Brain Structural Features of Myotonic Dystrophy Type 1 and their Relationship with CTG Repeats

Abstract

Background: Few adequately-powered studies have systematically evaluated brain morphology in adult-onset myotonic dystrophy type 1 (DM1). Objective: The goal of the present study was to determine structural brain differences between individuals with and without adult-onset DM1 in a multi-site, case-controlled cohort. We also explored correlations between brain structure and CTG repeat length. Methods: Neuroimaging data was acquired in 58 unaffected individuals (29 women) and 79 individuals with DM1 (50 women). CTG repeat length, expressed as estimated progenitor allele length (ePAL), was determined by small pool PCR. Statistical models were adjusted for age, sex, site, and intracranial volume (ICV). Results: ICV was reduced in DM1 subjects compared with controls. Accounting for the difference in ICV, the DM1 group exhibited smaller volume in frontal grey and white matter, parietal grey matter as well as smaller volume of the corpus callosum, thalamus, putamen, and accumbens. In contrast, volumes of the hippocampus and amygdala were significantly larger in DM1. Greater ePAL was associated with lower volumes of the putamen, occipital grey matter, and thalamus. A positive ePAL association was observed for amygdala volume and cerebellar white matter. Conclusions: Smaller ICV may be a marker of aberrant neurodevelopment in adult-onset DM1. Volumetric analysis revealed morphological differences, some associated with CTG repeat length, in structures with plausible links to key DM1 symptoms including cognitive deficits and excessive daytime somnolence. These data offer further insights into the basis of CNS disease in DM1, and highlight avenues for further work to identify therapeutic targets and imaging biomarkers.

Variant repeats within the DMPK CTG expansion protect function in myotonic dystrophy type 1

“…Participants with adult-onset DM1 were recruited to the University of Iowa "DM1 Brain Study" from across the United States by advertisements through the Myotonic Dystrophy Foundation or word of mouth, as described previously. 22 Recruitment was targeted to adult-onset DM1 only, with symptom onset at age 18 years or older. Unaffected participants were primarily recruited from the local community through advertisements.…”

“…For genotyping of CTG repeats in participants with DM1, we used the same methodology as the one used in previous studies. 22,23 For variant repeat identification, small-pool PCR products underwent AciI enzyme digestion (New England Biolabs UK Ltd.; restriction site 59CCGC-39) and Southern blotting to indicate the presence of CCG interruptions within the CTG repeat array in the expanded allele as previously described. 13 Motor testing Motor, neurocognitive, and behavioral outcome measures of interest were selected a priori to reduce the number of comparisons.…”

Abnormal Cortical Thickness Is Associated With Deficits in Social Cognition in Patients With Myotonic Dystrophy Type 1

“…Consistent evidence has been produced proving that structural and functional changes in DM1 brains account for some specific higher-level dysfunctions. So far, structural magnetic resonance imaging (MRI) studies have mainly focused on the assessment of regional gray matter volumetric and microstructural changes of the white matter tissue (4)(5)(6)(7)(8)(9)(10)(11)(12). Importantly, a strict relationship has been reported not only between structural brain abnormalities and DM1 patients' cognitive profile (e.g., executive functions, reasoning and visuospatial abilities) (7,9) but also with patients' CTG triplet expansion (6,8,13).…”

Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex

“…Future studies should similarly examine transcriptome changes and repeat length distributions in those regions so that molecular features can be better linked to particular symptoms. Of particular interest may be the hippocampus and amygdala, because these regions show anatomical differences in DM1 and are known to play roles in memory processing and emotional experiences 56 . Surprisingly few transcripts showed mis-splicing across DM1 TA, heart, and FC.…”