Heterogeneity in the presentation and course of DM1 is a well-recognized feature that has, thus far, complicated the management of patients and design of clinical trials. Gene discovery in other muscular dystrophies (e.g., CMD or LGMD) provided the means, not only for better classification, but of supporting patient care and therapy development. While we understand the relevant genes in DM, knowledge of modifiers of the DM1 clinical spectrum is lacking. In the absence of genetic or environmental disease modifiers, or of diagnostic or predictive biomarkers, the French Myotonic Dystrophy Clinical Network has evaluated a large cohort of DM1 patients in the DM-Scope registry and developed discrete disease profiles to support a five-grade model of DM1.
Although we understand the existence of heterogeneity in DM1 (differences in onset age, organ systems affected, and severity and order of appearance of symptoms), the curious dilemma for the field is what lies behind the substantial clinical variability. As yet, no modifier genes have been discovered that provide molecular links to DM1 molecular mechanisms and the observed heterogeneity, nor have any biomarkers been validated that can predict time of onset and severity of the multi-organ system consequences of DM1.
The French DM Clinical Network sought to better understand the heterogeneity of DM1, with the rationale that better characterized phenotypes would support improvements in mechanistic research, patient care, and clinical phases of drug development. Members of the Network recently published findings from a cohort of 2,167 adult DM1 patients evaluated across the 28 member neuromuscular centers.
Basing analysis on CTG repeat length and detailed evaluation of the occurrence, onset time and order of occurrence, and severity of symptoms, their data support a classification scheme with five types of DM1: congenital, infantile, juvenile, adult-onset, and late-onset. While CTG repeat lengths overlapped, the investigators showed differences in repeat length distribution among the five categories. CTG length alone did not appear to be a valid marker for disease prognosis.
The investigators established that co-varying patterns in CTG length distribution and age of onset and frequency of systems define five disease grades and suggest that patient care should be aligned with disease grade. Several of the clinical features of DM1 appeared to exhibit specific onset times that were linked to disease grade. Disease grade, for example, then could be used to predict the timing of need for specialty care, as the authors noted that cardiac and aging-associated features (e.g., cataracts, endocrine symptoms) can develop very early in specific DM1 grades. The classification scheme also appears to better refine understanding of patterns of symptomatology in childhood DM1.
Taken together, the five-grade classification system published by the French DM Research Network provides an important framework to guide patient care and, potentially, to stratify patients in interventional clinical trials. Clearly, taking the next step to better understand and track the mechanistic factors behind the heterogeneity in DM1 will be essential to characterization of patients, refinement of the five-grade model, and improvement of patient care and the design/stratification of clinical studies and trials.
Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.
De Antonio M, Dogan C, Hamroun D, Mati M, Zerrouki S, Eymard B, Katsahian S, Bassez G.
French Myotonic Dystrophy Clinical Network. Rev Neurol (Paris). 2016 Sep 21. pii: S0035-3787(16)30205-3. doi: 10.1016/j.neurol.2016.08.003.