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

Abstract

ObjectiveTo 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.MethodsAdult 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.ResultsVR 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.ConclusionsThe 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 InformationClinicalTrials.govNCT02118779.

FAN1 exo- not endo-nuclease pausing on disease-associated slipped-DNA repeats: A mechanism of repeat instability

“…The disease-hastening modifier FAN1 p.R507H differentially processed the genetically stabilizing disease-delaying CAA interrupted CAG repeats-yielding a qualitatively distinct exo-nucleolytic pause (Figure S11), which we speculate may render the repeat expansion prone. FAN1 may have similar effect on the interruptions in the expanded CTG tract of DM1, known to affect instability and clinical presentation (Braida et al, 2010;Musova et al, 2009;Tome ´et al, 2018;Wenninger et al, 2021).…”

Identification of a CCG-enriched expanded allele in DM1 patients using Amplification-free long-read sequencing

“…In the literature, the interrupted expanded allele has recently been shown to be a key factor in the severity of DM1 symptoms and the age of onset of these symptoms 1,[13][14][15][16][17][18][19][20][21][22] . The identification of interruptions in DM1 patients at diagnosis is therefore important to improve genetic counseling in DM1.…”

Molecular and Clinical Implications of Variant Repeats in Myotonic Dystrophy Type 1

“…The majority of previous manuscripts reported that the phenotype of DM1 patients with variant repeats was milder, at least in some aspects of the disease, including less pronounced muscle weakness, less pronounced myotonia, and less pulmonary dysfunction ( Table 1 ) [ 37 , 39 , 40 , 43 ]. Accordingly, in the OPTIMISTIC trial, DM1 patients with variant repeats had better mobility, ventilation, and cardiac status [ 52 ]. Additionally, the presence of repeat interruptions, together with DMPK expansion size, was a significant contributor to muscle strength in DM1 patients [ 46 ].…”

“…Additional limitation is that comparison between patients with vs. without variant repeats should be controlled, at least, for the age at sampling and the expansion size. In two studies, this problem was partially resolved [ 48 , 52 ]. However, the problem of a small number of patients included in the studies and a low statistical power persists.…”