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

Abstract

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.

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

“…This study reports two castrated male Maine coon littermates that were presented at a young age (5–9 months) with clinical signs of an early-onset inherited myopathy and markedly elevated sCK activities. Only a small number of congenital and dystrophic myopathies have been reported in cats including nemaline rod myopathy [ 31 ], X-linked myotubular myopathy in a Maine coon cat [ 32 ], laminin α2 deficient muscular dystrophy [ 33 ], muscular dystrophy associated with β-sarcoglycan deficiency [ 34 ], and X-linked ddMD [ 13 , 14 ]. Usually, sCK activities are normal or slightly elevated in congenital myopathies, making these disorders unlikely in the cats in this report.…”

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

“…31 Specific tools from GATK 4.2 for genotyping, variant database construction, and hard‐filtering were completed as previously described. 32 The produced 22 cat dataset was combined with the previously produced 340 cat variant call file 24 , 32 , 33 and the 61 cat WES dataset for the 99 Lives Cat Genome Sequencing Initiative. 34 , 35 , 36 The National Center for Biotechnology Information (NCBI) RefSeq Felis catus annotation 104 and Ensembl Variant Effect Predictor 37 were used to characterize the variants.…”

“…Clinical examination cannot distinguish among various myopathies including the MDs, and further diagnostic testing is necessary including evaluation of muscle biopsy samples by histopathology, histochemistry, immunohistochemistry, and measurement of serum creatine kinase (CK) activity. With the improvement of molecular techniques, such as short-read whole genome sequencing (WGS) and, to some extent, whole exome sequencing (WES), distinguishing among various myopathies is now possible by rapid identification of the underlying variant responsible for causing disease, 23,24 including MD in both dogs and cats. 17,25 Increased availability of next-generation sequencing allows identification of new pathogenic genes and the wide spectrum of clinical phenotypes associated with known defective proteins.…”

Feline precision medicine using whole-exome sequencing identifies a novel frameshift mutation for vitamin D-dependent rickets type 2

“…This variant was not identified in the 99 Lives WGS dataset that included 340 cats, none of which had clinical signs of rickets (see Supplementary File 1 ). 22 …”