# Progrès dans la classification clinique de la dystrophie myotonique de type 1

Céline Dogan, Marie de Antonio, Dalil Hamroun, Pascale Chevalier, Malya Mati, Bruno Eymard, Guillaume Bassez et le groupe d'étude français dystrophie myotonique

La dystrophie myotonique de type 1 (DM1, maladie de Steinert) est considérée comme l'une des maladies génétiques les plus variables [1]. L'émergence de thérapies innovantes renforce encore la nécessité d'harmoniser, à l'échelon international, la classification clinique de la maladie [2, 10]. Malgré les initiatives de groupes de travail d'experts internationaux aucun consensus n'existe à ce jour. Plus récemment, le développement de bases de données fournit de puissants outils pour appréhender la complexité de maladies hétérogènes sur une large population. Nous nous appuyons sur les données de l'Observatoire national des dystrophies myotoniques, DM-Scope, pour évaluer la robustesse d'une classification de la DM1 en cinq formes cliniques, définies selon l'âge de début de la maladie. L'étude a été réalisée à partir d'une large collection de données standardisées issues de 1 962 patients DM1 français adultes. Les patients ont été classés comme suit : forme congénitale (3,7 %), forme infantile (17,8 %), forme juvénile (25,9 %), forme adulte (39,4 %) et forme tardive (13,1 %). Dans un premier temps, les cinq formes cliniques ont été comparées pour la distribution de la taille de l'expansion CTG, la fréquence et l'âge d'apparition des principaux symptômes. De plus, nous avons déterminé, grâce à une méthode statistique originale combinant fréquence et temporalité, les profils d'apparition des manifestations cliniques dans chacune des formes. Les résultats ont permis de valider le modèle de classification de la DM1 en cinq groupes. Nous montrons qu'au-delà du continuum, qui s'étend depuis la forme congénitale jusqu'à la forme tardive, les cinq formes cliniques se distinguent par des particularités cliniques propres. Cette étude confirme la robustesse d'un modèle de classification de la DM1 en cinq formes et met en exergue des caractéristiques cliniques spécifiques à chacune d'elles. Ces résultats devraient permettre d'optimiser le design des essais cliniques et plus particulièrement la constitution de groupes homogènes de patients.

## Refining myotonic dystrophy type 1 clinical classification

Myotonic dystrophy (DM) is considered to be one of the most variable genetic diseases [1]. With the arrival of innovative DM therapies, it is becoming of crucial importance to reach harmonization on the classification of the disease [2-10]. In spite of ongoing initiatives involving working-groups of experts, no consensus is yet available. Databases are powerful tools to address the complex issue of heterogeneous diseases. Here, we assessed the robustness of a DM1 classification model divided into five clinical forms based on age of onset. The study was performed using a large collection of standardized data obtained in 1,962 French DM1 patients (> 18 years) from the nationwide DM-Scope registry. Patients were classified as follows: congenital (3.7%), infantile (17.8%), juvenile (25.9%), adult (39.4%) and late onset forms (13.1%). The five clinical forms were first compared regarding the distribution of CTG expansion size and the occurrence and onset of the main symptoms. Then, using a special two-dimensional method combining time and frequency as parameters, we determined the clinical profile of the DM1 manifestations for each clinical form. Analyses validated the five-grade model of DM1 classification with regard to the triplet repeat expansion size, frequency, age of onset and clinical profiles of the main symptoms. We show that the assumption that there is a continuum from the congenital form to the late onset form is a reality. Furthermore, our data allows us to highlight clinical manifestations specific to some clinical forms. This study provides strong evidence supporting a five-grade DM1 clinical classification model. In addition we observed specific features in clinical profiles related to particular DM1 forms. Together these results contribute to refine the DM1 classification and to improve clinical trial design, in particular enhancing the enrolment of homogeneous patients in clinical studies.

Céline Dogan
Pascale Chevalier

Malya Mati
Guillaume Bassez

Centre de Référence
Maladies
Neuromusculaires, CHU
Henri Mondor, Créteil,
France

Marie De Antonio

Centre de Référence
Maladies
Neuromusculaires, CHU
Henri Mondor, Créteil,
France
Inserm UMRS1138,
team22, Centre
de recherche des
Cordeliers, Paris, France

Dalil Hamroun

Institut Universitaire
de Recherche Clinique,
CHU de Montpellier,
France

Bruno Eymard

Centre de Référence
Maladies
Neuromusculaires
Paris-Est, CHU
Pitié-Salpêtrière, Paris,
France
<figure><img src="image_1.png" /></figure>

## BACKGROUND

* Rare genetic disease with highest clinical variability

* Innovative therapeutic strategies approaching for DM

* Harmonization for disease classification (no consensus yet)

## OBJECTIVE

To assess the robustness of a age-of-onset-based DM1 classification model divided into five clinical forms

## METHOD

### DM SCOPE REGISTRY: STUDIED POPULATION

<figure><img src="image_2.png" /></figure>

1962 French DM1 patients
(>18yrs)

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<table><thead><tr><th></th><th>Congenital</th><th>intermittent</th><th>Recurrent</th><th>Adult</th><th>late onset</th></tr></thead><tbody><tr><th>DM1 patients (n)</th><td>3.7</td><td>17.8</td><td>35.0</td><td>16.4</td><td>33.1</td></tr><tr><th>Gender (n)</th><td>46.3</td><td>51.9</td><td>33.6</td><td>52.9</td><td>33.7</td></tr><tr><th>Age (yrs)</th><td>31.24</td><td>119.00</td><td>38.42</td><td>119.71</td><td>41.44</td></tr></tbody></table>

Characteristics of the five clinical forms

### ANALYSES DESIGN

* Distribution of CTG expansion size

* Frequency and age of onset of the main symptoms

* Clinical profile of DM1 manifestations for each clinical form (particular two-dimensional method combining time and frequency as parameters)

## RESULTS

### Genetic characteristics

Distribution of CTG repeats number across the five clinical forms

<figure><img src="image_13.png" /></figure>

* CTG (Exp) size is significantly different between each subtype

### Temporal profiles

Overall age of onset of the DM1 manifestations

<figure><img src="image_14.png" /></figure>

* Temporal succession of distinct profiles :

* Earliest symptoms in congenital form

* Particular profile in late forms in which DM1 manifestations occur within 5 years

* Clustering in early onsets for myotonia, cataract, cardiac defects and respiratory insufficiency

* Age of onset of pacemaker, GI troubles and muscular weakness could discriminate clinical forms

* Temporal continuum across the five subtypes But some clinical specificities

### The frequency of symptoms

Frequency across the five clinical forms

<figure><img src="image_15.png" /></figure>

* The frequency of symptoms is form dependant excepted for GI and somnolence

### Two-dimension clinical profiles

<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /></figure>

* Close clinical profiles

* Visualization of the clinical characteristics (examples)

* Switch of myotonia as first symptom from congenital to juvenile form

* Early cataract combined with muscular symptoms in late form

### Split of the childhood period ?

Relevance of congenital and infantile subtypes

<table><thead><tr><th></th><th>Congenital</th><th>intermittent</th></tr></thead><tbody><tr><th>Cognitive impairment</th><td>96.9%</td><td>73.0%</td></tr><tr><th>Educational level (CITE=3)</th><td>36.5%</td><td>70.7%</td></tr><tr><th>Specialized professional field</th><td>66.7%</td><td>44.1%</td></tr><tr><th>Respiratory modifcyency (PVC=70%)</th><td>66.7%</td><td>68.5%</td></tr><tr><th>Facial dysmorphism</th><td>85.4%</td><td></td></tr><tr><th>Overweight/Obesity (BMI=25)</th><td>25.0%</td><td>37.9%</td></tr></tbody></table>

* Confirmation of two distinct subtypes

* Not only a different severity in the expression of the disease

* Specific clinical characteristics

### Focus on Juvenile form

<table><thead><tr><th></th><th>Infantile</th><th>Adolescent</th><th>Adult</th></tr></thead><tbody><tr><th>Cognitive impairment</th><td>73.0%</td><td>60.2%</td><td>60.5%</td></tr><tr><th>Educational level (CITE=3)</th><td>70.7%</td><td>31.5%</td><td>9.8%</td></tr><tr><th>Specialized professional environment</th><td>44.7%</td><td>31.8%</td><td>30.5%</td></tr><tr><th>Respiratory modifcyency (PVC=70%)</th><td>68.7%</td><td>45.0%</td><td>32.2%</td></tr><tr><th>Facial dysmorphism</th><td>74.5%</td><td>67.6%</td><td>69.6%</td></tr><tr><th>Muscular weakness (MRTS=3)</th><td>33.8%</td><td>26.5%</td><td>22.6%</td></tr><tr><th>Severe myotonia</th><td>41.7%</td><td>48.5%</td><td>53.1%</td></tr></tbody></table>

* The three forms seem to have specific clinical characteristics

### SUM-UP

<table><thead><tr><th>Clinical form</th><th>Specificities</th></tr></thead><tbody><tr><td rowspan="2">Congenital</td><td>Severe cognitive impairment</td></tr><tr><td>Earlier respiratory and cardiac defects</td></tr><tr><td rowspan="2">Infantile</td><td>Less overweight/obesity</td></tr><tr><td>Early muscular weakness</td></tr><tr><td rowspan="2">Juvenile</td><td>Marked cognitive impairment</td></tr><tr><td>Earlier myotonia</td></tr><tr><td rowspan="2">Adult</td><td>Milder cognitive impairment</td></tr><tr><td>More severe myotonia</td></tr><tr><td rowspan="2">Late form</td><td>Earlier endocrine disorders</td></tr><tr><td>Early cataract</td></tr><tr><td></td><td>Short lapse of time in occurrence of symptoms</td></tr></tbody></table>

## CONCLUSION

* Our work validated the DM1 classification model into five clinical forms. We demonstrated that all the forms differ in CTG expansion size, symptoms' frequency, DM1 manifestations' age of onset and clinical profiles.

* Using a particular two-dimension representation with frequency and time as parameters, we show that the continuum assumption from congenital form to late onset form is a reality. Furthermore, our study allow us to highlight clinical manifestations specific for some clinical forms.

* Together these results may refine the DM1 classification and optimize enrolment of homogenous cohort of patients in clinical studies.

<caption>Figure 1
Contribution de l'Observatoire national des dystrophies myotoniques, DM-Scope, à la validation d'un modèle de classification de la DM1 divisé en cinq formes cliniques.</caption>

<footnote n="1">¹Centre de Résistance Maladies Neuromusculaires, CHU Montpellier, Crotal, France</footnote>

<footnote n="2">²Institut UMR1113-1, Team2, Centre de recherche des Cordeliers, Paris, France</footnote>

<footnote n="3">³Institut Universitaire de Recherches Cliniques, CHU de Montpellier, France</footnote>

<footnote n="4">⁴Centre de Résistance Maladies Neuromusculaires Paris-Eud, CHU Pitié-Salpêtrière, Paris, France</footnote>
## Refining myotonic dystrophy type 1 clinical classification

### LIENS D'INTÉRÊT

Les auteurs déclarent n'avoir aucun lien d'intérêt concernant les données publiées dans cet article.

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