Respiratory assessment in centronuclear myopathies

Abstract

The centronuclear myopathies (CNMs) are a group of inherited neuromuscular disorders classified as congenital myopathies. While several causative genes have been identified, some patients do not harbor any of the currently known mutations. These diverse disorders have common histological features, which include a high proportion of centrally-nucleated muscle fibers, and clinical attributes of muscle weakness and respiratory insufficiency. Respiratory problems in CNMs may manifest initially during sleep, but daytime symptoms, ineffective airway clearance, and hypoventilation predominate as more severe respiratory muscle dysfunction evolves. Respiratory muscle capacity can be evaluated using a variety of clinical tests selected with consideration for the age and baseline motor function of the patient. Similar clinical tests of respiratory function can also be incorporated into preclinical CNM canine models to offer insight for clinical trials. Since respiratory problems account for significant morbidity in patients, routine assessments of respiratory muscle function are discussed.

Diaphragm assessment in mice overexpressing phospholamban in slow‐twitch type I muscle fibers

“…Studies examining diaphragm function in animal models of CNM are limited as recently highlighted in a review by Smith Goddard, and Childers (Smith et al. ). However, in a study published in the same year, Cowling et al.…”

“…A recently published review highlighted that although diaphragm and ventilatory function have been examined in several murine models of myopathy including Pompe disease and Duchenne muscular dystrophy, among other neuromuscular diseases, similar reports are not available for animal models of CNM (Smith et al. ). Compared with the other two major CNM variants, X‐linked myotubular myopathy and autosomal‐recessive CNM, respiratory function in patients with autosomal dominant CNM, for the most part, is intact and patients live a normal lifespan (Bitoun et al.…”

“…; Romero ; Smith et al. ). Thus, it was of interest to determine whether or not the diaphragm muscles of the Pln OE mouse, which more closely resembles autosomal dominant CNM, would exhibit CNM pathology and muscle weakness.…”

Gene therapy in monogenic congenital myopathies

“…Methods of functional assessment developed for use in the clinic have also been successfully adapted for use in dogs. 22 Many naturally-occurring musculoskeletal diseases, similar to those seen in human patients, have been identified and characterised 92 (Table 5) facilitating the use of that dog model for the pre-clinical assessment of potential treatments. 2,93,94 …”

Gene Therapy in Monogenic Congenital Myopathies

“…Methods of functional assessment developed for use in the clinic have also been successfully adapted for use in dogs. 22 Many naturally-occurring musculoskeletal diseases, similar to those seen in human patients, have been identified and characterised 92 (Table 5) facilitating the use of that dog model for the pre-clinical assessment of potential treatments. 2,93,94 AAV8-mediated delivery of myotubularin in the XLMTM dog provides a successful example of gene therapy in preclinical practice.…”