Variants in CLCN1 and PDE4C Associated with Muscle Hypertrophy, Dysphagia, and Gait Abnormalities in Young French Bulldogs.

(1) Background: Muscle hypertrophy, swallowing disorders, and gait abnormalities are clinical signs common to many muscle diseases, including muscular dystrophies, non-dystrophic myotonias, genetic myopathies associated with deficiency of myostatin, and acquired inflammatory myopathies. Here, we investigated underlying causes of this triad of clinical signs in four young French bulldogs via muscle histopathology coupled with whole genome and Sanger sequencing. (2) Methods: Dogs were evaluated by veterinary clinical internists and neurologists, and biopsies were obtained for histopathological diagnosis. DNA was submitted for whole genome sequencing, followed by bioinformatics evaluation and confirmation of variants via Sanger sequencing in two cases. (3) Results: Two novel variants were identified. The first, found in two related French bulldogs, was a homozygous variant in the chloride channel gene CLCN1 known to cause non-dystrophic congenital myotonia, and the second, found in an unrelated French bulldog, was a heterozygous variant in the cAMP phosphodiesterase gene PDE4C, which is the major phosphodiesterase expressed in skeletal muscle and may play a role in decreasing muscle atrophy. An underlying molecular basis in one other case has not yet been identified. (4) Conclusions: Here, we identified two novel variants, one in the CLCN1 and one in the PDE4C gene, associated with clinical signs of muscle hypertrophy, dysphagia, and gait abnormalities, and we suggested other bases of these phenotypes in French bulldogs that are yet to be discovered. Identification of genes and deleterious variants associated with these clinical signs may assist breeders in improving the overall health of this very popular breed and may lead to the identification of new therapies to reverse muscle atrophy in people and animals with neuromuscular diseases.

Precision medicine using whole genome sequencing identifies a novel dystrophin (DMD) variant for X-linked muscular dystrophy in a cat.

BACKGROUND: Muscular dystrophies (MDs) are a large, heterogeneous group of degenerative muscle diseases. X-linked dystrophin-deficient MD in cats is the first genetically characterized cat model for a human disease and a few novel forms have been identified. HYPOTHESIS/OBJECTIVES: Muscular dystrophy was suspected in a young male domestic shorthair cat. Clinical, molecular, and genetic techniques could provide a definitive diagnosis. ANIMALS: A 1-year-old male domestic shorthair cat presented for progressive difficulty walking, macroglossia and dysphagia beginning at 6 months of age. The tongue was thickened, protruded with constant ptyalism, and thickening and rigidity of the neck and shoulders were observed. METHODS: A complete neurological examination, baseline laboratory evaluation and biopsies of the trapezius muscle were performed with owner consent. Indirect immunofluorescence staining of muscle cryosections was performed using several monoclonal and polyclonal antibodies against dystrophy-associated proteins. DNA was isolated for genomic analyses by whole genome sequencing and comparison to DNA variants in the 99 Lives Cat Genome Sequencing dataset. RESULTS AND CLINICAL IMPORTANCE: Aspartate aminotransferase (687 IU/L) and creatine kinase (24 830 IU/L) activities were increased and mild hypokalemia (3.7 mmol/L) was present. Biopsy samples from the trapezius muscle confirmed a degenerative and regenerative myopathy and protein alterations identified by immunohistochemistry resulted in a diagnosis of a in dystrophin-deficient form of X-linked MD. A stop gain variant (c.4849C>T; p.Gln1617Ter) dystrophin was identified by genome sequencing. Precision/genomic medicine efforts for the domestic cat and in veterinary medicine support disease variant and animal model discovery and provide opportunities for targeted treatments for companion animals.

Novel COL6A3 frameshift variant in American Staffordshire Terrier dogs with Ullrich-like congenital muscular dystrophy.

Two (male and female) 10-month-old American Staffordshire Terrier littermates presented for progressive weakness, joint contracture, and distal limb joint hyperlaxity beginning around 6 months of age. Neurological examination, serum creatine kinase activity, infectious disease titers, cerebrospinal fluid analysis, and electrodiagnostic testing were performed. Muscle biopsies were collected for histopathology and immunofluorescence staining for localization of dystrophy associated proteins. Whole-genome sequencing (WGS) was performed on 1 affected dog. Variants were compared to a database of 671 unaffected dogs of multiple breeds. Histopathology confirmed a dystrophic phenotype and immunofluorescence staining of muscle cryosections revealed an absence of staining for collagen-6. WGS identified a homozygous 1 bp deletion in the COL6A3 gene, unique to the first affected dog. Sanger sequencing confirmed the homozygous presence of the frameshift variant in both affected dogs. This report describes the clinical features and most likely genetic basis of an Ullrich-like recessively inherited form of congenital muscular dystrophy in American Staffordshire Terriers.

Current Classification of Canine Muscular Dystrophies and Identification of New Variants.

The spectrum of canine muscular dystrophies has rapidly grown with the recent identification of several more affected breeds and associated mutations. Defects include those in genes and protein products associated with the sarcolemma (dystrophin deficient X-linked muscular dystrophy and sarcoglycan-deficient limb-girdle muscular dystrophy) and with the extracellular matrix (collagen 6, laminin α2, and α-dystroglycan-deficient congenital muscular dystrophies). With the increasing application of whole genome sequencing and whole exome sequencing, the clinical and pathological spectra associated with specific neuromuscular genetic defects are constantly evolving. In this report, we provide a brief overview of the current status of gene defects reported in canine muscular dystrophies. We also report the causative mutations for novel forms of X-linked muscular dystrophy in Brittany spaniels and in a French bulldog.

A Nonsense Variant in the DMD Gene Causes X-Linked Muscular Dystrophy in the Maine Coon Cat.

(1) Feline dystrophin-deficient muscular dystrophy (ddMD) is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles and is caused by variants in the DMD gene. To date, only two feline causal variants have been identified. This study reports two cases of male Maine coon siblings that presented with muscular hypertrophy, growth retardation, weight loss, and vomiting. (2) Both cats were clinically examined and histopathology and immunofluorescent staining of the affected muscle was performed. DMD mRNA was sequenced to identify putative causal variants. (3) Both cats showed a significant increase in serum creatine kinase activity. Electromyography and histopathological examination of the muscle samples revealed abnormalities consistent with a dystrophic phenotype. Immunohistochemical testing revealed the absence of dystrophin, confirming the diagnosis of dystrophin-deficient muscular dystrophy. mRNA sequencing revealed a nonsense variant in exon 11 of the feline DMD gene, NC_058386.1 (XM_045050794.1): c.1180C > T (p.(Arg394*)), which results in the loss of the majority of the dystrophin protein. Perfect X-linked segregation of the variant was established in the pedigree. (4) ddMD was described for the first time in the Maine coon and the c.1180C>T variant was confirmed as the causal variant.

Dystrophin-Deficient Muscular Dystrophy in Two Male Juvenile Brittanys.

A 6 mo old and a 7 mo old male intact Brittany were presented for progressive exercise intolerance, failure to grow, and dysphagia. Creatine kinase activity was markedly and persistently elevated in both dogs. Based on the neurological examination, clinical signs localized to the neuromuscular system. Electromyography revealed complex repetitive discharges in multiple muscle groups. Immunofluorescence of biopsies confirmed dystrophin-deficient muscular dystrophy. This is the first report describing dystrophin-deficient muscular dystrophy in the Brittany breed. Currently, no specific therapies are available for this form of myopathy. The presence of dystrophin deficiency in the two dogs suggests an inherited myopathy rather than a spontaneous mutation. The location of the dogs in the United States and Japan suggests a wide distribution of this dystrophy and should alert clinicians to the existence of this myopathy in the Brittany breed. A mutation in the DMD gene has not yet been identified.

X-linked myotubular myopathy associated with an MTM1 variant in a Maine coon cat.

OBJECTIVE: Describe the clinical course and diagnostic and genetic findings in a cat with X-linked myotubular myopathy. CASE SUMMARY: A 7-month-old male Maine coon was evaluated for progressively worsening gait abnormalities and generalized weakness. Neurolocalization was to the neuromuscular system. Genetic testing for spinal muscular atrophy (LIX1) was negative. Given the progressive nature and suspected poor long-term prognosis, the owners elected euthanasia. Histopathology of skeletal muscle obtained post-mortem disclosed numerous rounded atrophic or hypotrophic fibers with internal nuclei or central basophilic staining. Using oxidative reactions mediated by cytochrome C oxidase and succinic dehydrogenase, scattered myofibers were observed to have central dark staining structures and a "ring-like" appearance. Given the cat's age and clinical history, a congenital myopathy was considered most likely, with the central nuclei and "ring-like" changes consistent with either centronuclear or myotubular myopathy. Whole genome sequencing identified an underlying missense variant in myotubularin 1 (MTM1), a known candidate gene for X-linked myotubular myopathy. NEW OR UNIQUE INFORMATION PROVIDED: This case is the first report of X-linked myotubular myopathy in a cat with an MTM1 missense mutation. Maine coon cat breeders may consider screening for this variant to prevent production of affected cats and to eradicate the variant from the breeding population.

Glossitis in an older non-corgi dog: Diagnosis and long-term follow-up.

A 9-year-old spayed female 18.8 kg mixed breed boxer dog was referred for evaluation of a 7-month history of difficulty swallowing and prehending food, regurgitation, hypersalivation, and an abnormal dorsiflexion of the tongue. Prior to referral, a barium study was performed, which revealed a mildly dilated esophagus. Treatment with sucralfate, cisapride, and prednisone was initiated. Physical examination revealed bilateral, symmetric atrophy of the temporalis muscles, dorsiflexion of the distal aspect of the tongue with concurrent muscle atrophy, and a reduced gag reflex. Electrodiagnostic examinations revealed spontaneous electrical activity in the muscles of mastication and tongue. Biopsies from the right temporalis, tongue, and biceps femoris muscles were collected. An immune-mediated myositis with fibrosis, scattered CD3, CD4, and CD8+ T-lymphocytes, and upregulation of markers for major histocompatibility antigens were observed in the tongue and temporalis muscles. The dog was treated with a tapering course of prednisone over 2 months and cyclosporine long-term. The dog was maintained on cyclosporine alone for > 2 years and clinical signs remained static, although multiple episodes of aspiration pneumonia occurred. Ultimately, euthanasia was performed due to chronic kidney disease with associated anemia, lethargy, and anorexia.

Glossite chez un chien âgé non-corgi : diagnostic et suivi à long terme. Une chienne boxer de race mixte de 18,8 kg stérilisée âgée de 9 ans a été référée pour l'évaluation d'une histoire de 7 mois de difficulté à avaler et de préhension des aliments, de régurgitation, d'hypersalivation et d'une dorsiflexion anormale de la langue. Avant la référence, un examen baryté a été réalisée et a révélé un oesophage légèrement dilaté. Un traitement par sucralfate, cisapride et prednisone a été initié. L'examen physique a révélé une atrophie bilatérale et symétrique des muscles temporaux, une flexion dorsale de la face distale de la langue avec atrophie musculaire concomitante et un réflexe nauséeux réduit. Les examens électrodiagnostiques ont révélé une activité électrique spontanée dans les muscles de la mastication et de la langue. Des biopsies des muscles temporaux droits, de la langue et du biceps fémoral ont été recueillies. Une myosite à médiation immunitaire avec fibrose, des lymphocytes T CD3, CD4 et CD8+ dispersés et une régulation positive des marqueurs des principaux antigènes d'histocompatibilité ont été observées dans la langue et les muscles temporaux. Le chien a été traité avec une posologie décroissante de prednisone sur 2 mois et de cyclosporine à long terme. Le chien a été maintenu sous cyclosporine seule pendant > 2 ans et les signes cliniques sont restés stables, bien que plusieurs épisodes de pneumonie par aspiration se soient produits. En fin de compte, l'euthanasie a été pratiquée en raison d'une maladie rénale chronique associée à une anémie, une léthargie et une anorexie.(Traduit par Dr Serge Messier).

Tandem duplication within the DMD gene in Labrador retrievers with a mild clinical phenotype.

A form of dystrophinopathy with mild or subclinical neuromuscular signs has been previously reported in a family of Labrador retrievers. Markedly and persistently elevated creatine kinase activity was first noted at 6 months of age. Skeletal muscle biopsies revealed a dystrophic phenotype, with dystrophin non-detectable on western blotting and immunohistochemical staining, and with increased utrophin expression. In this report we demonstrate with western blotting that α-dystroglycan is present at essentially normal levels. Whole genome sequencing has also now revealed an approximately 400kb tandem genomic DNA duplication including exons 2-7 of the DMD gene that was inserted into intron 7 of the wild type gene. Skeletal muscle cDNA from 2 cases contained DMD transcripts as expected from an in-frame properly-spliced exon 2-7 tandem insertion. A similar 5' duplication involving DMD exons 2-7 has been reported in a human family with dilated cardiomyopathy but without skeletal myopathy. This is the 3rd confirmed mutation in the DMD gene in Labrador retrievers.

An EHPB1L1 Nonsense Mutation Associated with Congenital Dyserythropoietic Anemia and Polymyopathy in Labrador Retriever Littermates.

In this report, we describe a novel genetic basis for congenital dyserythropoietic anemia and polymyopathy in Labrador Retriever littermates characterized by incidental detection of marked microcytosis, inappropriate metarubricytosis, pelvic limb weakness and muscle atrophy. A similar syndrome has been described in English Springer Spaniel littermates with an early onset of anemia, megaesophagus, generalized muscle atrophy and cardiomyopathy. Muscle histopathology in both breeds showed distinctive pathological changes consistent with congenital polymyopathy. Using whole genome sequencing and mapping to the CanFam4 (Canis lupus familiaris reference assembly 4), a nonsense variant in the EHBP1L1 gene was identified in a homozygous form in the Labrador Retriever littermates. The mutation produces a premature stop codon that deletes approximately 90% of the protein. This variant was not present in the English Springer Spaniels. Currently, EHPB1L1 is described as critical to actin cytoskeletal organization and apical-directed transport in polarized epithelial cells, and through connections with Rab8 and a BIN1-dynamin complex generates membrane vesicles in the endocytic recycling compartment. Furthermore, EHBP1L1 knockout mice die early and develop severe anemia. The connection of EHBP1L1 to BIN1 and DMN2 functions is particularly interesting due to BIN1 and DMN2 mutations being causative in forms of centronuclear myopathy. This report, along with an independent study conducted by another group, are the first reports of an association of EHBP1L1 mutations with congenital dyserythropoietic anemia and polymyopathy.

Congenital muscular dystrophy in a dog with a LAMA2 gene deletion.

A 2-year-old female spayed dog was presented with a chronic history of short-strided gait and inability to completely open the jaw. Clinical signs were present since the dog was adopted from a humane society at a few months of age. Serum creatine kinase activity was abnormally high. Neurological examination, electromyography, muscle biopsies with immunofluorescent staining, and whole genome sequencing (WGS) were performed. A dystrophic phenotype was identified histologically in muscle biopsies, deficiency of laminin α2 protein was confirmed by immunofluorescent staining, and a deletion in the LAMA2 gene was identified by analysis of the WGS data. Congenital muscular dystrophy associated with a disease variant in LAMA2 was identified.

LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy.

A 4-month-old, male Italian Greyhound with clinical signs of a neuromuscular disease was investigated. The affected dog presented with an abnormal short-strided gait, generalized muscle atrophy, and poor growth since 2-months of age. Serum biochemistry revealed a marked elevation in creatine kinase activity. Electrodiagnostic testing supported a myopathy. Histopathology of muscle biopsies confirmed a dystrophic phenotype with excessive variability in myofiber size, degenerating fibers, and endomysial fibrosis. A heritable form of congenital muscular dystrophy (CMD) was suspected, and a genetic analysis initiated. We sequenced the genome of the affected dog and compared the data to that of 795 control genomes. This search revealed a private homozygous nonsense variant in LAMA2, XM_022419950.1:c.3285G>A, predicted to truncate 65% of the open reading frame of the wild type laminin α2 protein, XP_022275658.1:p.(Trp1095*). Immunofluorescent staining performed on muscle cryosections from the affected dog confirmed the complete absence of laminin α2 in skeletal muscle. LAMA2 loss of function variants were shown to cause severe laminin α2-related CMD in humans, mouse models, and in one previously described dog. Our data together with current knowledge on other species suggest the LAMA2 nonsense variant as cause for the CMD phenotype in the investigated dog.

Muscular dystrophy-dystroglycanopathy in a family of Labrador retrievers with a LARGE1 mutation.

Alpha-dystroglycan (αDG) is a highly glycosylated cell surface protein with a significant role in cell-to-extracellular matrix interactions in muscle. αDG interaction with extracellular ligands relies on the activity of the LARGE1 glycosyltransferase that synthesizes and extends the heteropolysaccharide matriglycan. Abnormalities in αDG glycosylation and formation of matriglycan are the pathogenic mechanisms for the dystroglycanopathies, a group of congenital muscular dystrophies. Muscle biopsies were evaluated from related 6-week-old Labrador retriever puppies with poor suckling, small stature compared to normal litter mates, bow-legged stance and markedly elevated creatine kinase activities. A dystrophic phenotype with marked degeneration and regeneration, multifocal mononuclear cell infiltration and endomysial fibrosis was identified on muscle cryosections. Single nucleotide polymorphism (SNP) array genotyping data on the family members identified three regions of homozygosity in 4 cases relative to 8 controls. Analysis of whole genome sequence data from one of the cases identified a stop codon mutation in the LARGE1 gene that truncates 40% of the protein. Immunofluorescent staining and western blotting demonstrated the absence of matriglycan in skeletal muscle and heart from affected dogs. Compared to control, LARGE enzyme activity was not detected. This is the first report of a dystroglycanopathy in dogs.

Congenital dyserythropoiesis and polymyopathy without cardiac disease in male Labrador retriever littermates.

BACKGROUND: Two Labrador retriever littermates were identified based on incidentally noted marked microcytosis and inappropriate metarubricytosis. Muscle atrophy was noted and associated with distinctive pathological findings in biopsy samples from 1 dog studied. The disorder represents a rare clinical entity of suspected congenital dyserythropoiesis and polymyopathy. Clinicopathologic changes were similar to a previously reported syndrome of congenital dyserythropoiesis, congenital polymyopathy, and cardiac disease in 3 related English Springer Spaniel (ESS) dogs, but the dogs reported here did not have apparent cardiac disease. INTERVENTIONS: Bone marrow aspiration, electromyography, muscle biopsies, and an echocardiogram were performed on dog 1. Results supported dyserythropoiesis and congenital polymyopathy similar to reports in ESS dogs, but did not identify obvious cardiac disease. CONCLUSION: The clinicopathologic changes of dyserythropoiesis and polymyopathy provide an easily recognizable phenotype for what appears to be a low morbidity syndrome. Early recognition may decrease unnecessary testing or euthanasia.

Sarcoglycan A mutation in miniature dachshund dogs causes limb-girdle muscular dystrophy 2D.

BACKGROUND: A cohort of related miniature dachshund dogs with exercise intolerance, stiff gait, dysphagia, myoglobinuria, and markedly elevated serum creatine kinase activities were identified. METHODS: Muscle biopsy histopathology, immunofluorescence microscopy, and western blotting were combined to identify the specific pathologic phenotype of the myopathy, and whole genome SNP array genotype data and whole genome sequencing were combined to determine its genetic basis. RESULTS: Muscle biopsies were dystrophic. Sarcoglycanopathy, a form of limb-girdle muscular dystrophy, was suspected based on immunostaining and western blotting, where α, ß, and γ-sarcoglycan were all absent or reduced. Genetic mapping and whole genome sequencing identified a premature stop codon mutation in the sarcoglycan A subunit gene (SGCA). Affected dachshunds were confirmed on several continents. CONCLUSIONS: This first SGCA mutation found in dogs adds to the literature of genetic bases of canine muscular dystrophies and their usefulness as comparative models of human disease.

A mutation in MTM1 causes X-Linked myotubular myopathy in Boykin spaniels.

The purpose of this study was to report the findings of clinical and genetic evaluation of a 3-month old male Boykin spaniel (the proband) that presented with progressive weakness. The puppy underwent a physical and neurological examination, serum biochemistry and complete blood cell count, electrophysiological testing, muscle biopsy and whole genome sequencing. Clinical evaluation revealed generalized neuromuscular weakness with tetraparesis and difficulty holding the head up and a dropped jaw. There was diffuse spontaneous activity on electromyography, most severe in the cervical musculature. Nerve conduction studies were normal, the findings were interpreted as consistent with a myopathy. Skeletal muscle was grossly abnormal on biopsy and there were necklace fibers and abnormal triad structure localization on histopathology, consistent with myotubular myopathy. Whole genome sequencing revealed a premature stop codon in exon 13 of MTM1 (ChrX: 118,903,496 C > T, c.1467C>T, p.Arg512X). The puppy was humanely euthanized at 5 months of age. The puppy's dam was heterozygous for the variant, and 3 male puppies from a subsequent litter all of which died by 2 weeks of age were hemizygous for the variant. This naturally occurring mutation in Boykin spaniels causes a severe form of X-linked myotubular myopathy, comparable to the human counterpart.

Pathogenic variants in COL6A3 cause Ullrich-like congenital muscular dystrophy in young Labrador Retriever dogs.

The collagen VI-related muscular dystrophies in people include a broad spectrum of diseases ranging from the severe Ullrich congenital muscular dystrophy to the mild Bethlem myopathy. Clinical features are attributable to both muscle and connective tissue and include progressive muscle weakness and respiratory failure, hyperlaxity of distal joints, and progressive contracture of large joints. Here we describe two different COL6A3 pathogenic variants in Labrador Retriever dogs that result in autosomal recessive or autosomal dominant congenital myopathies with hyperlaxity of distal joints and joint contracture, similar to the condition in people.

Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BACKGROUND: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog. HYPOTHESIS/OBJECTIVE: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies. ANIMALS: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs. METHODS: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database. RESULTS: Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.

A Mutation in the Mitochondrial Aspartate/Glutamate Carrier Leads to a More Oxidizing Intramitochondrial Environment and an Inflammatory Myopathy in Dutch Shepherd Dogs.

BACKGROUND: Inflammatory myopathies are characterized by infiltration of inflammatory cells into muscle. Typically, immune-mediated disorders such as polymyositis, dermatomyositis and inclusion body myositis are diagnosed. OBJECTIVE: A small family of dogs with early onset muscle weakness and inflammatory muscle biopsies were investigated for an underlying genetic cause. METHODS: Following the histopathological diagnosis of inflammatory myopathy, mutational analysis including whole genome sequencing, functional transport studies of the mutated and wild-type proteins, and metabolomic analysis were performed. RESULTS: Whole genome resequencing identified a pathological variant in the SLC25A12 gene, resulting in a leucine to proline substitution at amino acid 349 in the mitochondrial aspartate-glutamate transporter known as the neuron and muscle specific aspartate glutamate carrier 1 (AGC1). Functionally reconstituting recombinant wild-type and mutant AGC1 into liposomes demonstrated a dramatic decrease in AGC1 transport activity and inability to transfer reducing equivalents from the cytosol into mitochondria. Targeted, broad-spectrum metabolomic analysis from affected and control muscles demonstrated a proinflammatory milieu and strong support for oxidative stress. CONCLUSIONS: This study provides the first description of a metabolic mechanism in which ablated mitochondrial glutamate transport markedly reduced the import of reducing equivalents into mitochondria and produced a highly oxidizing and proinflammatory muscle environment and an inflammatory myopathy.

Beta-sarcoglycan-deficient muscular dystrophy presenting as chronic bronchopneumonia in a young cat.

CASE SUMMARY: A 5-month-old cat was evaluated for a 3 week history of cough, nasal discharge, decreased appetite and weight loss. Musculoskeletal examination was normal and serum creatine kinase (CK) activity was within the reference interval. The cat was treated during the next 10 months for chronic, persistent pneumonia. Weakness then became apparent, the cat developed dysphagia and was euthanized. Post-mortem evaluation revealed chronic aspiration pneumonia and muscular dystrophy associated with beta (ß)-sarcoglycan deficiency. RELEVANCE AND NOVEL INFORMATION: This is the first report of a cat with muscular dystrophy presenting for chronic pneumonia without obvious megaesophagus, dysphagia or prominent neuromuscular signs until late in the course of the disease. The absence of gait abnormalities, marked muscle atrophy or hypertrophy and normal serum CK activity delayed the diagnosis in this cat with ß-sarcoglycan deficiency.