DM2 vs DM1 Disease Progression

Overview

This lecture reviewed current research on disease severity and progression in myotonic dystrophy type 2 (DM2), comparing it to DM1, and discussed clinical milestones, functional assessments, biomarkers, and open research questions.

DM2 vs DM1: Disease Progression and Milestones

• DM2 has slower progression than DM1, but still causes significant disability, particularly with aging.
• Registry data from 222 DM2 participants showed longitudinal milestones up to 17 years.
• At age 50, about 10% of DM2 patients use a walker; at age 60, it's about 28%.
• Wheelchair use in DM2 at age 60 is approximately 13%.
• Disability due to DM2 forces 10% of patients to stop working by age 40.
• Non-invasive ventilation use (for sleep apnea or respiratory weakness) is higher in DM1, but 12% of DM2 patients use it by age 50.
• Pacemaker placement risk is 8–10% by age 60 in DM2.
• Cancer risk by age 60 is similar in DM1 and DM2 (24%).
• Diabetes risk is higher in DM2 (24% by age 60) than DM1.

Natural History and Functional Assessments in DM2

• STAB-DM2 natural history study follows DM2 patients over three years.
• Manual muscle testing (MMT) shows most DM2 weakness in neck flexion, hip flexion, hip abduction, and shoulder abduction.
• Significant progression in MMT scores occurs over 3 years, not 1 year.
• Proximal composite muscle scores strongly correlate with lower extremity function index (self-reported, 0–80 scale).
• Functional declines over three years are best detected in proximal muscles.
• Quantitative muscle testing (QMT) is less sensitive in DM2 because it does not focus on the most affected muscles.

Biomarkers and Transcriptomic Analysis

• Muscle biopsy splicing analyses show ~96% concordance between DM1 and DM2, with both differing from controls.
• Splicing changes are similar in different muscles, but biopsies often miss DM2's preferentially affected muscles.
• Current DM1 biomarker tools are likely applicable to DM2, but further muscle-specific studies are needed.

Research Questions and Limitations

• Age of onset and disease duration did not significantly affect DM2 progression data.
• No correlation found between repeat length and disease milestones in DM2.
• No current data on the correlation between mis-splicing and muscle function in DM2, likely due to choice of biopsy site.
• BMI and metabolic factors should be analyzed further regarding DM2 and diabetes risk.

Key Terms & Definitions

• DM1 / DM2 — Myotonic dystrophy types 1 and 2, genetic muscle disorders.
• Milestone — A significant disease event (e.g., need for walker, wheelchair, pacemaker).
• MMT (Manual Muscle Testing) — Clinical strength assessment of various muscle groups.
• QMT (Quantitative Muscle Testing) — Instrument-based muscle strength measurement.
• Proximal composite score — Combined measure of strength in key affected proximal muscles.
• Lower extremity function index — Patient-reported outcome measuring ability in daily activities involving the legs.
• Splicing biomarker — Molecular indicator of RNA splicing changes typical of these disorders.

Action Items / Next Steps

• Analyze DM2 biopsies from preferentially affected muscles for better biomarker correlation.
• Further investigate metabolic factors (e.g., BMI) related to diabetes risk in DM2.
• Continue longitudinal follow-up to gather more robust progression data for DM2.