Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale.

OBJECTIVE: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD. METHODS: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories. RESULTS: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline. INTERPRETATION: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978.

Comparison of strength testing modalities in dysferlinopathy.

INTRODUCTION/AIMS: Dysferlinopathy demonstrates heterogeneity in muscle weakness between patients, which can progress at different rates over time. Changing muscle strength due to disease progression or from an investigational product is associated with changing functional ability. The purpose of this study was to compare three methods of strength testing used in the Clinical Outcome Study (COS) for dysferlinopathy to understand which method and which muscle groups were most sensitive to change over time. METHODS: Patients were evaluated at each study visit using functional scales, manual muscle testing, and handheld dynamometry (HHD) at all 15 sites. A fixed-frame system (Fixed) was used at a subset of seven sites. Screening and baseline visits were evaluated for reliability. Data over a 1-year period were analyzed to determine sensitivity to change among strength modalities and individual muscle groups. RESULTS: HHD and Fixed captured significant change across 1 year in summed muscle strength score of four muscle groups (P < .01). Strength summed scores were significantly correlated with functional scales (rho = 0.68-0.92, P < .001). Individual muscle groups, however, showed high levels of variability between visits. DISCUSSION: Although both HHD and Fixed demonstrate change over 12 months, HHD is a less expensive option that provides data on a continuous scale and may be easier to implement. Due to variability in strength measures, researchers should carefully consider use of strength testing as an outcome and may wish to select functional measures with less variability as clinical trial endpoints.

Cardiac and pulmonary findings in dysferlinopathy: A 3-year, longitudinal study.

INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype. METHODS: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo). RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population. DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

The CINRG Becker Natural History Study: Baseline characteristics.

We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected longitudinal medical, strength, and timed function assessments. Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6-75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.

Six-Minute Walk Test as a Measure of Walking Capacity in Ambulatory Individuals With Amyotrophic Lateral Sclerosis.

OBJECTIVE: To determine the validity of the 6-minute walk test (6MWT) as an outcome measure to evaluate walking capacity in ambulatory patients with amyotrophic lateral sclerosis (ALS). DESIGN: Observational study. SETTING: Multidisciplinary ALS clinic at an academic medical center. PARTICIPANTS: Patients with ALS (N=186) who ambulate without (stage I) or with (stage II) an assistive device. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Walking distance obtained from the 6MWT. RESULTS: Participants performed the 6MWT, 25-foot walk test (25FWT), Timed Up and Go (TUG) test, lower extremity maximum voluntary isometric contraction (MVIC), ALS Functional Rating Scale-Revised (ALSFRS-R), and forced vital capacity (FVC). Walking capacity was reduced to 66% predicted of healthy subjects (75.2%±22% in stage I; 42.6%±22% in stage II). The 6MWT correlated with all other outcome measures in ambulatory patients with ALS (25FWT: r=-.74, P≤.0001; TUG test: r=-.80, P≤.0001; MVIC: r=.64, P≤.0001; percent predicted FVC: r=.25, P≤.0007; ALSFRS-R: r=.52, P≤.0001; ALSFRS-R gross motor subscore: r=.71, P≤.0001). When ambulatory patients with ALS were stratified by stage of ambulation, the 6MWT was associated with all other outcome measures in stage I (25FWT: r=-.56, P≤.0001; TUG test: r=-.66, P≤.0001; MVIC: r=.51, P≤.0001; percent predicted FVC: r=.40, P≤.02; ALSFRS-R: r=.52, P≤.0001; ALSFRS-R gross motor subscore: r=.61, P≤.0001). In stage II, the 6MWT correlated with the 25FWT (r=-.83, P≤.0001), TUG test (r=-.77, P≤.0001), MVIC (r=.47, P≤.0001), and ALSFRS gross motor subscore (r=.61, P≤.0001), but not with percent predicted FVC (r=.09, P≤.513) or ALSFRS-R (r=.21, P≤.141). CONCLUSIONS: The 6MWT is a valid measure of walking capacity of ambulatory patients with ALS that is associated with measures of lower extremity muscle strength and function in both stages of ambulation. The discordance between the 6MWT with the ALSFRS-R and percent predicted FVC in stage II ambulatory patients with ALS indicates that the 6MWT is an independent measure of ambulatory function in both stages of ambulation. The 6MWT may provide a quantitative, simple, and inexpensive outcome measure of walking capacity for early stage clinical trials in ambulatory patients with ALS.

Power Wheelchair Use in Persons With Amyotrophic Lateral Sclerosis: Changes Over Time.

The objectives of this study were to survey persons with Amyotrophic Lateral Sclerosis (ALS) at 1 and 6 months after receiving power wheelchairs to determine long-term use, comfort, and function as well as the power wheelchair's impact on daily tasks and quality of life. A 33-question survey and Psychosocial Impact of Assistive Devices Scale (PIADS) were sent 1 month after getting a new power wheelchair; a follow-up survey was sent at 6 months. Based on satisfaction and feature use survey results, at 1 month, 81% of users found the power wheelchair overall comfort to be high, 88% found their overall mobility to be improved, and 95% found it easy to use. Their quality of life increased and pain decreased at 1 and 6 months. According to the PIADS, the power wheelchair gave users increased ability to participate and sense of competence. This study has important results for the ALS community, as it is the first to assess power wheelchair users at 1 and 6 months after power wheelchair procurement. The results demonstrate the impact the power wheelchair has on mobility, psychosocial issues, functional abilities, and quality of life for a person with ALS.

Vestibular deficits leading to disequilibrium and falls in ambulatory amyotrophic lateral sclerosis.

OBJECTIVE: To assess vestibular deficits in response to disequilibrium in ambulatory individuals with amyotrophic lateral sclerosis (ambALS). DESIGN: All participants completed standard protocols for the Sensory Organization Test (SOT) by computerized dynamic posturography. SETTING: Multidisciplinary amyotrophic lateral sclerosis clinic at an academic medical center. PARTICIPANTS: Study participants (N=34) consisted of ambALS (n=19) and healthy controls (HC) (n=15). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Equilibrium scores (ESs) obtained from averaged sway amplitude in condition 5 (ES5) and condition 6 (ES6) of the SOT. RESULTS: In conditions of altered somatosensory information with vision absent or vision sway-referenced, the mean ± SD scores for ambALS (ES5=51.4±22.5; ES6=50.8±22.1) were lower than those for HC (ES5=65.4±11.7, P≤.03; ES6=58.9±12.5, P>.05). Seven ambALS (37%) experienced a total of 19 falls during the sway-referenced support test conditions. There were no falls in the HC. CONCLUSIONS: Nearly 37% of ambALS with normal clinical balance testing have decreased ability to use the vestibular input and required increased reliance on visual input for postural orientation to sustain equilibrium. The mechanism of this alteration in sensory preference is not completely clear. Extrapyramidal involvement early in ALS may be indicated.

Expanding the muscle imaging spectrum in dysferlinopathy: description of an outlier population from the classical MRI pattern.

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.

Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy.

Myostatin is a myokine which acts upon skeletal muscle to inhibit growth and regeneration. Myostatin is endogenously antagonised by follistatin. This study assessed serum myostatin and follistatin concentrations as monitoring or prognostic biomarkers in dysferlinopathy, an autosomal recessively inherited muscular dystrophy. Myostatin was quantified twice with a three-year interval in 76 patients with dysferlinopathy and 38 controls. Follistatin was quantified in 62 of these patients at the same timepoints, and in 31 controls. Correlations with motor function, muscle fat fraction and contractile cross-sectional area were performed. A regression model was used to account for confounding variables. Baseline myostatin, but not follistatin, correlated with baseline function and MRI measures. However, in individual patients, three-year change in myostatin did not correlate with functional or MRI changes. Linear modelling demonstrated that function, serum creatine kinase and C-reactive protein, but not age, were independently related to myostatin concentration. Baseline myostatin concentration predicted loss of ambulation but not rate of change of functional or MRI measures, even when relative inhibition with follistatin was considered. With adjustment for extra-muscular causes of variation, myostatin could form a surrogate measure of functional ability or muscle mass, however myostatin inhibition does not form a promising treatment target in dysferlinopathy.

Water T2 could predict functional decline in patients with dysferlinopathy.

BACKGROUND: Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. METHODS: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. RESULTS: A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. CONCLUSIONS: In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach.

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.

Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease.

This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments.

Supported treadmill ambulation for amyotrophic lateral sclerosis: a pilot study.

OBJECTIVES: To determine the feasibility, tolerability, safety, and exercise treatment-effect size of repetitive rhythmic exercise mediated by supported treadmill ambulation training (STAT) for patients with amyotrophic lateral sclerosis (ALS). DESIGN: Interventional with repeated-measures design. SETTING: Multidisciplinary ALS clinic at academic medical center. PARTICIPANTS: Convenience sample of patients with ALS (N=9) who were ambulatory with assistive devices (Sinaki-Mulder stages II-III). INTERVENTIONS: Repetitive rhythmic exercise-STAT (30min total; 5min of exercise intercalated with 5min of rest) performed 3 times a week for 8 weeks. MAIN OUTCOME MEASURE: ALS Functional Rating Scale-Revised (ALSFRS-R), percentage of predicted vital capacity (VC), total lower-extremities manual muscle test (MMT), rate of perceived exertion (RPE), Fatigue Severity Scale (FSS), and maximum voluntary isometric contraction (MVIC) in 10 lower and 10 upper extremities. Gait performance, which included walking distance, speed, steps, and stride length, was evaluated during treadmill and ground 6-minute walk tests (6MWTs) and 25-foot walk test (25FWT). RESULTS: Feasibility issues decreased screened participants by 4 patients (31%). Nine patients were enrolled, but 6 patients (67%) completed the study and 3 (23% of original cohort; 33% of enrolled cohort) could not complete the exercise intervention because of non-ALS-related medical problems. Tolerability of the intervention measures during the treadmill 6MWT showed improvement in RPE (P≤.05) and FSS score (P≥.05). Safety measures (ALSFRS-R, VC, MMT) showed no decrease and showed statistical improvement in ALSFRS-R score (P≤.05) during the study interval. Exercise treatment-effect size showed variable improvements. Gait speed, distance, and stride length during the treadmill 6MWT improved significantly (P≤.05) after 4 weeks and improvements were maintained after 8 weeks compared with baseline. Walking distance during the ground 6MWT increased significantly after 4 weeks and was maintained after 8 weeks compared with baseline (P≤.05). Walking speed during the 25FWT and lower-extremity MVIC improved, but were not statistically significant. CONCLUSIONS: Repetitive rhythmic exercise-STAT is feasible, tolerated, and safe for patients with ALS. Repetitive rhythmic exercise-STAT treatment-effect size across a number of ALS-related measures was consistent with improved work capacity and gait function in patients with ALS who are dependent on assistive devices for ambulation. Repetitive rhythmic exercise-STAT should be evaluated further in larger studies to determine the stability of this improved function in relation to the rate of progression of the underlying ALS.

Power wheelchair prescription, utilization, satisfaction, and cost for patients with amyotrophic lateral sclerosis: preliminary data for evidence-based guidelines.

OBJECTIVES: To determine the features most frequently selected in a power wheelchair (PWC), level of satisfaction with the selections, and how often the PWC features are used by patients diagnosed with amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). DESIGN: Internally generated questionnaire. SETTING: An ALS/Muscular Dystrophy Association center. PARTICIPANTS: Convenience sample of current patients (N=45) of our clinic with ALS/MND who are PWC users (men, n=27; women, n=18; age range, 27-85 y). INTERVENTION: Self-administered survey. MAIN OUTCOME MEASURE: Thirty-two patients completed a 31-question survey investigating patients' patterns of selection, satisfaction, and frequency of PWC use; technical and psychometric influences; and other aspects of decision-making processes that patients experience before, during, and after acquiring a PWC. RESULTS: Ninety percent of respondents received their evaluations at a multidisciplinary ALS clinic, 1 via the Department of Veterans Affairs, and 1 was unknown. Sixty-six percent of patients thought the chair evaluation was timed correctly, and 19% wished they had started sooner. Forty-five percent of people were able to walk a few steps, and 55% were able to stand when their chairs arrived. When they first received the chair, 79% were satisfied with the overall comfort of the chair, and 86% were satisfied with the ease of use; currently, 69% are satisfied with the overall comfort, and 72% are satisfied with ease of use. There was a statistically significant difference in how patients used their wheelchair features initially and currently in terms of seat elevate and attendant control, but not tilt, recline, and elevating leg rests. The average cost for the power chairs was $26,404 (range, $19,376-$34,311), and the average cost a month is $917. Overall, 88% of respondents said they would get the same type of chair with the same features again, and 81% felt that the chair was a good value for the cost. CONCLUSIONS: We obtained first-hand knowledge from 32 patients with ALS/MND who are current PWC users on their use and satisfaction with their PWCs from initial to current use. Based on this survey, patients with ALS/MND seen for their wheelchair evaluation with experienced clinicians exhibit high use and satisfaction with their PWCs.

Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity on T1W Magnetic Resonance Imaging in Adults With Dysferlinopathy.

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of <15 years there was a trend toward greater fatty replacement in the muscles of the thigh. These findings define key muscles involved in the exercise-phenotype effect that has previously been observed only clinically in dysferlinopathy and support recommendations that pre-symptomatic patients should avoid very intensive exercise.

The Clinical Outcome Study for dysferlinopathy: An international multicenter study.

OBJECTIVE: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy. METHODS: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments. RESULTS: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies. CONCLUSIONS: These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.