X-linked myotubular myopathy

Carina Wallgren-Pettersson MD (Dr. Wallgren-Pettersson of the University of Helsinki and Folkhalsan has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released April 26, 1994; last updated June 21, 2016; expires June 21, 2019

This article includes discussion of X-linked myotubular myopathy, centronuclear myopathy, MTMX, X-linked centronuclear myopathy, XLMTM, XMTM, autosomal-dominant myotubular (centronuclear) myopathy, and autosomal-recessive myotubular (centronuclear) myopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

X-linked myotubular (centronuclear) myopathy is a severe muscle disorder mainly affecting newborn boys. Diagnostic methods have improved so that the majority of patients may now have their diagnosis verified by molecular methods. Currently, the complex pathogenetic mechanisms are better understood and include defects in membrane tubulation and excitation-contraction coupling, providing evidence towards a common basis for the X-linked and autosomal forms of centronuclear myopathy. Several studies of potential therapeutic modalities aimed at ameliorating disease severity have reached proof of concept, natural history studies are underway, canine and other animal models have been established, and therapeutic trials are being planned in terms of a variety of potentially disease-modifying interventions.

Key points

 

• X-linked myotubular (centronuclear) myopathy is caused by mutations in the myotubularin gene MTM1.

 

• Molecular genetic verification is often possible through sequencing, but it should be noted that copy number variations may also be causative, and this may require other analytic methods.

 

• Although no curative treatment exists to date for this usually very severe disorder, active treatment is indicated, at least initially, because of the favorable course in some neonatally severe cases.

 

• Prognosis cannot be based solely on the nature of the mutation, and decisions about treatment have to be taken on an individual basis.

 

• Differential diagnoses include the autosomal forms of centronuclear myopathy and myotonic dystrophy.

 

• Most, but not all, mothers of affected boys are mutation carriers; mosaicism has been reported.

Historical note and terminology

X-linked myotubular or centronuclear myopathy is assigned to the group of congenital myopathies (OMIM #310400) (Dubowitz 1985). These myopathies were defined after the advent of histochemical staining methods of muscle biopsy sections on the basis of structural abnormalities in the muscle fibers. The X-linked form of myotubular myopathy was first described in a large Dutch pedigree in which the affected males showed muscle fibers resembling fetal myotubes (Van Wijngaarden et al 1969). A long-term follow-up study of this and another Dutch family shows wide variability in the clinical picture (Barth and Dubowitz 1998), confirmed by 2 reports of patients diagnosed as adults (Hoffjan et al 2006; Penisson-Besnier 2007).

Image: Myotubes in fetal muscle (photomicrographs)
The coining of the alternative name "centronuclear" myopathy reflects the argument about whether the basic defect in this disorder is an arrest of maturation of the fetal muscle fibers or whether the central nuclei constitute the main histologic feature.
Image: Central nuclei in muscle fiber (photomicrographs)

Autosomal forms with similar histology have been described (OMIM #60150, #255200). They usually present later and follow a milder course than the X-linked form (Wallgren-Pettersson et al 1995; Jeannet et al 2004), but exceptionally severe cases have also been reported (Jungbluth et al 2013). Mutations in the dynamin 2 gene (Bitoun et al 2005) are a common cause of the dominantly inherited form (Fischer et al 2006; Bitoun et al 2007; Echaniz-Laguna et al 2007; Schessl et al 2007), whereas mutations in the ryanodine receptor gene RYR1 are increasingly being identified, including recessively inherited mutations (Jungbluth et al 2007; Wilmshurst et al 2010; Bevilacqua et al 2011; Jungbluth et al 2013). The first causative gene for autosomal recessive myotubular/centronuclear myopathy was identified as amphiphysin 2 (BIN1) (Nicot et al 2007). Subsequently, a patient with internalized nuclei, the histopathology resembling centronuclear myopathy, was found to have compound heterozygous mutations in the titin gene TTN (Ceyhan-Birsoy et al 2013; Dowling 2013).

It is to be noted that female carriers of the X-linked form can manifest muscle disease (Hammans et al 2000; Wallgren-Pettersson 2000; Sutton et al 2001; Jungbluth et al 2003; Kristiansen et al 2003; Schara et al 2003; Grogan et al 2005; Penisson-Besnier et al 2007; Biancalana et al 2012; Jungbluth et al 2013; Savarese et al 2016). A female patient described with cardiomyopathy requiring heart transplantation had not undergone analysis of the myotubularin gene.

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