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The International Clinical Outcome Study for Dysferlinopathy (COS) was the first multi-country natural history study in dysferlinopathy with the aim to characterise disease presentation and improve clinical trial readiness. In the absence of validated disease specific motor assessment scales, The North Star Assessment for limb girdle type muscular dystrophies (NSAD), was developed and validated in the COS I cohort. The Performance of upper limb (PUL 2.0), originally developed for DMD was assessed in COS I and found to be suitable to measure upper limb function in dysferlinopathy. The extension study, COS II, recruited 203 participants (119 new) from 16 sites in nine countries with the aim to validate the findings from COS I in an expanded cohort. We now examine the psychometric performance of the NSAD and PUL in the new COS II participants using Rasch Unidimensional Measurement Model (RUMM). Psychometric evaluation of 117 available assessments evaluated NSAD and PUL performance in seven areas: targeting, response categories, fit, reliability, dependency, stability and unidimensionality using RUMM2030 software. NSAD and PUL demonstrated unidimensional construct of functional motor performance and upper limb motor performance respectively, high reliability with a PSI of 0.96 and 0.95 respectively. A potential ceiling effect still existed for the strongest/ asymptomatic subjects in both scales. 27/29 items of the NSAD and 19/22 items of the PUL demonstrated ordered response categories, meaning the scoring categories for each item are logical and appropriate for dysferlinopathy. No items of NSAD with fit residuals outside ±2.5 but three on the PUL. The items fit well together to make use of the total score appropriate. Differential item functioning analysis, which indicates if a person factor influences the probability of scoring on an item was not present for gender on either scale. This study validated previous data from COS, confirming that the NSAD and PUL are suitable measurements for use in dysferlinopathy. Ongoing analysis is underway to examine the psychometric properties of these scales and responsiveness to change in functional ability over time. [ABSTRACT FROM AUTHOR]

Patients with limb girdle muscular dystrophy (LGMD) R2/2B (dysferlinopathy) lose the ability to independently move into standing from a seated position (STS) prior to loss of independent ambulation. Clinically, individuals report this impacts their ability to socialise or to work, however there are no studies evaluating this. The aim of this study was to examine the impact of loss of STS on social participation/employment in individuals with dysferlinopathy. We examined the baseline visit data of 205 participants in the Clinical Outcome study for Dysferlinopathy, a two-year, 16-site natural history study. Data analysed included scores of STS from the North Star assessment for limb-girdle type muscular dystrophies (NSAD), responses to the participant-reported Activity limitations for patients with upper and/or lower limb impairments (ACTIVLIM) and participant-reported responses to the Quality of Life in Genetic Neuromuscular Disease Questionnaire (QOLgNMD). Chi square test for association (χ2) were used to test the relationship between clinician-reported ability to STS and participant-reported ability to complete activities requiring STS. Statistically significant associations were found between the following variables: clinician-reported ability to STS (NSAD) and patient-reported ability to get on/off a toilet, in/out of a car (ACTIVLIM), how often getting to the toilet restricted activities outside the home and how often participants felt able to leave the house alone (QOLgNMD). Loss of ability to STS was associated with reduced social participation and employment, which can be detected by deterioration on NSAD or ACTIVLIM STS items. The use of equipment or support from others is helpful in managing difficulties with STS, which enables people with dysferlinopathy to remain socially active or employed. Clinicians should proactively instigate early referrals to equipment and wheelchair providers after any deterioration on NSAD or ACTIVLIM STS scores, regardless of ambulatory status. [ABSTRACT FROM AUTHOR]

Skeletal muscle quantitative muscle magnetic resonance imaging (MRI) is sensitive to changes in fat content over time. The Dysferlinopathy Clinical Outcome Study 1 is an international, multicentre study in which patients were followed up clinically and radiologically for 3 years. Dixon scans of the lower limbs were obtained yearly for 109 patients. The aim of this study is to describe changes in fat fraction (FF) over time, correlate these with clinical characteristics and build a model that can predict FF progression over time. We used linear mixed effect modelling to analyse changes in FF over time according to patients' age. We calculated the average FF trajectory for each muscle, for lower leg and, for thigh. We then built complex models for lower leg and thigh FF progression adding other clinical and radiological variables and using likelihood ratio test and residuals' analysis to determine if they better predicted FF progression in this cohort. Before the age of 30, lower leg muscles showed higher FF values than thigh muscles. Thigh muscles (except for sartorius and gracilis) progressed significantly faster than lower leg muscles (ANOVA, p<0.05). The more severely affected muscles at age 40 (median age of our cohort) were the hamstrings, adductor magnus and gastrocnemius medialis, whereas the least affected were sartorius, gracilis and the anterior lower leg compartment. Young severely affected patients had a significantly earlier age at disease onset than old mildly affected ones, however no significant differences in disease duration and rate of disease progression were observed. We built two models for FF progression of the thigh and lower leg muscles as two segments adding age at disease onset, baseline MRI data (age, thigh FF% and lower leg FF%) and velocity when performing 6MWT as covariates and obtained two models that predicted FF progression with mean±SD residual values of 2.32×10 −14 ±3.96 and 1.36×10 −15 ±3.96 respectively. In conclusion, this study provides granularity into the way FF progresses over time in the lower limbs. Moreover, the thigh muscles model has a very strong fit with our data and, if validated, could potentially be used in clinical trials to measure effects of upcoming treatments. [ABSTRACT FROM AUTHOR]

An important requirement for interventional studies and clinical management is the identification of minimal clinically important differences (MCID) in outcomes of interest. This is lacking for many neuromuscular diseases; however, the Dysferlinopathy Clinical Outcome Study (COS) has given us the opportunity to assess the meaningful change in several outcomes in individuals with dysferlinopathy. We identified 378 12-month observation intervals in 240 COS participants to calculate several MCID values. We utilized both distribution-based and anchor-based methods to calculate MCIDs for three outcomes, the ACTIVLIM patient reported activity questionnaire, forced vital capacity (FVC), and forced expiratory volume in first second (FEV1). We chose two different anchors, a ≥3 point decrease in total NSAD score and a ≥1 point decrease in NSAD item 29 (timed 10-meter walk/run), along with several different methods of MCID calculation to determine consensus values. 12-month MCID estimates using all methods for the ACTIVLIM ranged from a decrease of 0.4 to 1.7 points, a decrease of 1.0 to 4.4 % points for % predicted FEV1, and a decrease of 0.9 to 4.8 % points for % predicted FVC. Anchor-based MCID values based on total NSAD change and NSAD item 29 change were very similar using the multiple methods. However, the distribution-based methods produced MCID values that were either greater decreases than anchor-based values or smaller decreases than anchor-based values. Anchor-based MCID values for the ACTIVLIM show a decrease of 1.0 point is associated with a 3+ point drop in the NSAD and a 0.9-point decrease is associated with a 1+ point decrease in NSAD item 29. A decrease of 1.5 and 1.8 for FEV1, and 2.0 and 3.0 for FVC, respectively, were calculated. To better refine these, we plan to evaluate MCID values in sex-stratified cohorts alongside other factors that may mediate the 12-month observed changes in outcomes. [ABSTRACT FROM AUTHOR]

Dysferlin plays a key role in cell membrane repair, and its absence or malfunction in patients with dysferlin-deficient limb girdle muscular dystrophy leads to muscle fibre death. Muscle magnetic resonance imaging (MRI) allows non-invasive and repeatable measurements that report on pathological changes observed in dysferlinopathy patients (DP) that lead to muscle dysfunction. We have employed a standardised leg exercise protocol and dynamic 1H- and 23Na-MR imaging and spectroscopy methods to quantify the impact of dysferlin-deficiency on muscle sodium homeostasis. Ten adult DP and 10 age and sex matched healthy volunteers (HV) were recruited and scanned by 23Na and 1H MR imaging and spectroscopy on a 3T clinical MR scanner. Participants performed physiotherapist-guided isometric dorsiflexion contractions to achieve tibialis anterior (TA) muscle exhaustion. Dynamic volume-localised 23Na- and 1H-MR spectroscopy scans were acquired serially for 35 minutes post-exercise. MR data were analysed to determine TA lipid content and the change in TA sodium content, sodium T2* relaxation properties, and TA water 1H T2 relaxation properties. Biexponential analysis of 23Na T2* data was performed to assess dynamic change in the fraction of fast- vs slow-relaxing 23Na. Baseline muscle water 1H T2 and sodium content were significantly higher in DP compared to matched controls. 1H T2 and sodium content dynamics in healthy controls showed post-exercise elevation with slower time-to-peak for sodium content compared to 1H T2. Magnitude of 1H T2 and sodium content post-exercise dynamic change was highly variable in the DP group. Notably, 23Na dynamics in a DP with normal muscle fat fraction were similar to that of the HV group. Biexponential analysis of 23Na T2* showed a post-exercise increase in the slow-relaxing component, consistent with oedematous changes. We have implemented volume-localised 23Na MR spectroscopy for measurement of tissue sodium dynamics with high temporal resolution. Assessment of TA muscle fat fraction, 1H T2, sodium content and sodium T2* relaxation properties revealed differences at baseline and differences in post-exercise dynamics between patients with dysferlinopathy and matched controls. Alterations in sodium content and in post-exercise sodium content and relaxation dynamics in DP may reflect altered ion homeostasis that worsens as chronic muscle damage increases. [ABSTRACT FROM AUTHOR]

Dysferlin-deficient limb girdle muscular dystrophy (LGMD R2), also referred to as dysferlinopathy, can be associated with respiratory muscle weakness as the disease progresses. Clinical practice guidelines recommend biennial lung function assessments in patients with dysferlinopathy to screen for respiratory impairment. However, lack of universal access to spirometry equipment and trained specialists makes regular monitoring challenging. This study investigated the use of the Performance of Upper Limb (PUL) clinical scale entry item as a low-cost screening tool to identify patients with dysferlinopathy at risk of respiratory impairment. Using data from 193 patients from the Jain Foundation's International Clinical Outcomes Study, modelling identified a significant positive relationship between the PUL entry item and forced vital capacity (FVC). Eighty-eight percent of patients with the lowest PUL entry item score of 1 presented with FVC % predicted values of <60 %, suggestive of respiratory impairment. By contrast, only 10 % of the remainder of the cohort (PUL entry item of 2 or more) had an FVC of <60 %. This relationship also held true when accounting for ambulatory status, age, and sex as possible confounding factors. In summary, our results suggest that the PUL entry item could be implemented in clinical practice to screen for respiratory impairment where spirometry is not readily available., Competing Interests: Declaration of competing interest Apart from the grant from the Jain Foundation that financed the study, there are no relevant conflicts of interest that impact on the paper referenced above., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dysferlinopathy is a muscle disease characterized by a variable clinical presentation and is caused by mutations in the DYSF gene. The Jain Clinical Outcome Study for Dysferlinopathy (COS) followed the largest cohort of patients (n=187) with genetically confirmed dysferlinopathy throughout a three-year natural history study, in which the patients underwent muscle function tests and muscle magnetic resonance imaging (MRI). We previously described the pattern of muscle pathology in this population and established a series of imaging criteria for diagnosis. In this paper, we describe the muscle imaging and clinical features of a subgroup of COS participants whose muscle imaging results did not completely meet the diagnostic criteria. We reviewed 184 T1-weighted (T1w) muscle MRI scans obtained at the baseline visit of the COS study, of which 106 were pelvic and lower limb only and 78 were whole-body scans. We identified 116 of the 184 patients (63%) who did not meet at least one of the established imaging criteria. The highest number found of unmet criteria was four per patient. We identified 24 patients (13%) who did not meet three or more of the nine established criteria and considered them as "outliers". The most common unmet criterion (27.3% of cases) was the adductor magnus being equally or more affected than the adductor longus. We compared the genetic, demographic, clinical and muscle function data of the outlier patients with those who met the established criteria and observed that the outlier patients had an age of disease onset that was significantly older than the whole group (29.3 vs 20.5 years, p=0.0001). This study expands the phenotypic muscle imaging spectrum of patients with dysferlinopathy and can help to guide the diagnostic process in patients with limb girdle weakness of unknown origin., Competing Interests: Declarations of Competing Interest Authors have no conflict of interest related to the content of this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy ( 31 P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients., Methods: Quantitative MRI/ 31 P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T 2 in both global leg and thigh segments and individual muscles and 31 P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31 P MRS markers and functional markers., Results: Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P < 0.001). SRM values for global thigh FF were over 0.8 for all years. Vastus lateralis muscle showed the highest SRM values across all time points. cCSA decreased significantly after 3 years with median values of 11.0% and 12.8% in global thigh and global leg, respectively (P < 0.001). Water T 2 values in ambulant patients were significantly increased, as compared with control values (P < 0.001). The highest water T 2 values were found in the anterior part of thigh and leg. Almost all 31 P MRS indices were significantly different in patients as compared with controls (P < 0.006), except for pH w , and remained, similar as to water T 2 , abnormal for the whole study duration. Global thigh water T 2 at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P < 0.001). There was also a significant relationship between the change in functional score and change in FF after 3 years in ambulant patients (ρ = -0.55, P = 0.010)., Conclusions: This multi-centre study has shown that quantitative MRI/ 31 P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy., Competing Interests: MJ receives fee support for PhD studies from the Jain Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mayhew, James, Moore, Sutherland, Jacobs, Feng, Lowes, Alfano, Muni Lofra, Rufibach, Rose, Duong, Bello, Pedrosa-Hernández, Holsten, Sakamoto, Canal, Sánchez-Aguilera Práxedes, Thiele, Siener, Vandevelde, DeWolf, Maron, Gordish-Dressman, Hilsden, Guglieri, Hogrel, Blamire, Carlier, Spuler, Day, Jones, Bharucha-Goebel, Salort-Campana, Pestronk, Walter, Paradas, Stojkovic, Mori-Yoshimura, Bravver, Díaz-Manera, Pegoraro, Mendell and Straub.)

Objective: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year., Methods: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis., Results: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint., Conclusion: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials., Clinicaltrialsgov Identifier: NCT01676077., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objective: Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests., Methods: We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed., Results: In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment., Conclusions: The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials., Clinical Trial Registration: NCT01676077., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)