Associations Between Variant Repeat Interruptions and Clinical Outcomes in Myotonic Dystrophy Type 1

Stephan Wenninger; Sarah A Cumming; Kristina Gutschmidt; Kees Okkersen; Aura Cecilia Jimenez-Moreno; Ferroudja Daidj; Hanns Lochmüller; Fiona Hogarth; Hans Knoop; Guillaume Bassez; Darren G Monckton; Baziel G M van Engelen; Benedikt Schoser

doi:10.1212/NXG.0000000000000572

Associations Between Variant Repeat Interruptions and Clinical Outcomes in Myotonic Dystrophy Type 1

Neurol Genet. 2021 Mar 9;7(2):e572. doi: 10.1212/NXG.0000000000000572. eCollection 2021 Apr.

Affiliation

¹ Department of Neurology (S.W., K.G., B.S.), Friedrich-Baur-Institute, Ludwig-Maximilians-Universität München, Germany; Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow, United Kingdom; Department of Neurology (K.O., B.G.M.v.E.), Radboud University, Nijmegen, The Netherlands; Institute of Genetic Medicine (A.C.J.-M.), Institute for Ageing and Health, Newcastle University, United Kingdom; Neuromuscular Reference Centre (F.D., G.B.), Assistance Publique-Hôpitaux de Paris, France; Department of Neuropediatrics and Muscle Disorders (H.L.), University of Freiburg, Breisgau, Germany; Center for Genomic Regulation (H.L.), Barcelona Institute of Science and Technology, Spain; Tayside Clinical Trials Unit (F.H.), The University of Dundee, United Kingdom; and Department of Medical Psychology (H.K.), Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.

Abstract

Objective: To assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention.

Methods: Adult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory-fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions.

Results: VR interruptions were detectable in 21/250 patients (8.4%)-12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions.

Conclusions: The presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention.

Trial registration information: ClinicalTrials.gov NCT02118779.

Associated data

ClinicalTrials.gov/NCT02118779