muscle by fat; the small islands of atrophic fibers remaining consisted primarily of type I fibers (Fig 2A,B). The extensor carpi radialis muscle had mild generalized myofiber atrophy with a mild increase in endomysial connective tissue.

 Extensive metabolic testing was performed on antemortem blood and urine samples (Dr W.L. Nyhan, Biochemical Genetics Laboratory, University of California, San Diego, CA). Analyses included plasma concentrations of 28 amino acids, urine concentrations of 40 amino acids, and urine concentrations of 79 organic acids evaluating intermediates in all the major metabolic pathways. Free and esterified carnitine were quantified in plasma, urine, and muscle (Dr W.L. Nyhan, Biomedical Genetics Laboratory, University of California).3-5 Abnormalities included decreased total and free plasma carnitine and decreased total and free muscle carnitine concentrations (Table 1).

Table 1.  Plasma, urine, and muscle carnitine concentrations in 4 Rottweiler pups with distal myopathy.
 
 

.	Dog 1	Dog 2	Dog 3	Dog 4	Reference Range
Plasma carnitine Total ( mol/L) Free ( mol/L)  Esters ( mol/L)  Ratio esters/free	15.2  14.3  0.9  0.06	14.6  12.9  1.7  0.13	9.4  9.0  0.4  0.04	11.1  10.2  0.0  0.09	17-43 17-38 0-23 0-0.54
Muscle carnitine Total (nmol/mg protein)  Free (nmol/mg protein)  Esters (nmol/mg protein)	9.4  9.4  0	17.2  11.8  5.4	9.5  7.4  2.1	0.7  0.5  0.2	12-41 11-33 0-11

 

 Dog 2

 The 2nd male pup from the same litter as the 1st was brought to the hospital at the age of 7 months. This pup had always had splayed forepaw digits (Fig 3) and hyperflexion of both hocks (Fig 4). The pup was lethargic and exercise-intolerant. Physical examination revealed an area of excoriation and flea infestation above the tail head, but no other abnormalities. A serum biochemistry panel showed a mild hypercholesterolemia (324 mg/dL, reference range = 130-300 mg/dL) and a mild increase in CK activity (378 IU/L, reference range = 50250 IU/L). A thyroid-stimulating hormone (TSH) stimulation test showed normal thyroid function. Urinalysis was normal, and a CBC showed an eosinophilia of 3,400 cells/ L (normal = 100-1,200 cells/ L). A fecal flotation and an occult heartworm test were negative; tapeworm proglottids were later found in the stool. An echocardiogram showed normal ventricular wall thickness and contractility.

 EMGs of the proximal and distal appendicular muscles, axial muscles, masticatory muscles, and lingual muscles were normal. Motor nerve conduction velocities of the sciatic-tibial and ulnar nerves were normal (sciatic-tibial nerve 57.2 m/second, reference range for sciatic-tibial nerve conduction velocity for dogs 6-12 months old = 65.0 ± 8.8 m/second6; ulnar nerve velocity = 50 m/second, reference range for ulnar nerve conduction velocity for dogs 3-24 months old = 49.5-73.3
m/second)6, but compound muscle action potentials recorded from the interosseous muscles were decreased. Stimulation of the tibial nerve at the level of the hock yielded an action potential of 7.0 mV (reference range = 22.2 ± 2.6 mV)7 and stimulation of the ulnar nerve at the level of the carpus produced a potential of 6.9 mV (reference range = 23.2 ± 3.1 mV).7 Biopsy samples from the vastus lateralis, triceps brachii, gastrocnemius, and common digital extensor muscles were processed as described for dog 1. The triceps brachii muscle was normal, but the vastus lateralis muscle had perimysial fat with marked type I fiber predominance (Fig 5). The common digital extensor muscle had increased perimysial connective tissue with occasional myofibers undergoing necrosis and phagocytosis. The gastrocnemius muscle had moderate variation in myofiber size, with round atrophic type I and II fibers. There was increased perimysial fat and focal areas of increased endomysial connective tissue. Multifocal areas of myofibers undergoing necrosis and phagocytosis also were present (Fig 6). The histopathologic changes were not as severe as those seen in the muscles of dog 1. Immunohistochemistry for the carboxy terminus and rod domains of dystrophin in this sample was normal (Novacastra Laboratories. UK).

 Metabolic testing was performed as in dog 1. While awaiting results of this testing, L-carnitine (Carnitor®, Sigma Tau Pharmaceuticals, Gaithersburg, MD) therapy was initiated at a dose of 107 mg/kg/day per os, divided into 3 daily doses. This dose is slightly higher than the top of the range recommended for humans.8 The rationale for this therapy was the similarity in clinical presentation between the 2 pups, and the decreased carnitine concentrations in the 1st pup. After 1 month of
therapy, dog 2 had minimal improvement. The dose of L-carnitine was then increased to 175 mg/kg/day, which approximates that recommended for dogs with cardiomyopathic carnitine deficiency.9 One month later the pup had moderate clinical improvement. He played vigorously and maintained a nearly normal hock posture. He did, however, continue to show splaying of the thoracic limb digits. A 2nd biopsy from the gastrocnemius muscle after L-carnitine therapy showed a marked decrease in myonecrosis with no appreciable change in perimysial fat.

 The results of the pretreatment metabolic testing became available when dog 2 had been on carnitine therapy for 6 weeks. Plasma carnitine concentration was mildly decreased, whereas free muscle carnitine concentration was at the low end of normal (Table 1). To determine whether the improvement in clinical signs was due to carnitine supplementation, carnitine therapy was
withdrawn. The pup showed no deterioration in strength or exercise tolerance within the next 6 months. He was then euthanized at the owner's request because of unrelated behavioral problems. A necropsy showed no gross lesions in any organ system. Samples were collected from the gastrocnemius, extensor carpi radialis, vastus lateralis, and triceps muscles. Within the gastrocnemius myofiber size varied moderately, with scattered round atrophic fibers of both fiber types. There was increased endomysial and perimysial connective tissue and increased perimysial lipid. No evidence of myonecrosis was observed. Similar but milder changes were present within the vastus lateralis and triceps muscles. A mild variation in myofiber size was also present within the extensor carpi radialis muscle.

 Dog 3

 A 15-week-old male Rottweiler from a breeder in southern California was found to have weakness and postural changes similar to those of dog 1. Because of the severity of the dog's condition, the owners elected euthanasia. The following muscles were evaluated: gastrocnemius, vastus lateralis, extensor carpi radialis, cranial tibial, biceps femoris, triceps, and flexor carpi
ulnaris. No abnormalities were found within the proximal muscles. The changes within the gastrocnemius muscle were similar to those described for dog 1, with marked replacement of muscle by fatty tissue, islands of round atrophic myofibers, and scattered singular necrotic fibers undergoing phagocytosis. Peroneal, radial, and sciatic nerves were normal. Immunocytochemical staining for dystrophin was normal (Novacastra Laboratories). There were no abnormalities in amino or organic acids. Plasma and muscle carnitine concentrations were decreased (Table 1).

 Dog 4

 Muscles from a 16-week-old female Rottweiler with a history of walking plantigrade since 3 weeks of age were evaluated. This dog was 1 of 3 affected dogs in a litter of 8 from another breeder in southern California. Histopathologic changes in the semitendinosus and gastrocnemius muscles were similar to those in dog 2. Serum CK activity was 408 IU/L (reference range = 20-350 IU/L). Quantification of organic and amino acids revealed no abnormalities. Plasma carnitine concentrations were decreased and muscle carnitine concentrations were markedly decreased (Table 1).

 Discussion

 The cases in this report represent a unique form of muscular dystrophy in dogs, varying from previously reported cases in the clinical signs, distribution of lesions, serum CK activity, and muscle fiber dystrophin staining. The muscular dystrophies have been defined as a group of primary inherited myopathies characterized by progressive degeneration of muscle.10 The myopathy in these Rottweilers can be considered a type of muscular dystrophy due to the degeneration of muscle in
the absence of an identifiable underlying cause. Although the criterion of heritability has not been proven, a heritable basis is suspected based on the relationship between dogs 1 and 2, the presence of 2 other clinically affected dogs in dog 4's litter, and the fact that all affected dogs were young Rottweilers bred in southern California.

 The Rottweilers in this report demonstrated a unique distribution of muscle lesions. They had predominantly distal limb weakness and had histopathologic changes mainly in the distal limb muscles. These findings resemble those of distal myopathies in humans, which start in the hands or feet.1 These human diseases may involve mild changes in proximal muscles, but lesions
predominate distally. Distal myopathies in humans are a heterogenous group of diseases with either an inherited basis or sporadic occurrence.1 It is of interest that EMG was not definitive in determining the distribution of lesions in dog 1. We suspect that spontaneous activity was not found in the more severely affected muscles (gastrocnemius and extensor carpi radialis muscles) because of the paucity of muscle fibers and marked replacement with fatty and fibrous connective tissue.

 The distribution of lesions in the present cases is different from the X-linked muscular dystrophy of dogs, described in Golden Retrievers,11 Irish Terriers,12 and Rottweilers.13 These conditions in dogs resemble Duchenne muscular dystrophy of humans. Affected Golden Retriever and Irish Terrier pups have signs that include stiffness of the limbs, enlargement of the tongue, dysphagia, and ptyalism beginning at 6-8 weeks of age.

 An additional difference between the present cases and those previously reported is the serum CK activity. Dogs 2 and 4 in this series had only mild increases in CK. Serum CK activities in types of canine muscular dystrophy described by other authors are markedly increased, sometimes greater than 5,000 IU/L in affected Golden Retrievers. Clinically normal females in Golden Retriever litters occasionally have mild increases in CK activity, marking them as carriers of the X-linked disease.
Histopathologic changes in these Rottweilers bore some similarity to those in other animals with muscular dystrophy.10-13 The pups in this study had atrophy, myofiber necrosis, and replacement of muscle with fibrous and fatty connective tissue. Type I fiber predominance, a consistent finding in humans with Duchenne muscular dystrophy, was seen occasionally in muscle samples. Lesions in muscles from Golden Retrievers and Irish Terriers with muscular dystrophy include marked
variation in muscle fiber size, numerous hyaline fibers, occasional internal nuclei, and mild endomysial proliferation. More severe cases have mineralization of necrotic muscle fibers and clusters of small basophilic fibers.10-12 Affected Rottweilers have severe muscle necrosis.13,14 Myonecrosis in the Rottweilers of this report was not severe, and only occasional necrotic fibers
were present.

 A final difference between the pups in this report and other cases of muscular dystrophy in dogs is the pathogenesis, as suggested by the disparity in dystrophin staining. Dystrophin is a subsarcolemmal protein that is thought to play an important role in maintenance of membrane integrity.15 Dystrophin abnormalities were not found in 2 dogs tested using an immunocytochemical assay. This is in contrast to reported cases of Golden Retrievers and Rottweilers with Duchenne-like
muscular dystrophy that have absent or deficient muscle dystrophin.13 Dystrophin is typically normal in humans with Welander distal myopathy,16 but is decreased in those with Duchenne muscular dystrophy.17 Because of the important role of the dystrophin molecule in healthy muscle and its implication in the pathogenesis of some types of muscular dystrophy, a difference in pathogenesis between distal myopathy and Duchenne muscular dystrophy is likely.

 The neuronopathy described by Shell et al18 might be considered in the differential diagnosis for a young Rottweiler with paresis. However, the dogs in that report had signs not seen in the dogs described here, including megaesophagus, head and limb tremors, and decreased gag reflex.

 Extensive metabolic testing was performed in an attempt to clarify the pathogenesis of the present cases. Based on the presence of increased intramyofiber lipid in the muscle biopsy from dog 1, we hypothesized that a metabolic defect might be important in this distal myopathy. Because of the vital function of carnitine in muscle lipid metabolism,19 carnitine deficiency was an important differential diagnosis. Carnitine concentrations were evaluated in muscle, plasma, and urine. Plasma
carnitine concentrations alone would not have adequately ruled out carnitine as part of the pathogenesis of this disease, because many dogs with carnitine-responsive cardiomyopathy have normal plasma carnitine but decreased myocardial carnitine concentrations. It is speculated that these dogs have a defect in sarcolemmal transport of carnitine.20,21 Plasma carnitine concentrations (total and free) were decreased in all 4 dogs. Total muscle carnitine concentration was decreased in the 3
worst affected dogs, and severely decreased in 1 dog (dog 4). Free muscle carnitine concentration also was low in 3 dogs and borderline low in the least affected dog. Neither excessive urinary loss of carnitine nor loss of an esterified form of carnitine occurred. This is consistent with the fact that no abnormal organic acids were found in the urine of any dogs.

 The significance of the low plasma and muscle carnitine is not certain and may be secondary to the degenerative process. The majority of carnitine deficiencies in humans are secondary to an inborn error of metabolism; therefore, all carnitine deficiencies should be considered secondary until defects in several metabolic pathways have been excluded.19,22 Extensive metabolic testing in all dogs did not reveal abnormalities in any of the important intermediary metabolites.

 Because evidence for carnitine abnormalities was present in all dogs tested, we initiated carnitine therapy in dog 2 at a dose approximately equal to the top of the dose range for people. After 1 month we saw only modest clinical improvement. We then increased the dose to that recommended for dogs with cardiomyopathic carnitine deficiency. One month later the pup showed
increased activity and strength. Evaluation of the gastrocnemius muscle after carnitine therapy and evaluation of additional muscle biopsies postmortem showed decreased myonecrosis and fatty infiltration. It is uncertain whether these changes are a result of carnitine therapy or simply part of the natural course of this disease. Because exercise has been shown to be of benefit in a human patient with distal myopathy,23 the regular exercise the pup received also might have contributed to improvement. This possibility is supported by the lack of deterioration after carnitine withdrawal.

 These 4 cases of canine myopathy are unique due to the decreasing severity of the lesions from distal to proximal, which has not been described previously in dogs. The mild manifestation of disease in dog 2, however, raises the possibility that some cases of this distal myopathy may have been overlooked. Postural abnormalities due to muscle disease could be erroneously dismissed as conformational defects. Increased awareness of this condition may allow recognition of more cases, determination of the true incidence of the myopathy, and analysis of a possible genetic basis.

Acknowledgments

        We wish to thank Ms Sharlene Dyer, Elizabeth, CO, and Dr Ginny Bischel, Chula Vista, CA, for alerting us to affected animals included in this report. We also thank Drs L.A. Obert and D.C. Baker (Colorado State University Department of Pathology) for performing the postmortem examination of the central nervous system and viscera of dog 1. This work was done predominantly at the College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO.

References

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 7. Walker T, Redding R, Braund K. Motor nerve conduction velocity and latency in the dog. Am J Vet Res 1979;40:1433-1439.

 8. Olin B. Drug Facts and Comparisons. St Louis, Mo: Facts and Comparisons; 1995:178.

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10. Kornegay J. The X-linked muscular dystrophies. In: Kirk R, Bonagura J. ed. Current veterinary Therapy Xi. Philadelphia, PA: WB Saunders; 1992:1042-1047.

11. Kornegay J. Golden Retriever myopathy. In: Kirk R. ed. Current veterinary Therapy IX. Philadelphia, PA: WB Saunders; 1986: 792-795.

12. Wentink G, van der Linde-Sepman J, Meijer A. Myopathy with a possible recessive X-link inheritance in a litter of Irish Terriers. Vet Pathol 1972;9:328-394.

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14. Kakulas B, Cooper B. Experimental and animal models of human neuromuscular disease. In: Walton J, Karpati G, Hilton-Jones D, eds. Disorders of Voluntary Muscle. New York, NY: Churchill Livingstone; 1994:437-496.

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17. Gardner-Medwin D, Walton J. The muscular dystrophies. In: Walton J, Karpati G, Hilton-Jones D, eds. Disorders of Voluntary Muscle. New York, NY: Churchill Livingstone; 1994:543-594.

18. Shell LG, Jortner BS, Leib MS. Spinal muscular atrophy in two Rottweiler littermates. J Am Vet Med Assoc 1987;190:878-880.

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Fig 1. Dog 1 upon presentation at 5 months of age. This pup has a plantigrade and palmigrade stance.

Fig 2. (A) Hematoxylin and eosin stain of a fresh frozen muscle biopsy section from the gastrocnemius muscle of dog 1. Marked myofiber atrophy and replacement of myofibers with perimysial lipid are present. (B) Myofibrillar adenosine triphosphatase reaction at pH 9.8 for differ entiation of fiber types within the gastrocnemius from dog 1. Thick arrow indicates light-staining type I fibers and the thin arrow indicates darker Staining type II fibers. Bar = 100 µm.

Fig 3. Forepaws of dog 2 upon presentation al 7 months of age. The digits are flat and splayed rather than arched and apposed.

Fig 4. Hindquarters of dog 2 upon presentation at 7 months of age. Both hocks are markedly hyperflexed.

Fig 5. Myofibrillar adenosine triphosphatase reaction at pH 4.3 of the vastus lateralis muscle from dog 2. The type I fibers are dark staining, type 2A fibers are light staining, and type 2C fibers are intermediate staining (arrow). Bar = 50 µm.

Fig 6. Hematoxylin and cosin stain of a fresh frozen muscle biopsy section from the gastrocnemius muscle of dog 2. Myofiber atrophy is present with increased perimysial lipid and scattered singular necrotic fibers undergoing phagocytosis (arrows). Bar = 117 µm.

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