Study Tracks Myotonic Dystrophy Progression in 5-Year Follow-up

A longitudinal 5-year observational study to examine functional and structural cerebral changes in adult-onset myotonic dystrophies found some differences between the 2 types of this incurable genetic disorder and said that additional brain studies are needed in light of upcoming treatment trials for this rare disease.

Adult-onset myotonic dystrophies type 1 and 2 (DM1 and DM2) are a genetic muscle disorder, but they affect the brain as well as other systems of the body.

According to the National Organization for Rare Disease (NORD), the mild form of DM1 is characterized by cataracts and sustained muscle contractions (myotonia), in which the muscles do not relax. “Classic” DM1 is characterized by muscle weakness and atrophy, myotonia, early-onset cataracts (ie, before the age of 50), and cardiac abnormalities. Congenital DM1 is characterized by hypotonia, difficulty breathing, intellectual disability, and early death. DM1 is caused by an alteration in the DMPK gene.

DM2 is similar to DM1 but is generally a less severe disorder and does not cause congenital disease. DM2 is caused by an alteration in the CNBP gene.

According to NORD, the prevalence of DM1 in the general population is about 1 in 8000 to 20,000 individuals, but the true prevalence may not be known because some people may go undiagnosed.

This study enrolled 16 patients with adult-onset DM1, 16 patients with DM2, and 17 controls. At baseline and after a mean (SD) of 5.5 (0.4) years, participants underwent neurological, neuropsychological, and brain magnetic resonance imaging examinations using identical study protocols that included voxel-based morphometry and diffusion tensor imaging. Data were analyzed by group comparisons between patients and controls at baseline and follow-up, and group comparisons using difference maps (baseline—follow-up in each participant) were used to focus on disease-related effects over time.

Researchers found minor neuropsychological deficits, with mild progression seen more in DM1 than DM2. Daytime sleepiness was restricted to DM1. Fatigue was seen in both types and was stable over time.

White matter changes were more pronounced in DM1 than DM2 and exceeded gray matter involvement. Comparing results of cross-sectional neuroimaging analyses at baseline and follow-up revealed an unchanged pattern of pronounced white matter alterations in DM1. There was mild additional gray matter reduction in DM1 at follow-up.

In DM2, white matter reduction was somewhat less, but there were some additional alterations at follow-up. Gray matter seemed unaffected in DM2. Longitudinal analyses using difference maps and comparing them between patients and controls did not reveal any significant differences of cerebral changes over time between patients and controls.

The lack of significant disease-related progression of gray and white matter involvement over 5 years in both groups suggests either a slow, progressive process or even a stable course of cerebral changes in middle-aged, adult-onset patients.

The cause of white matter alterations in myotonic dystrophies is not yet fully understood, the researchers said. The fact that vascular risk factors were not more frequent than in the controls hints that white matter abnormalities might stem from multiple factors, but they said that microvascular changes cannot be ruled out completely.

As with other studies of rare diseases, larger patient groups and longer observation periods are difficult to achieve. The researchers said they addressed age differences between groups by including age as a covariate in the statistical design. A more refined definition of cerebral changes and its surrogate markers is needed for the development of therapy compounds in addition to uniform study protocols, biomarkers, and appropriate clinical trial outcome parameters.

Reference

Gliem C, Minnerop M, Roeske S, et al. Tracking the brain in myotonic dystrophies: A 5-year longitudinal follow-up study. PloS ONE [published online March 7, 2019]. doi: 10.1371/journal.pone.0213381.