Myopathy due to a creatine deficiency disorder in a family of mixed breed dogs with a glycine amidinotransferase gene mutation

Abstract

BACKGROUND: Myopathies caused by genetic abnormalities are increasingly recognized in veterinary medicine. HYPOTHESIS/OBJECTIVES: Clinically and genetically characterize a novel creatine deficiency disorder (CDD) myopathy in a family of mixed breed dogs. ANIMALS: Three siblings from the same litter were evaluated and genetically tested, including 2 dogs that were clinically affected and one dog clinically normal. All dogs were client owned. METHODS: Case series describing clinical, imaging, electrodiagnostic, histopathologic investigations, and response to treatment. Whole genome sequencing and bioinformatics were performed to identify a causative variant followed by Sanger sequencing to confirm the suspected variant in related dogs. RESULTS: Clinical signs included megaesophagus with generalized muscle atrophy in both affected dogs. One dog showed exercise intolerance. Computed tomography (CT) scan revealed bilateral and symmetrical diffuse hypoattenuating muscle lesions. Electromyography was characterized by nonspecific abnormal spontaneous activity in electrodiagnostically affected muscles. Type 2 fiber atrophy and excessive intramyofiber lipid droplets in type 1 muscle fibers were the predominant findings in histopathology. Both affected dogs were homozygous for a unique GATM p.R414C (NP_001274013.1) missense variant, while the unaffected sibling did not have this variant. All clinical signs improved after 3 days of creatine (800-1500 mg/kg/day) and L-carnitine (80-150 mg/kg) supplementation and remained stable at the time of writing 4 months after diagnosis. CONCLUSIONS AND CLINICAL IMPORTANCE: This is a report of CDD in dogs characterized by a glycine amidinotransferase (GATM) variant, which showed a good short-term outcome with supplementation with creatine and L-carnitine.