Clinical Phenotype of X‐Linked Myotubular Myopathy in Labrador Retriever Puppies

Abstract

BackgroundSeven male Labrador Retriever puppies from 3 different litters, born to clinically normal dams and sires, were evaluated for progressive weakness and muscle atrophy. Muscle biopsies identified a congenital myopathy with pathologic features consistent with myotubular myopathy. Further investigations identified a pathogenic mutation in the myotubularin gene, confirming that these puppies had X‐linked myotubular myopathy (XLMTM).ObjectiveTo review the clinical phenotype, electrodiagnostic and laboratory features of XLMTM in this cohort of Labrador Retrievers.ResultsMale puppies with XLMTM were small and thin compared with their normal littermates. Generalized weakness and muscle atrophy were present by 7 weeks of age in some puppies and evident to most owners by 14 weeks of age. Affected puppies stood with an arched spine and low head carriage, and walked with a short, choppy stride. Muscle atrophy was severe and progressive. Patellar reflexes were absent. Laryngeal and esophageal dysfunction, and weakness of the masticatory muscles occurred in puppies surviving beyond 4 months of age. Serum creatine kinase activity was normal or only mildly increased. EMG findings were nonspecific and included positive sharp waves and fibrillation potentials. Clinical signs progressed rapidly, with most affected puppies unable to walk within 3–4 weeks after clinical signs were first noticed.Conclusions and Clinical ImportanceAlthough initial clinical signs of XLMTM are similar to the phenotypically milder centronuclear myopathy in Labrador Retrievers, XLMTM is a rapidly progressive and fatal myopathy. Clinicians should be aware of these 2 distinct myopathies with similar clinical presentations in the Labrador retriever breed.

Long‐term effects of systemic gene therapy in a canine model of myotubular myopathy

“…15,16 XLMTM dogs experience weakness and atrophy of skeletal muscles, causing difficulty with standing, eating, and respiratory function. [17][18][19][20] The average lifespan of affected animals is 18-20 weeks of age. 15,18,21 Additional supporting information may be found in the online version of this article.…”

“…In Labrador retriever and mixed breed dogs, a p.N155K missense mutation in canine MTM1 results in profound skeletal muscle weakness in affected puppies analogous to the phenotype seen in boys with XLMTM . XLMTM dogs experience weakness and atrophy of skeletal muscles, causing difficulty with standing, eating, and respiratory function . The average lifespan of affected animals is 18–20 weeks of age .…”

Validity of a neurological scoring system for canine X-linked myotubular myopathy

“…2,[5][6][7] Analogous to patients with myotubular myopathy, a series of related male Labrador retriever dogs with an early onset of weakness progressing to death by 3-6 months of age was described in Western Canada. [8][9][10] Muscle biopsy in these dogs showed changes on histology and electron microscopy consistent with human cases of X-linked myotubular myopathy (XLMTM). Western immunoblots failed to detect myotubularin.…”

“…[8][9][10] Severely affected dogs also have dysphagia, a dropped jaw, and a hoarse bark. 8,9 Affected dogs typically require humane euthanasia between 15 and 26 weeks of age because of progressive tetraparesis and laryngeal, pharyngeal, and esophageal dysfunction.…”

Noninvasive Assessment of Neuromuscular Disease in Dogs: Use of the 6‐minute Walk Test to Assess Submaximal Exercise Tolerance in Dogs with Centronuclear Myopathy

“…Clinical signs develop within the first 1-7 months of life, and are characterized by generalized weakness and exercise intolerance, generalized muscle atrophy, and abnormal spinal reflexes. 2,[7][8][9][10][11][12] The severity of signs and the rapidity of progression differs between the autosomal recessive and X-linked conditions; dogs affected with the latter typically develop signs earlier in life, progress more rapidly and develop more severe signs than those with the autosomal recessive form of the disease. 1,4,[7][8][9]11,12 Both groups develop characteristic muscle pathology, including an increased number of centralized nuclei within myofibers, atrophy of type II myofibers, and mitochondrial aggregates.…”