Natural History of Adult-Onset Myotonic Dystrophy Type 1: Longitudinal Changes in Radiologic, Clinical, and...

Adult-onset myotonic dystrophy type 1 (DM1) is a progressive, multisystemic disorder, characterized by distal muscle weakness and myotonia. As disease-modifying therapies emerge, robust and sensitive outcome measures are urgently needed. This study characterized the natural history of adult-onset DM1 over 2 years and evaluated quantitative MRI (qMRI) and clinical outcome measures for clinical trials.

This prospective, monocentric study assessed patients with genetically confirmed adult-onset DM1 and age-matched and sex-matched healthy controls at baseline and 12, 18, and 24 months. qMRI measured proton density fat fraction (PDFF, %) and T2_H2O (ms) of 18 proximal and 10 distal leg muscles using 3D segmentation. Clinical outcomes included 32-item motor function measure (MFM32), 6-minute walk distance (6MWD), 10-meter walk test, 30-second sit-to-stand, 9-hole peg test, hand opening time, MRC sum score, hand grip and pinch dynamometry, and peak cough flow. Patient-reported outcome measures included DM1-ActivC, Individualized Neuromuscular Quality of Life (INQoL), Brief Pain Inventory, and Fatigue and Daytime Sleepiness Scale.

Thirty patients (median 38 years, 60% female, Muscular Impairment Rating Scale 3-4) and 30 matched controls were included. Baseline PDFF (%) was significantly higher in patients with distal (31.8% vs 5.9%, p < 0.001) and proximal (13.0% vs 7.6%, p < 0.001) leg muscles. T2_H2O was significantly elevated in the distal leg muscles (+3.3, p < 0.001). Over 24 months, PDFF (%) increased significantly in 9 of 10 distal and 15 of 18 proximal muscles. Distal leg PDFF (%) showed the largest progression (+3.5%, 95% CI 2.9-4.1, standardized response mean [SRM] = 1.6), with significant changes detectable within 6-month intervals (+1.0%, 95% CI 0.4-1.6, SRM = 1.1). T2_H2O remained stable. MFM32 (-3.2, -6.7, -7.3; SRM = 0.8, 1.9, 1.8) and MRC sum score (-5.0, -7.6, -9.6; SRM = 1.1, 1.4, 1.6) declined at 12, 18, and 24 months (p < 0.001). DM1-ActivC declined significantly at 12, 18, and 24 months (24 months: -10.3, 95% CI -14.0 to -6.7; SRM = 0.8). INQoL overall quality of life deteriorated significantly at 12 months (+5.4, 95% CI 0.8-10.0) and 18 months (+6.9, 95% CI 2.0-11.8), but not at 24 months. Distal leg PDFF (%) correlated strongly with 6MWD (ρ = -0.81) and MFM32 D1 (ρ = -0.75).

PDFF (%) is a sensitive, objective outcome measure for adult-onset DM1, detecting change within 6-month intervals. MFM32, MRC sum score, DM1-ActivC, and INQoL demonstrate meaningful deterioration over 12-24 months, supporting their combined use with qMRI as outcomes in future trials for adult-onset DM1.