Canine X-linked muscular dystrophy is a spontaneously occurring, progressive, degenerative myopathy of dogs that is clinically and pathologically similar to Duchenne muscular dystrophy in man. The molecular basis for the disease has been shown to be a lack of dystrophin, the protein product of the Duchenne muscular dystrophy gene. Breeding colonies of dystrophic dogs have been established. This report reviews the findings of genetic, clinical, pathologic, molecular biologic, and immunocytochemical studies of the canine model, and compares the features of the canine disease to those of Duchenne dystrophy in man.

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A retrospective study of 86 dogs with brain tumors was undertaken. Sixty-nine dogs had histologic confirmation of tumor type, whereas the remaining 17 dogs had CT evidence of a brain tumor. All dogs had neurologic abnormalities. Seven dogs received no treatment, 38 dogs received only symptomatic treatment, and 41 dogs received some form of definitive treatment, in addition to medical management. Types of definitive treatment included surgery, cobalt-60 radiation, whole-body hyperthermia, '"I implants, and chemotherapy, alone or in combination. The factor that was most associated with survival duration was mode of therapy. Those dogs who were treated with cobalt-60 radiation, with or without other combinations of therapy, lived significantly longer than dogs who received surgery (f '*'I implants), or dogs who received symptomatic treatment (P = 0.01 and P < 0.001, respectively). After THE INCIDENCE of intracranial neoplasia in dogs is approximately 14.5 per 100,000 at risk.' Recent studies suggest that meningiomas are the most common intracranial neoplasm, followed by astrocytoma~.~-~ Secondary brain tumors can arise by local extension of nasal, skull, or pituitary gland tumors, or by metastasis from distant tumors. Lymphosarcoma can be either a primary or secondary brain tumor, depending on the site of origin.Little data exist concerning survival of dogs with brain tumors. In one study, a median survival time of 56 days (range: 10-307 days) was reported for dogs that received

Duchenne muscular dystrophy (DMD) is the most common and the most severe of the muscular dystrophies in man. It is inherited as an X-linked recessive trait and is characterized by ongoing necrosis of skeletal muscle fibres with regeneration and eventually fibrosis and fatty infiltration. Although the gene and gene product which are defective in DMD have recently been identified, the pathogenesis of the disease is still poorly understood. A myopathy has been described in the dog which has been shown to be inherited as an X-linked trait and which is therefore a potential model of the human disease. We have studied the phenotypic expression of the disease, canine X-linked muscular dystrophy (CXMD), and have examined the molecular relationship between it and DMD. We report here that dogs with CXMD faithfully mimic the phenotype of Duchenne muscular dystrophy and that they lack the Duchenne gene transcript and its protein product, dystrophin.

The success of many gene therapy applications hinges on efficient whole body transduction. In the case of muscular dystrophies, a therapeutic vector has to reach every muscle in the body. Recent studies suggest that vectors based on adeno-associated virus (AAV) are capable of body-wide transduction in rodents. However, translating this finding to large animals remains a challenge. Here we explored systemic gene delivery with AAV serotype-9 (AAV-9) in neonatal dogs. Previous attempts to directly deliver AAV to adult canine muscle have yielded minimal transduction due to a strong cellular immune response. However, in neonatal dogs we observed robust skeletal muscle transduction throughout the body after a single intravenous injection. Importantly, systemic transduction was achieved in the absence of pharmacological intervention or immune suppression and it lasted for at least 6 months (the duration of study). We also observed several unique features not predicted by murine studies. In particular, cardiac muscle was barely transduced in dogs. Many muscular dystrophy patients can be identified by neonatal screening. The technology described here may lead to an effective early intervention in these patients.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified.

Clinicopathologic findings from two golden retriever dogs with an inherited, progressive, degenerative muscle disease that were studied until 27 and 40 months of age are described. Initial clinical signs included stilted gait and simultaneous advancement of their pelvic limbs. Further gait restriction and muscle hypertrophy eventually occurred. Serum creatine kinase was dramatically elevated (greater than 10,000 U/L). There were persistent "spontaneous" high-frequency discharges (pseudomyotonia) on electromyographic evaluation. Features of both muscle fiber degeneration (hyaline fibers, myophagocytosis) and regeneration (small basophilic fibers) were seen on light microscopy. Similar ultrastructural changes (fiber hypercontraction, increased myoblasts) were present. On morphometric histochemical evaluation, mean fiber diameter of both type 1 and 2 fibers was increased compared with controls in two of three muscles examined. There was no apparent fiber type predominance. Scattered ragged red fibers were seen, but this appeared to be a nonspecific finding of either muscle fiber regeneration or degeneration. These findings and potential contributing pathophysiologic mechanisms are discussed in relation to Duchenne muscular dystrophy.

Clinical features of 36 dogs with histologically confirmed fibrocartilaginous embolism (FCE) were contrasted with those of 26 dogs in which FCE was suspected based on characteristic clinical findings and the absence of compressive spinal cord disease on myelography. Dogs with confirmed and suspected FCE were of similar signalment, and had acute, nonprogressive dysfunction, often associated with trauma or exercise. The "suspected group included ibrocartilaginous embolism (FCE) is a syndrome of F acute spinal cord infarction caused by embolization of fibrocartilage, histochemically identical to the nucleus pulposus of intervertebral disks. Histopathologic evaluation is necessary to establish a definitive diagnosis. Based on published data from histologically confirmed cases, FCE appears to have a high prevalence in large and giant-breed dogs, and a predilection for the spinal intumescence^.'-'^ However, considering that large dogs with intumescence involvement could be at increased risk for euthanasia, we were concerned that data from necropsy cases could be skewed. To more critically evaluate this point, clinical findings of histologically confirmed cases were contrasted with those from dogs in which FCE was suspected, but not confirmed at necropsy. Materials and MethodsWe analyzed the historical, clinical, and necropsy features of 36 dogs with histologically confirmed FCE. Thirty-one of these dogs have been reported previo~sly'~'~; the other 5 were evaluated at the North Carolina State University College of Veterinary Medicine (NCSU-CVM). Data from one large retrospective series that did not clearly distinguish between confirmed and suspected cases were not in~1uded.l~ Case signalment; acuity of onset and progression of signs, and their association with trauma or exercise; history of pain; spinal cord segment involvement; symmetry; hyperesthesia; presence of deep nociception; cerebrospinal fluid evaluation results (site of collection was not consistently identified); spinal radiographic and myelographic findings; and gross and microscopic necropsy findings were recorded when found in case material from the published cases. These features were,,also characterized in 26 dogs with suspected FCE evaluated at the NCSU-CVM between 1985 and 1992. Criteria for inclusion in our study included peracute/acute, nonprogressive paresis or paralysis that was not associated with myelographic spinal cord compression, as detailed in the radiographic report found in the medical record. Dogs with suspected lesions were subsequently discharged. Follow-up information beyond the day of discharge was not consistently obtained. ResultsData to address certain features were not available on all dogs. The actual numbers of dogs from which data could be collected are included for each feature. Data from "confirmed" and "suspected" cases are given in Tables 1 and 2, respectively. Differences between the 2 groups are contrasted in Table 3. SignalmentNone of the dogs with confirmed or suspected FCE was a chondrodystrophoid breed. Sixteen of t...