Longitudinal Psychometric Properties of the Myotonic Dystrophy Health Index in a Large Multicenter Cohort of People Living With Myotonic Dystrophy Type 1 Valeria A. Sansone, Andrea Lizio, Carola R. Ferrari Aggradi, Lucia C. Greco, Cynthia Gagnon, Sub Subramony, Richard H. Roxburgh, Karlien Mul, Johanna Hamel, Kate Eichinger, Man Hung, Jeffrey M. Statland, Chris Turner, Bakri Elsheikh, Benedikt Schoser, Thomas Ragole, Emma Matthews, Jacinda Sampson, Masanori P. Takahashi, Matthew Wicklund, Andrea Swenson, Chamindra G. Laverty, Perry Shieh, Ericka P. Greene, Maria Beretta, Jacopo L. Casiraghi, Jeanne Dekdebrun, Jennifer Raymond, Ruby Langeslay, Erin DeSpain, Charles A. Thornton, Chad Heatwole, Nicholas E. Johnson, Myotonic Dystrophy Clinical Research Network Muscle and Nerve, 2026 Introduction/Aim The Myotonic Dystrophy Health Index (MDHI) is a patient‐reported outcome measure assessing disease burden in DM1. In prior cross‐sectional studies, the MDHI correlated with disability status and with several functional measures and activities of daily living. To aid its use and interpretation, we investigated the longitudinal performance of MDHI. Methods Patients with genetically confirmed DM1 were enrolled as part of an observational longitudinal study within the Myotonic Dystrophy Clinical Research Network (DMCRN). Internal consistency and construct validity were evaluated to confirm previous findings. Both the Minimal Detectable Change (MDC) and the Minimal Clinically Important Difference (MCID) were calculated using distribution‐ and anchor‐based methods, respectively. Sensitivity to change and responsiveness were also investigated, along with potential factors associated with the progression of overall burden. Results 451 DM1 patients were assessed, with 147 completing 24‐month follow‐up. The MDHI showed excellent internal consistency ( α = 0.95) and confirmed construct validity. MDC for the total score ranged from ±4.24 (effect size change‐based approach) to ±9.72 (Standard Error Method‐based approach) points, while MCID ranged from small changes (−0.12 improvement/+1.25 worsening) to large changes (−2.17 improvement/+4.71 worsening). Changes in MDHI total and subscale scores were statistically significant at individual‐ or subgroup‐levels and consistently mirrored changes in corresponding clinical measures. Discussion The MDHI demonstrates robust sensitivity and responsiveness to individual and subgroup‐level changes in disease burden, offering valuable insights into patient‐perceived progression. These findings support MDHI use over time and as a potential additional outcome measure at subgroup levels in clinical trials.
The goal attainment scale in primary mitochondrial disease: Construct validity and lessons learned from a randomized controlled trial Kristofoor E. Leeuwenberg, Joanna IntHout, Jan T. Groothuis, Edith Cup, Jan Smeitink, Karlien Mul, Mirian C.H. Janssen Molecular Genetics and Metabolism, 2026 BACKGROUND: Primary mitochondrial diseases (PMD) are rare heterogeneous disorders caused by defective oxidative phosphorylation, with symptoms varying widely between individuals with PMD. Despite extensive research, no consensus exists on outcome measures that adequately reflect function, activities, and participation for adults with mitochondrial diseases. The Goal Attainment Scale (GAS) offers a personalized, patient-centered way to capture these outcomes. However, its validity and standardized use in trials remain unclear. This study assessed GAS construct validity in a PMD trial, including comparison with the Canadian Occupational Performance Measure (COPM), and provides guidance for future application. METHODS: Data from a double-blind, randomized, placebo-controlled, exploratory Phase IIA cross-over trial on the safety and efficacy of sonlicromanol (KH176) in 18 adult m.3243 A>G patients, were retrospectively analyzed. GAS goals were categorized using the World Health Organization International Classification of Functioning, Disability and Health. Additional outcome measures with overlapping content were selected to evaluate GAS validity. Implementation quality was evaluated using 17 GAS appraisal criteria. RESULTS: Most goals addressed fatigue or lack of energy (85%, 22/26). GAS showed weak to moderate negative correlations with the Checklist Individual Strength (CC = -0.40) and Beck Depression Inventory-II scores (CC = -0.37), indicating higher GAS scores were associated with reductions in fatigue and depressive symptoms. Moderate correlations were observed between GAS and COPM scores (CC = 0.50-0.55). No significant correlations were found with the 6-min walk test, 36-item Short Form Health Survey or Newcastle Mitochondrial Disease Scale for Adults. Only 6 out of 17 (35%) implementation criteria were fully met. CONCLUSIONS: GAS demonstrated some construct validity in relation to fatigue and depressive symptoms, showed limited overlap with conventional outcome measures and suffered from suboptimal implementation. Although exploratory, these findings suggest GAS may capture patient-relevant change in individuals with PMD. To realize its potential, standardized methodology and further validation are essential for its use as a robust outcome measure in future PMD trials.
Development and Validation of a Deep Learning-Based Facial Weakness Score for Objective Assessment in Facioscapulohumeral Muscular Dystrophy T. G. J. Loonen, T. C. ten Harkel, S. C. C. Vincenten, C. G. C. Horlings, C. H. G. Beurskens, S. Knuijt, G. W. A. M. Padberg, B. G. M. van Engelen, T. J. J. Maal, K. Mul Muscle and Nerve, 2026 Introduction/Aims Facioscapulohumeral muscular dystrophy (FSHD) is a muscle disease that leads, among other manifestations, to facial weakness. This weakness can severely impact communication and quality of life, yet it remains under‐researched with limited objective clinical measures. Current manual scoring methods are subjective and exhibit suboptimal inter‐observer agreement. This study aimed to develop and validate a deep learning‐based facial weakness score (DLFWS) as an objective clinical outcome measure for facial weakness in FSHD. Methods One hundred and twenty‐two genetically confirmed FSHD patients and 56 controls were recruited. Sixty‐four patients had a 5‐year follow‐up visit. Video recordings of participants performing seven facial exercises, each repeated three times, were analyzed using a convolutional neural network. The deep learning‐based facial weakness score (DLFWS) was trained by comparing start and end frames from these exercises with the manual facial weakness scores (MFWS) assigned by three experienced observers. Pearson correlation coefficients and intraclass correlation coefficients (ICC) were used to evaluate the DLFWS's performance and reliability. Results The DLFWS showed a strong correlation with the MFWS across exercises, with a mean Pearson correlation of 0.79 and a maximum of 0.85 for individual exercises. The DLFWS demonstrated excellent test–retest reliability, with an ICC of 0.90. Over a 5‐year follow‐up period, no significant progression of facial weakness was detected. Discussion The DLFWS provides a reliable and objective assessment of facial weakness in FSHD patients. This automated tool holds potential for widespread clinical and research applications, enabling standardized assessment of facial weakness in FSHD.
Electrical Impedance Myography Detects Disease Progression over 12 to 24 Months in Facioscapulohumeral Muscular Dystrophy Karlien Mul, Michael P. McDermott, Russell J. Butterfield, Bakri Elsheikh, Kate Eichinger, Nicholas E. Johnson, Doris G. Leung, Samantha LoRusso, Leann Lewis, William B. Martens, Perry B. Shieh, Leo H. Wang, Michaela Walker, Rabi Tawil, Jeffrey M. Statland, and Annals of Neurology, 2026 Objective Targeted therapies for facioscapulohumeral muscular dystrophy (FSHD) are progressing through clinical trials. Electrical impedance myography (EIM) provides a noninvasive biomarker of muscle composition that may be valuable especially in early phase trials. This study evaluated EIM data from a multicenter FSHD cohort over 24 months. Methods Adult patients with FSHD at 8 sites underwent EIM in 6 muscles bilaterally (deltoid, biceps, triceps, vastus lateralis, tibialis anterior, and medial gastrocnemius). EIM outcomes phase and reactance (50 and 100 kHz [kilohertz] frequencies) and 50 of 211 kHz phase ratio were evaluated for reliability, correlations with clinical measures, and sensitivity to change. Results One hundred fifty‐seven patients (53% male patients) were included. Test–retest reliability was excellent for all EIM outcomes (intraclass correlation coefficient [ICC] ≥0.94). Phase outcomes strongly correlated with the FSHD‐composite outcome measure (FSHD‐COM; r ≤ −0.69) and Motor Function Measure Domain 1 (MFM1; r ≥ 0.75); reactance outcomes exhibited moderate correlations with the FSHD‐COM ( r ≥ –0.41) and MFM1 ( r ≤ 0.44). Mean declines in phase and phase ratio were apparent at 12 months (eg, –0.25, 95% confidence interval [CI] = –0.45 to –0.05 at 50 kHz), and further progressed through 24 months (–0.66, 95% CI = –0.92 to –0.40] at 50 kHz and –0.65 [95% CI = –0.87 to –0.44] at 100 kHz; both p < 0.0001). Reactance changes were smaller and not significant: –0.21 (95% CI = –0.44 to 0.02) at 50 kHz and –0.13 (95% CI = –0.35 to 0.10) at 100 kHz. Interpretation EIM phase outcomes are reliable, valid, and sensitive to change over 12 to 24 months, supporting their potential utility as biomarkers in FSHD clinical trials. ANN NEUROL 2026
Late-onset facioscapulohumeral muscular dystrophy defines a distinct clinical subgroup Giulia Tammam, Sandra Dhifallah, Hongmei Yang, Manuela Gambella, Jonathan Pini, Russell J Butterfield, Elena Carraro, Katy Eichinger, Bakri Elsheikh, Nicholas E. Johnson, Doris G. Leung, Leann Lewis, William B. Martens, Karlien Mul, Valeria A Sansone, Perry B. Shieh, Kathryn R. Wagner, Leo H. Wang, Michaela Walker, Rabi Tawil, Jeffrey M. Statland, Sabrina Sacconi Neuromuscular Disorders, 2026
Prospective Study of Video Hand Opening Time as a Quantitative Measurement of Myotonia in Patients With Myotonic Dystrophy Type 1 Kristofoor E. Leeuwenberg, Valeria A. Sansone, Johanna Hamel, Man Hung, Jeanne M. Dekdebrun, Andrea Lizio, Katy Eichinger, Cynthia Gagnon, Richard H. Roxburgh, Sub H. Subramony, Jeffrey M. Statland, Bakri H. Elsheikh, Chris Turner, Emma L. Matthews, Thomas E. Ragole, Jacinda B. Sampson, Benedikt Schoser, Masanori P. Takahashi, Matthew P. Wicklund, Andrea J. Swenson, Chamindra G. Laverty, Perry B. Shieh, Ericka P. Greene, Jennifer Raymond, Erin DeSpain, Charles A. Thornton, Karlien Mul, Nicholas E. Johnson, , Kaneshia Hives, Andrea Jaworek, Rebecca Clay, Sandhya Sasidharan, Whitney Miller, Donovan Lott, Dennis Fernando, Christy Skura, Sara Ismail, Tina Duong, Kadeesia Brown, Dora Maldonado, Maegan Tyrell, Amy Yotty, Carino Jennings, Aileen Jones, Silvano Gefferie, Judith van Engelen-Kanters, Erica di Natale, Valentina Franchino, Corinna Wirner-Piotrowski, Nikoletta Nikolenko, Enza Leone, Alyssa Avilez, Robert Will, Sarah Nagar, Sarah Mollet, Elizabeth Moreno, Kristine Negrete, Claire Gilmartin, Claire O'Farrell, Justine Dolbec, Marc-Olivier Dugas, Shizuko Taima, Suzuki Manabu, Marlon H. Tamayo Muradas, Megan Iammarino, Charlotte Massey Neurology, 2026 BACKGROUND AND OBJECTIVES: Delayed grip relaxation is a common symptom of myotonic dystrophy type 1 (DM1), differing from other muscle diseases. Preclinical studies suggest myotonia may reverse quickly with targeted treatment and video hand opening time (vHOT) could be a straightforward method for assessing myotonia in multicenter trials, but few studies have evaluated vHOT in large DM1 cohorts. This study aimed to evaluate how vHOT performs and relates to other disease aspects in a large, well-characterized DM1 population. METHODS: The vHOT was conducted in the END-DM1 natural history study across 22 international sites, including adult DM1 patients with a genetic or research criteria diagnosis. The primary outcome involved video-recorded hand opening after a maximum 3-second grip, performed twice at each study visit with 5-minute rest between trials, and blinded scoring at a central site. Muscle strength and function were assessed by myometry, timed functional tests, and patient-reported outcomes. Procedures were repeated after 1 year for a subset of participants. Wilcoxon signed-rank was used to evaluate differences and Spearman correlation for associations. RESULTS: = 0.34). DISCUSSION: The vHOT procedure was performed successfully in a large international study, with grip relaxation delay varying from minimal to highly prolonged in an unselected cohort. The weak correlation with grip weakness supports the notion that myotonia and weakness are mechanistically distinct. Study limitations include underrepresentation of congenital DM1 and lack of other myotonia measures (e.g., handgrip relaxation myometry). It seems that vHOT is not suitable to assess disease progression, but stability over 1 year may support its use to assess improvement. TRIAL REGISTRATION INFORMATION: The END-DM1 observational study is registered with number NCT03981575.
Health-related quality of life, pain, and fatigue in myotonic dystrophy type 2: a 13-year follow-up study M. J. Damen, K. Mul, B.G.M. van Engelen, N. C. Voermans, A. A. Tieleman Disability and Rehabilitation, 2026 PURPOSE: To examine the long-term progression of health-related quality of life (HRQoL), pain, and fatigue in myotonic dystrophy type 2 (DM2) compared to adult-onset myotonic dystrophy type 1 (DM1). MATERIALS AND METHODS: Data on HRQoL (Short Form 36 Health Survey (SF-36)), pain (McGill Pain Questionnaire), and fatigue (Checklist Individual Strength) were assessed in DM2 patients and age- and sex-matched DM1 patients, at baseline and after 13 years. RESULTS: Twenty-nine DM2 and 29 DM1 patients participated at baseline. Data of 18 DM2 and 16 DM1 patients were recollected at follow-up. Ten DM2 and 13 DM1 patients had passed away, and one DM2 patient did not consent participation. In DM2, mental health on SF-36 subscales (social functioning, mental health) decreased during follow-up without significant increase in pain or fatigue. In contrast, in DM1, both physical and mental health decreased, and pain and fatigue increased. CONCLUSIONS: HRQoL decreased over 13 years in DM2. Pain was present early in the DM2 disease course and did not increase significantly. Healthcare professionals should be aware of the long-term impact of myotonic dystrophy (DM) on pain, fatigue, physical and mental functioning, including social functioning. Symptomatic treatment of these aspects may decrease disease impact, because DM cannot be cured.
The complementary use of muscle ultrasound and MRI in FSHD: Early versus later disease stage follow-up Sanne C.C. Vincenten, Nicol C. Voermans, Donnie Cameron, Baziel G.M. van Engelen, Nens van Alfen, Karlien Mul Clinical Neurophysiology, 2026 Muscle MRI and ultrasound provide complementary techniques for characterizing muscle changes and tracking disease progression in facioscapulohumeral muscular dystrophy (FSHD). In this cohort study, we provide longitudinal data that compares both imaging modalities head-to-head. FSHD patients were assessed at baseline and after five years. Standardized muscle MRI and ultrasound images of five leg muscles were assessed bilaterally. Fat replacement was quantified using MRI fat-fraction (FF) and ultrasound Heckmatt and echogenicity z-scores (EZ-score). Muscle edema was evaluated using T2-weighted turbo inversion recovery magnitude (TIRM) MRI. Twenty FSHD patients were included. Muscles with normal baseline imaging showed increases in ultrasound EZ-scores (≥1; in 17%) more often than MRI FF increases (≥10%; in 7%) over time. Muscles with only baseline ultrasound abnormalities often showed considerable FF increases (in 22%), and TIRM positivity at follow-up (44%). Muscles with increased FF at baseline showed stable (80%) or increasing FF (20%) over time. EZ-scores of those muscles either increased (23%), decreased (33%) or remained stable (44%). Muscle ultrasound may capture accelerated pathological muscle changes in FSHD in early disease, while muscle MRI appears better-suited to detecting and monitoring pathology in later stages. Our results help establish each techniques’ optimal use as imaging biomarker.
The blind men and the elephant: recognising the multisystem symptoms of myotonic dystrophy type 1 Kristofoor E. Leeuwenberg, Johanna E. Bruijnes, llse Karnebeek, Fran Smulders, Sandra Altena-Rensen, Caroline M.L. Gorissen-Brouwers, Sylvia Klinkenberg, Catharina G. Faber, Hilde Braakman, Karlien Mul Orphanet Journal of Rare Diseases, 2025 Although myotonic dystrophy type 1 (DM1) is named after its characteristic muscle symptoms, it is in fact a multisystem disorder that can affect many different organs. It is therefore not surprising that this disease can manifest with a myriad of symptoms, depending on the organs involved. The age of onset and severity of symptoms vary widely. Diagnostic delays of more than ten years are common and it’s not unusual for an entire family to be diagnosed only after the birth of a child with a severe phenotype. Knowledge of the spectrum of possible symptoms in DM1 can aid clinicians to recognise this disorder, thereby preventing unnecessary diagnostic delay and facilitating early treatment of disease complications. Here, we present an overview of the potential symptoms of DM1 at different ages, with the aim of raising awareness among healthcare professionals about the recognition of this disabling disease.
Establishing biomarkers and clinical endpoints in myotonic dystrophy type 1 (END-DM1): Protocol of an international natural history study Karlien Mul, Kate Eichinger, Man Hung, Valeria A. Sansone, Cynthia Gagnon, Sub Subramony, Richard H. Roxburgh, Johanna Hamel, Jeffrey M. Statland, Bakri Elsheikh, Chris Turner, Jacinda Sampson, Thomas Ragole, Emma Matthews, Benedikt Schoser, Andrea Swenson, Chamindra Laverty, Perry Shieh, Ericka P. Greene, Masanori Takahashi, Matthew Wicklund, Jeanne Dekdebrun, Jennifer Raymond, Erin DeSpain, Charles A. Thornton, Nicholas E. Johnson, and Plos One, 2025 Background Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited multi-system disorder that affects skeletal muscles but also many other organ systems. Molecular targets have been identified and targeted therapies are being developed and tested in first-in-human clinical trials. However, insufficient knowledge of the phenotypic heterogeneity and natural course of the disease, together with a lack of reliable biomarkers, complicate the design of clinical trials. Methods The main objectives of this study are to 1) characterize the phenotypic heterogeneity and disease progression of DM1 in a large cohort; 2) identify baseline characteristics that predict subsequent progression; 3) validate RNA biomarkers of disease severity. This is a prospective, multi-site observational study with a follow-up period of 24 months including approximately 700 adult DM1 patients. Visits will occur at baseline, and months 12 and 24. All patients will undergo strength testing, myotonia assessment, a battery of functional outcome assessments, spirometry, and complete various questionnaires and cognitive tests. Blood and urine samples will be taken at each visit for biomarker studies. A subset of 60 patients will undergo a muscle biopsy at baseline and at an additional 3-month visit. The sensitivity to disease progression and minimally clinically important differences will be determined for the various clinical outcome measures. Associations between baseline patient characteristics and the rate of disease progression will be evaluated. Discussion The results of this large international study on DM1 will contribute to optimizing clinical trial design. Both data and biological samples will be collected for future research as well. Trial registration Clinicaltrials.gov NCT03981575
Strength and functional correlates of reachable workspace in facioscapulohumeral muscular dystrophy Leo H. Wang, Maya N. Hatch, Michael P. McDermott, William B. Martens, Katy Eichinger, Leann Lewis, Michaela Walker, Doris G. Leung, Kathryn R. Wagner, Sabrina Sacconi, Karlien Mul, Perry B. Shieh, Bakri Elsheikh, Russell J. Butterfield, Nicholas E. Johnson, Valeria Sansone, Jay J. Han, Rabi Tawil, Jeffrey M. Statland Neuromuscular Disorders, 2025
Comprehensive four-year disease progression assessment of myotonic dystrophy type 1 Leandre A la Fontaine, Johanna E. Bruijnes, Fran HP Smulders, Carla Gorissen-Brouwers, Ilse EA Karnebeek, Hilde MH Braakman, Sylvia Klinkenberg, Karlien Mul, Peter-Bram AC ‘t Hoen, Sander MJ van Kuijk, Baziel GM van Engelen, Ingemar SJ Merkies, Catharina G Faber Neuromuscular Disorders, 2024
Meeting report: the 2021 FSHD International Research Congress Sujatha Jagannathan, Jessica C. de Greef, Lawrence J. Hayward, Kyoko Yokomori, Davide Gabellini, Karlien Mul, Sabrina Sacconi, Jamshid Arjomand, June Kinoshita, Scott Q. Harper Skeletal Muscle, 2022
Characterizing the face in facioscapulohumeral muscular dystrophy T. G. J. Loonen, C. G. C. Horlings, S. C. C. Vincenten, C. H. G. Beurskens, S. Knuijt, G. W. A. M. Padberg, J. M. Statland, N. C. Voermans, T. J. J. Maal, B. G. M. van Engelen, K. Mul Journal of Neurology, 2021
Deep phenotyping of facioscapulohumeral muscular dystrophy type 2 by magnetic resonance imaging G. Giacomucci, M. Monforte, J. Diaz‐Manera, K. Mul, R. Fernandez Torrón, L. Maggi, C. Marini Bettolo, J. R. Dahlqvist, J. Haberlova, P. Camaño, M. Gros, T. Tartaglione, L. Cristiano, S. Gerevini, P. Calandra, G. Deidda, E. Giardina, S. Sacconi, V. Straub, J. Vissing, B. Van Engelen, E. Ricci, G. Tasca European Journal of Neurology, 2020
FSHD type 2 and Bosma arhinia microphthalmia syndrome Karlien Mul, Richard J.L.F. Lemmers, Marjolein Kriek, Patrick J. van der Vliet, Marlinde L. van den Boogaard, Umesh A. Badrising, John M. Graham, Angela E. Lin, Harrison Brand, Steven A. Moore, Katherine Johnson, Teresinha Evangelista, Ana Töpf, Volker Straub, Solange Kapetanovic García, Sabrina Sacconi, Rabi Tawil, Stephen J. Tapscott, Nicol C. Voermans, Baziel G.M. van Engelen, Corinne G.C. Horlings, Natalie D. Shaw, Silvère M. van der Maarel Neurology, 2018
225th ENMC international workshop:: A global FSHD registry framework, 18–20 November 2016, Heemskerk, The Netherlands Karlien Mul, June Kinoshita, Hugh Dawkins, Baziel van Engelen, Rossella Tupler, Verònica Alonso Ferreira, Sharam Attarian, Angela Berardinelli, Betsy Bogard, Hugh Dawkins, Baziel van Engelen, Teresinha Evangelista, Kees van der Graaf, Chad Heatwole, June Kinoshita, Silvère Van der Maarel, Jean Mah, Karlien Mul, Jacqui van Rens, Armelle Richiardi, Richard Roxburgh, Sabrina Sacconi, Rabi Tawil, Rossella Tupler, Diana van der Meij-Kim, Nicole Voet, Stanislav Vohánka Neuromuscular Disorders, 2017
Adding quantitative muscle MRI to the FSHD clinical trial toolbox Karlien Mul, Sanne C.C. Vincenten, Nicol C. Voermans, Richard J.L.F. Lemmers, Patrick J. van der Vliet, Silvère M. van der Maarel, George W. Padberg, Corinne G.C. Horlings, Baziel G.M. van Engelen Neurology, 2017
