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

Abstract

A simple clinical neurological test was developed to evaluate response to gene therapy in a preclinical canine model of X-linked myotubular myopathy (XLMTM). This devastating congenital myopathy is caused by mutation in the myotubularin (MTM1) gene. Clinical signs include muscle weakness, early respiratory failure, and ventilator dependence. A spontaneously occurring canine model has a similar clinical picture and histological abnormalities on muscle biopsy compared with patients. We developed a neuromuscular assessment score, graded on a scale from 10 (normal) to 1 (unable to maintain sternal recumbency). We hypothesize that this neurological assessment score correlates with genotype and established measures of disease severity and is reliable when performed by an independent observer. At 17 weeks of age, there was strong correlation between neurological assessment scores and established methods of severity testing. The neurological severity score correctly differentiated between XLMTM and wild-type dogs with good interobserver reliability, on the basis of strong agreement between neurological scores assigned by independent observers. Together, these data indicate that the neurological scoring system developed for this canine congenital neuromuscular disorder is reliable and valid. This scoring system may be helpful in evaluating response to therapy in preclinical testing in this disease model, such as response to gene therapy.

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.…”

“…32 These assessments included muscle strength, neurological function, respiratory effort, and histological and molecular examination of muscle biopsies. 19,20 MATERIALS AND METHODS Dogs. Care and use of all laboratory animals was in keeping with the National Research Council guidelines and as approved by the Institutional Animal Care and Use Committee.…”

“…as described. 39 Parameters assessed included: cranial nerve function, postural reactions, segmental spinal reflexes, gait stride length, ability to run and jump, and muscle atrophy. Dogs were observed for exercise intolerance or increased respiratory rate and effort following activity.…”

“…Results of neurological scoring for normal controls and for some untreated XLMTM dogs have been reported. 39 Histology. Muscle samples were collected and processed as described previously.…”

“…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 .…”