Clinical Heterogeneity in Myotonic Dystrophy Type 1: Identifying Phenotype Categories Using Unsupervised Clustering

Myotonic dystrophy type 1 (DM1) is a genetic multisystem disorder with a wide variability in symptom severity and symptom co-occurrence. This study aimed to identify homogeneous patient subgroups in DM1 with distinct disease characteristics, determine key features underlying these subgroups, and evaluate their potential to inform clinical care and individualized therapy.

Adult patients with genetically confirmed DM1 were assessed during annual visits to the Dutch DM1 expert center using standardized examinations and questionnaires to characterize disease burden. K-means cluster analysis was conducted on 10 baseline parameters that reflect the multisystemic disease impact of DM1. External validation was conducted using baseline data from the END-DM1 natural history study.

Six hundred fifty-eight Dutch patients with DM1 were included, with a mean age of 45.33 ± 14.30 years and a mean disease duration of 13.24 ± 10.42 years. Four clusters were identified, including 166, 169, 149, and 174 patients. Cluster 1 included patients with severe myotonia, gastrointestinal complaints, fatigue and daytime sleepiness, and reduced ability to perform daily activities. Cluster 2 included patients severely affected across all domains except for myotonia. Cluster 3 showed reduced respiratory functioning and reduced ability to perform daily activities. Cluster 4 included patients with minimal symptoms. Clustering of 581 patients in the external data set resulted in similar cluster profiles.

Four distinct clinical subgroups with characteristic multisystemic profiles were identified and independently validated. These findings demonstrate that DM1 heterogeneity reflects qualitatively different disease patterns rather than a simple severity continuum and provide foundation for more targeted patient stratification in clinical trials and health care.