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:A total of 591 patients with DM1 (mean age 43.7 ± 12.9 years, 57% female) were included, showing a broad spectrum of vHOT severity (median 3.9 seconds, interquartile range 1.8-7.9 seconds). At a single study visit, there were no systematic difference and good agreement between trials (mean difference 0.1 ± 3.7 seconds [p = 0.05], intraclass correlation coefficient 0.84 [95% CI 0.81-0.86]). vHOT correlated relatively weak with self-reported myotonia (ρ = 0.39), and even lower for other measures of muscle impairments such as grip strength (ρ = -0.21) or 9-hole pegboard (ρ = 0.12). 270 patients completed the 1-year follow-up, with vHOT showing no progression (mean difference 0.4 ± 4.7 seconds, p = 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.

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) shows marked clinical heterogeneity, partly related to age at onset. We analysed baseline, 12- and 24-month follow-up data from 231 FSHD1 patients enrolled in the ReSolve study (NCT03458832) to compare clinical, genetic, and epidemiological features between adult-onset (n = 190) and late-onset (n = 41) patients. Differences were assessed using generalized linear models and repeated-measures covariance analyses adjusting for demographics and disease duration. Late-onset patients were predominantly female (58.5%, p = 0.039), older (64.8 ± 6.3 vs 47.6 ± 13.5 years; p < 0.001), and carried longer D4Z4 repeats (6.5 ± 1.6 vs 5.7 ± 1.8; p = 0.01). They showed milder facial and upper limb involvement but greater lower limb impairment, evaluated with TUG (2.37 vs 2.11 s, p = 0.001) and 6MWT (329.16 vs 415.22 meters, p = 0.002), despite shorter disease duration. Lower limb weakness was the most frequent initial symptom (30% vs 10.7%, p = 0.0029). After one year, late-onset patients maintained similar characteristics, while facial differences were no longer significant at two years. Disease progression was similar across outcome measures except for the FSHD clinical score, which worsened more in late-onset patients at two years. These findings indicate that late-onset FSHD1 represents a distinct clinical phenotype relevant for outcome measure selection and personalized management strategies.

BACKGROUND AND OBJECTIVES:We previously demonstrated the feasibility of remote assessments in individuals with myotonic dystrophy type 1 (DM1). This study aimed to evaluate test-retest reliability and agreement of remote assessments and the interrater reliability of video-recorded functional assessments in DM1. METHODS:Participants were remotely recruited from the National Registry and provided with a toolkit containing a tablet equipped with videoconferencing software and devices for strength and functional assessments. Two remote study visits (RSV1, RSV2) were conducted within 3 months. During each visit, participants completed video-supervised assessments: handgrip, pinch grip (PG), 9-hole peg test (9HPT), video hand opening time (vHOT), timed up and go (TUG), 10-meter walk/run test (10MWRT), sitting and supine forced vital capacity (FVC), sniff nasal inspiratory pressure (SNIP), and tongue and buccal strength tests. Timed tests were video-recorded and scored using standardized protocols. Intraclass correlation coefficients (ICCs) were calculated using 2-way mixed-effects model for test-retest reliability and 2-way random-effects model for interrater reliability. Agreement was evaluated using Bland-Altman plots and measurement sensitivity with minimal detectable differences at 95% confidence (MDD95%). Patient-reported outcomes (PROs) assessing dysphagia (Eating Assessment Tool-10 [EAT-10]) and upper and lower extremity function (Upper Extremity Function Index [UEFI], Lower Extremity Functional Scale [LEFS]) were collected at RSV1 and correlated with quantitative assessments (Spearman coefficient, ρ). RESULTS:Forty individuals with DM1 (average age 47, 55% female) completed both RSVs. Test-retest reliability (ICC, 95% CI) was excellent for handgrip (0.99, 0.98-0.99), sitting and supine FVC (0.98, 0.96-0.99), 10MWRT (0.96, 0.91-0.98), TUG (0.94, 0.89-0.97), and 9HPT (0.93, 0.86-0.97) with adequate measurement sensitivity (MDD95% <30% for all). ICCs were acceptable for PG (0.96, 0.92-0.98), tongue strength (0.93, 0.86-0.96), right (0.93, 0.85-0.97) and left buccal strength (0.88, 0.75-0.94), and SNIP (0.88, 0.77-0.94) and moderate for vHOT (thumb 0.67, 0.42-0.83; middle finger 0.66, 0.40-0.83), but with inadequate measurement sensitivity (MDD95% >30% for all). Interrater reliability (ICC, 95% CI) was excellent for 9HPT (1), vHOT (thumb 0.99, 0.98-0.99; middle finger 0.98, 0.97-0.99), 10MWRT, and TUG (both 0.99, 0.98-0.99). Bland-Altman plots showed no systematic bias. Correlation (ρ, |95% CI|) was strong between handgrip and UEFI (+0.70, 0.49-0.84), 10MWRT and LEFS (-0.72, 0.86-0.49), and moderate between PG and UEFI (+0.60, 0.30-0.82), TUG and LEFS (-0.53, 0.73-0.23), and tongue strength and EAT-10 (-0.49, 0.71-0.20). DISCUSSION:Remote assessments are feasible and safe. Many measurements demonstrate high reliability, show adequate measurement sensitivity, and correlate with PROs. These findings support remote research, facilitating broad participation, and reducing participant burden.

Facioscapulohumeral muscular dystrophy is a rare genetic disorder that manifests as progressive weakening and loss of skeletal muscles, with the face, shoulder girdle, and upper arms typically affected in early stages. Currently, there are no approved therapies, and no consensus on the outcome measures used to assess disease progression or effects of new interventions. This systematic literature review identified treatment outcomes used to date, and the extent of their psychometric validation. Electronic searches were executed from inception to October 2022, supplemented with manual searches of relevant conferences. Eligible studies evaluated patients with the disease; reported on treatment outcomes or their validation; were clinical trials or observational studies; and published in English. Across the 65 studies identified reporting on treatment outcomes, 89 measures were used to assess outcomes following interventions in patients with the disease, including 58 efficacy/effectiveness, 6 safety, and 25 humanistic outcomes. Only 22/89 treatment outcomes were previously validated. Measures of motor function, upper/lower limb function, and muscle strength were the most frequently used efficacy and effectiveness measures. Significant heterogeneity exists among outcomes used. A total of 38 full text articles and 15 conference abstracts reported data on the humanistic burden in FSHD. The most reported domains included general QoL, followed by fatigue then pain. QoL was assessed in both adult and pediatric FSHD patients, with some instruments developed exclusively for use among children and adolescents (for example, Kidscreen for general QoL and the FSHD-HI Peds for disease-specific QoL). Based on the available evidence, it is evident that FSHD impacts QoL, with pain and/or fatigue impacting QoL. 18 studies were identified that reported on economic burden. While limited, the available evidence suggests that FSHD is associated with a substantial economic burden for patients, their caregivers and society. Overall, the findings of this SLR indicate that despite being the second most prevalent form of muscular dystrophy, FSHD is not well characterized in the literature. Further effort is needed to build consensus around the most relevant measures, such that trials for emerging interventions are designed with the consistent evaluation of patient-relevant benefits in mind.

Background and Objectives:Effective therapies for facioscapulohumeral muscular dystrophy (FSHD) are currently limited. Recombinant human growth hormone (rHGH) combined with testosterone (combination therapy) may have meaningful clinical effects on ambulation, strength, muscle mass, and disease burden. As such, combination therapy has the potential to limit disease progression and functional decline in individuals with muscular dystrophy. The objective of this study was to evaluate the safety, tolerability, and potential efficacy of combination therapy in adult men with FSHD. Methods:This investigator-initiated, single-center (University of Rochester), single-arm, proof-of-concept study evaluated the safety and tolerability of combination therapy in ambulatory adult men with FSHD. Participants received daily rHGH combined with testosterone enanthate injections every 2 weeks for 24 weeks, followed by a 12-week washout period. Participants underwent serial safety and laboratory assessments to monitor safety and tolerability during the study. Participants were also evaluated for changes from baseline in lean body mass (LBM) and fat mass, measured by dual-energy X-ray absorptiometry; ambulation, measured by 6-minute walk distance; strength; clinical function, measured using the FSHD-Composite Outcome Measure (FSHD-COM); and patient-reported disease burden, measured by the FSHD Health Index (FSHD-HI). Results:Nineteen of 20 participants completed the study, with no participants experiencing a serious adverse event. The most common adverse event was mild injection site reaction at the rHGH and/or testosterone injection site. After 24 weeks, LBM improved by 2.21 kilograms (95% CI 1.35-3.07; p < 0.0001), fat mass decreased by 1.30 kilograms (95% CI -2.56 to -0.04; p = 0.04), 6-minute walk distance increased by 37.3 m (95% CI 18.3-56.9; p = 0.001), overall strength (average % of predicted normal) increased by 3% (95% CI 0.3-5.6; p = 0.03), clinical function (FSHD-COM) improved by 2.4 points (95% CI 4.0-0.8; p = 0.006), and total disease burden (FSHD-HI) decreased by 6.1 points (95% CI -12.0 to -0.2; p = 0.04). Discussion:Combination therapy was safe and well tolerated in men with FSHD. Participants experienced improvements in ambulation, strength, muscle mass, and disease burden after receiving this study intervention. Larger randomized, double-blind, placebo-controlled trials are needed to further investigate this promising therapeutic approach. Trial Registration Information:Registered on ClinicalTrials.gov: NCT03123913.

BACKGROUND:Electrical impedance myography (EIM) has been proposed as an efficient, non-invasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD). OBJECTIVE:We investigate whether EIM parameters are associated with muscle structure measured by magnetic resonance imaging (MRI), muscle histology, and transcriptomic analysis as well as strength at the individual leg muscle level. METHODS:We performed a multi-center cross-sectional study enrolling 33 patients with FSHD. EIM measurements were recorded from bilateral vastus lateralis, tibialis anterior (TA), and medial gastrocnemius muscles and compared to quantitative muscle volume measures by MRI as well as knee extension and ankle dorsiflexion strength by quantitative muscle testing. EIM measurements of the bilateral TA were further compared to histology and transcriptomic analysis (RNAseq) of muscle and fat content. RESULTS:EIM phase at multiple frequencies was positively associated to the amount of muscle measured by MRI (ρ = 0.48 to 0.70, p ≤ 0.001) and negatively associated to the amount of fat replacement of muscle (ρ = -0.53 to -0.73, p ≤ 0.001). EIM phase of the vastus lateralis and TA was positively associated with knee extension and ankle dorsiflexion strength normalized to age and sex (ρ = 0.45 to 0.60, p < 0.0001). The bilateral TA muscles were analyzed at the histopathological and molecular (transcriptomic) levels and showed that EIM phase was positively associated with amount of muscle (ρ = 0.33 to 0.35, p < .01) and negatively associated with amount of fat (ρ = -0.36 to -0.56, p < .001) by transcriptomic analysis. CONCLUSIONS:This study supports the hypothesis that the amount and quality of muscle tissue as assessed by EIM is associated with the amount and quality of muscle tissues as assessed by MRI and muscle biopsy, with all measures ultimately being strongly associated with muscle strength. These data provide further convergent validity for the use of EIM as a potential non-invasive biomarker to assess muscle health in FSHD.

Patients with FSHD can develop scapular winging and loss of ability to raise arm. Reachable workspace (RWS) is able to describe upper extremity (UE) reaching ability. We analyzed data from 175 clinically affected and genetically confirmed adults with FSHD enrolled in the Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study. Our objective was to 1) investigate the relationship between UE reaching ability and muscle strength (using quantitative muscle testing, QMT); and (2) describe how different reaching abilities correspond to patient-reported function at home. There were strong correlations between total relative surface area (i.e., upper extremity reachability in the frontal plane) and UE strength measured by QMT. For each successive 25% decrease in total relative surface area, there was a corresponding mean 18% decrease in predicted UE strength and a mean 9-point decrease in the Upper Extremity Functional Index. Individuals that could not reach the right upper medial quadrant reported more difficulty performing various upper extremity activities of daily living and had decreases in the physical function as reported by the PROMIS-57 questionnaire. RWS provides a meaningful measurement of upper extremity strength and function in patients with FSHD.

BACKGROUND AND OBJECTIVES:Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication of PMP22, is the most common hereditary peripheral neuropathy. For participants with CMT1A, few clinical trials have been performed; however, multiple therapies have reached an advanced stage of preclinical development. In preparation for imminent clinical trials in participants with CMT1A, we have produced a Clinical Outcome Assessment (COA), known as the CMT-Functional Outcome Measure (CMT-FOM), in accordance with the FDA Roadmap to Patient-Focused Outcome Measurement to capture the key clinical end point of function. METHODS:Participants were recruited through CMT clinics in the United States (n = 130), the United Kingdom (n = 52), and Italy (n = 32). To derive the most accurate signal with the fewest items to identify a therapeutic response, a series of validation studies were conducted including item and factor analysis, Rasch model analysis and testing of interrater reliability, discriminative ability, and convergent validity. RESULTS:A total of 214 participants aged 18-75 years with CMT1A (58% female) were included in this study. Item, factor, and Rasch analysis supported the viability of the 12-item CMT-FOM as a unidimensional interval scale of function in adults with CMT1A. The CMT-FOM covers strength, upper and lower limb function, balance, and mobility. The 0-100 point scoring system showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for adults with CMT1A exhibiting high inter-rater reliability across a range of clinical settings and evaluators. The CMT-FOM was significantly correlated with the CMT Examination Score (r = 0.643; p < 0.001) and the Overall Neuropathy Limitation Scale (r = 0.516; p < 0.001). Significantly higher CMT-FOM total scores were observed in participants self-reporting daily trips and falls, unsteady ankles, hand tremor, and hand weakness (p < 0.05). DISCUSSION:The CMT-FOM is a psychometrically robust multi-item, unidimensional, disease-specific COA covering strength, upper and lower limb function, balance, and mobility to capture how participants with CMT1A function to identify therapeutic efficacy.

Introduction/Aims: In preparation for clinical trials, it is important to better understand how disease burden changes over time in facioscapulohumeral muscular dystrophy (FSHD) and to assess the capability of select metrics to detect these changes. This study aims to evaluate FSHD disease progression over 1 year and to examine the sensitivity of several outcome measures in detecting changes during this interval.Methods: We conducted a 12-month prospective observational study of 41 participants with FSHD. Participants were evaluated at baseline, 6 months, and 12 months with serial strength testing (manual muscle testing or MMT and maximum voluntary isometric contraction testing or MVICT), functional testing (FSHD-Composite Outcome Measure or FSHD-COM, FSHD Clinical Severity Score or CSS, and FSHD Evaluation Score or FES), sleep and fatigue assessments, lean body mass measurements, respiratory testing, and the FSHD-Health Index patient-reported outcome. Changes in these outcome measures were assessed over the 12-month period. Associations between changes in outcome measures and both age and sex were also examined.Results: In a 12-month period, FSHD participant function remained largely stable with a mild worsening of strength, measured by MMT and standardized MVICT scores, and a mild loss in lean body mass.Discussion: The abilities and disease burden of adults with FSHD are largely static over a 12-month period with participants demonstrating a mild average reduction in some measures of strength. Selection of patients, outcome measures, and trial duration should be carefully considered during the design and implementation of future clinical studies involving FSHD patients.