Centronuclear myopathies under attack: A plethora of therapeutic targets

Abstract

Centronuclear myopathies are a group of congenital myopathies characterized by severe muscle weakness, genetic heterogeneity, and defects in the structural organization of muscle fibers. Their names are derived from the central position of nuclei on biopsies, while they are at the fiber periphery under normal conditions. No specific therapy exists yet for these debilitating diseases. Mutations in the myotubularin phosphoinositides phosphatase, the GTPase dynamin 2, or amphiphysin 2 have been identified to cause respectively X-linked centronuclear myopathies (also called myotubular myopathy) or autosomal dominant and recessive forms. Mutations in additional genes, as RYR1, TTN, SPEG or CACNA1S, were linked to phenotypes that can overlap with centronuclear myopathies. Numerous animal models of centronuclear myopathies have been studied over the last 15 years, ranging from invertebrate to large mammalian models. Their characterization led to a partial understanding of the pathomechanisms of these diseases and allowed the recent validation of therapeutic proof-of-concepts. Here, we review the different therapeutic strategies that have been tested so far for centronuclear myopathies, some of which may be translated to patients.

Keywords: Centronuclear myopathy; amphiphysin; autophagy; dynamin; gene therapy; myotubular myopathy; myotubularin; neuropathy; oligonucleotide; phosphoinositides.

Fig.1

Conceptual figure depicting the different cellular defects reported in X-linked and/or autosomal CNM (in red) and indicating the various therapeutic strategies tested (in green). CNM fibers can be rounder and smaller, especially for the X-linked form. NMJ: neuromuscular junction.