Sleepiness and Fatigue in the OPTIMISTIC Clinical Trial: Phenotypic and Transcriptomic Profiles in Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is a complex, multisystem form of muscular dystrophy caused by a CTG repeat expansion in the DMPK gene. There are a wide range of symptoms associated with DM1, including muscle weakness, myotonia, and early onset cataracts. One of the most prevalent and important symptoms for patients is excessive daytime sleepiness and chronic fatigue. The exact cause of this is not fully understood, and as of yet there are no effective treatments. Data in this study was obtained from a previously conducted clinical trial. The Observational Prolonged Trial in DM1 to Improve QoL-Standards (OPTIMISTIC) trial aimed to increase quality of life in those with DM1 through cognitive behavioral therapy (CBT). It took place from 2014 to 2016 in 4 European centres enrolling 255 participants. CBT was directed with the goal of increasing the activity and social participation, with additional optional graded exercise therapy (GET) offered in two of four clinical sites. The fatigue and sleepiness measures taken during this trial, the fatigue and daytime sleepiness scale (FDSS), and the checklist individual strength subscale fatigue (CIS Fatigue) were investigated. The combination of CBT and GET was found to produce a significant sustained improvement in these measures, much greater than that seen with CBT alone. This improvement was seen to be maintained in both genders and in younger and older participants. A casual mediation analysis using a range of other outcome measures from the trial did not yield any significant effects. Transcriptomic data from the cerebellum of the DMSXL mouse model of DM1 and blood samples from participants of the OPTIMISTIC trial were investigated for potential mechanisms underlying fatigue and daytime sleepiness in DM1. Ingenuity pathway analysis was used to identify significantly enriched pathways in differentially expressed genes. Multiple pathways related to the immune system and autoimmunity were uncovered, as well as mechanisms pertaining to central regulation of the circadian clock and sleep-wake cycle. In conclusion, there is a clear benefit to CBT in combination with GET for fatigue and daytime sleepiness symptoms in those with DM1. The reduction of inflammation by exercise may be underlying this, which warrants further investigation.