Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS

Abstract

Myotonic dystrophies are multisystemic diseases characterized not only by muscle and heart dysfunction but also by CNS alteration. They are now recognized as brain diseases affecting newborns and children for myotonic dystrophy type 1 and adults for both myotonic dystrophy type 1 and type 2. In the past two decades, much progress has been made in understanding the mechanisms underlying the DM symptoms allowing development of new molecular therapeutic tools with the ultimate aim of curing the disease. This review describes the state of the art for the characterization of CNS related symptoms, the development of molecular strategies to target the CNS as well as the available tools for screening and testing new possible treatments.

Keywords: DM CNS symptoms; animal models; myotonic dystrophy; therapeutic strategies; trinucleotide repeat diseases.

Figure 1

Complexity of myotonic dystrophies. The different cellular processes affected by the CTG and CCTG mutations and toxic RNAs are indicated in gray. The possible “mediator” proteins are written in the branches and some of downstream affected genes known so far are named red. The 4 possible entries for therapies are shown on the right side.

Figure 2

Local atrophy of gray matter (GM) and white matter (WM) in DM patients. (A) Local atrophy of GM (yellow) and WM (blue) in 12 DM1 patients compared to 28 healthy controls. (B) Local atrophy of GM (yellow) and WM (blue) in 15 DM2 patients compared to 28 healthy controls. Voxelwise multiple regression analysis with group and age as covariates. Age was used as a covariate of no interest. Areas with adjusted p at cluster level <0.05 after FWE correction are shown; X, Y, Z: MNI-coordinates: negative X-values reflect left side and positive X-values right sided location. Adapted from Schneider-Gold et al. (2015).