Clinical Outcome Study Of Dysferlinopathy Research Articles

Magnetic resonance imaging-based criteria to differentiate dysferlinopathy from other genetic muscle diseases

The identification of disease-characteristic patterns of muscle fatty replacement in magnetic resonance imaging (MRI) is helpful for diagnosing neuromuscular diseases. In the Clinical Outcome Study of Dysferlinopathy, eight diagnostic rules were described based on MRI findings. Our aim is to confirm that they are useful to differentiate dysferlinopathy (DYSF) from other genetic muscle diseases (GMD). The rules were applied to 182 MRIs of dysferlinopathy patients and 1000 MRIs of patients with 10 other GMD. We calculated sensitivity (S), specificity (Sp), positive and negative predictive values (PPV/NPV) and accuracy (Ac) for each rule. Five of the rules were more frequently met by the DYSF group. Patterns observed in patients with FKRP, ANO5 and CAPN3 myopathies were similar to the DYSF pattern, whereas patterns observed in patients with OPMD, laminopathy and dystrophinopathy were clearly different. We built a model using the five criteria more frequently met by DYSF patients that obtained a S 95.9%, Sp 46.1%, Ac 66.8%, PPV 56% and NPV 94% to distinguish dysferlinopathies from other diseases. Our findings support the use of MRI in the diagnosis of dysferlinopathy, but also identify the need to externally validate “disease-specific” MRI-based diagnostic criteria using MRIs of other GMD patients.

P281 Quality of life in adults with dysferlinopathy: international clinical outcome study of dysferlinopathy

P281 Quality of life in adults with dysferlinopathy: international clinical outcome study of dysferlinopathy

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.

P.164 Clinical outcome study of dysferlinopathy 2: Characterising involvement of the intrinsic muscles of the hand in LGMDR2

Progressive weakness of the intrinsic muscles of the hand is an under-recognized and -reported in LGMDR2/2B but has significant impact on the functional ability of the hand. The Jain Foundation Clinical Outcome Study of dysferlinopathy (COS2) is an international 2-year natural history study of patients with LGMDR2/2B with the aim to characterise disease progression and determine most appropriate clinical outcome assessments. COS2 includes an assessment of the hand with bilateral manual muscle testing (MMT) and dominant hand only testing of pinch and grip strength using a CITEC hand held dynamometer (HHD). Here we describe the characteristics of hand strength in the COS2 cohort using MMT and HHD. 92 COS2 participants with complete MMT and HHD data at their baseline visit were included in the analysis. HHM grip and pinch strength was performed on the dominant hand and includes the maximum of three trials. MMT scores and HHM values were compared between males and females using a Wilcoxon rank sum test. The correlation between MMT scores and HHM values and age at the study visit were calculated using a Spearman correlation. There were no significant differences between male and female subjects on any hand function test. The flexor digitorum profundus muscle group was most affected with a median MMT grade of 4/5. The flexor digitorum superficialis muscle was less involved with a median MMT of 5-/5. At the thumb, the flexor policis longus was the most affected muscle with a median MMT of 4/5. Dorsal interossei muscles were well preserved. Grip HHD was significantly correlated with age (p=.01). Future work will examine the longitudinal change in the function of the hand and relationship to Performance of Upper limb and motor function as measured by the North Star Assessment for Limb girdle type muscular dystrophies. This is the first study to characterise the function of the hand in LGMDR2 and indicates assessment of the hand should be included as part of the clinical review of patients with LGMDR2.

P.167 Clinical outcome study of dysferlinopathy: gait analysis of siblings and phenotype variation

Patients with limb girdle muscular dystrophy (LGMD) R2/2B, caused by mutations in the <i>DYSF</i> gene, have a distinct gait pattern, although this has not been characterised with instrumented gait analysis. In the Jain Foundation Clinical Outcome Study of dysferlinopathy (COS2, http://www.jain-foundation.org/dysferlinoutcomestudy), we are investigating the utility of instrumented gait analysis as a novel clinical biomarker. Patients with LGMDR2 have variability in the presentation of muscle weakness and rate of progression, even within family members. In a pair of siblings with LGMDR2, we conducted gait analysis at two points, six months apart when barefoot and shod. The aim was to quantify gait in siblings with LGMDR2 and evaluate temporospatial parameters changes over six months. Two COSII patients, a male aged 30, and his younger sister aged 27, completed gait analysis at baseline and six-month visits using an instrumented walkway (GAITRite, 240Hz). Patients were asked to walk at a comfortable walking speed when barefoot and shod, and to walk fast when shod only. Temporospatial characteristics including gait velocity, step length, step width, stance and swing duration were extracted. Barefoot gait velocities at baseline were similar between siblings with the male walking at 1.16m/s and his sister at 1.20m/s, however the male sibling walked with a step width double that of his sister. Functionally the male had a more severe disease presentation, with a North Star assessment for limb girdle type muscular dystrophy score of 28/54 at baseline, and the female 42/54. At baseline, both siblings had capacity to increase shod walking speed when asked to walk fast; by 25% for the male and 47% for the female sibling. At six months when shod, gait analysis determined very small changes (<5%) in walking speed, step length, stance time in both siblings. However, step width increased by 12% in the male subject. Gait analysis provides detailed evaluation of temporospatial parameters and captures differences across siblings and walking conditions.

P.166 Clinical outcome study of dysferlinopathy: The impact of lower limb orthoses on gait- a longitudinal single case study

Patients with limb girdle muscular dystrophy, LGMDR2/2B, caused by mutations in the <i>DYSF</i> gene, have a distinct gait pattern and may be prescribed Ankle Foot Orthosis (AFOs) to assist walking. However, there are few studies investigating the efficacy of orthoses in LGMD. In the Jain Foundation clinical outcome study for dysferlinopathy II (COSII, http://www.jain-foundation.org/dysferlinoutcomestudy), we are investigating the utility of instrumented gait analysis as a novel clinical biomarker. The aim of this study was to examine the temporospatial gait parameters of a 30-year-old male with LGMDR2, when walking shod, with and without a pair of silicon AFOs. The patient completed gait analysis at baseline and six-month visits using an instrumented walkway, the GAITRite, 240Hz. Temporospatial characteristics including gait velocity, step length, step width, stance and swing duration were extracted. The differences between walking with and without the AFO were examined at each time point and longitudinally. At baseline, when wearing the AFOs, there was negligible impact on walking speed, step length, stance time compared to shod walking without AFOs (<3% difference between walking conditions). Step width increased by 25% when wearing the AFOs. At six months, his shod walking speed and step length demonstrated little change (<5%), but step width increased by 12% and double limb support increased by 5%. When wearing the AFOs at six months, and compared to shod walking, walking speed and step length increased by <5%, double limb support reduced by 6% and step width increased by 11%. The patient reported at both time points that he wouldn't walk outside the home without wearing the AFO. This study has demonstrated that AFOs influenced gait outcomes relating to dynamic balance control and stability. Although only minimal changes were observed when wearing the AFO at baseline, substantial improvements in walking were observed when wearing the AFO at six months. Further work in a larger number of patients will help to understand indications for AFO prescription in LGMDR2 and other LGMDs.

FP.34 Clinical outcome study of dysferlinopathy: correlation between MRI fat fraction in lower limbs and clinical outcome assessments over a 3-year period

The Jain Foundation COS of dysferlinopathy is an international study in genetically confirmed dysferlinopathy patients, with the aim to identify relevant outcome measures to facilitate trial readiness. Due to its wide range of clinical phenotypes and rates of disease progression, an objective marker to quantify disease progression would be ideal. We assessed the application of quantitative magnetic resonance imaging (MRI) as a prognostic tool for these patients. Our aim is to establish whether there is a correlation between fat fraction (FF) in thigh and/or lower leg muscles and clinical outcome assessments (COA) when comparing baseline (BL) values and changes from BL to year 1 (Y1) and to year 3 (Y3). We selected 84 patients from COS1 who had a Dixon MRI of the lower limbs (LL) and at least one of the following COA: time to rise from floor (RFF), time to climb / descend 4 steps (4SC/4SD), time up and go (TUG), time to walk 10m (10MWT), 6 min walk test (6MWT) and North Star Assessment for limb girdle type muscular dystrophy (NSAD) score. Spearman correlation (rs) was performed using SPSS statistics, p value 0.05. We found a significant correlation at BL between LL FF values and all COA, with the highest rs between thigh FF and NSAD (-.675) and 6MWT (-.665). We didn't find any correlations between changes in FF between BL and Y1 and changes in COA during that same period, but we did observe a significant correlation with changes in TUG (.445) and 4SC (.41) between BL and Y3. We observed a significant correlation between changes in thigh FF between BL and Y3 and changes in TUG (.706), RFF (.607), 4SC (.545) and NSAD[HR1] (-.374). No correlations were found when analysing changes in lower legs FF and COA. Our results show that changes in FF of the thigh muscles over one year could predict functional changes at a later stage, in a three-year period, suggesting that MRI could be used to identify dysferlinopathy patients at risk of more severe disease progression in routine clinical care.

P.162 Clinical outcome study of dysferlinopathy: Performance of upper limb entry item to predict forced vital capacity in dysferlinopathy (LGMDR2)

P.162 Clinical outcome study of dysferlinopathy: Performance of upper limb entry item to predict forced vital capacity in dysferlinopathy (LGMDR2)

P.165 Clinical outcome study of dysferlinopathy: Lower limb water T2 predicts functional decline in patients with dysferlinopathy

P.165 Clinical outcome study of dysferlinopathy: Lower limb water T2 predicts functional decline in patients with dysferlinopathy

Deep phenotyping of an international series of patients with late-onset dysferlinopathy.

To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients. Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited. Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range30-57) years and most patients showed a limb-girdle (n=26) or distal (n=10) phenotype. However, compared with EO dysferlinopathy patients (n=48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p=0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p=0.01), and higher NSAD (p=0.008) and ACTIVLIM scores (p=0.016). Loss of ambulation in LO patients tended to occur later (23±4.4years after disease onset vs. 16.3±6.8years; p=0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p=0.021), no differences in dysferlin protein expression were found on Western blot. Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.

P.185The clinical outcome study for dysferlinopathy: quantitative MRI and physiotherapy outcomes to capture disease progression

The Jain Clinical Outcome Study of Dysferlinopathy (COS) is an international study that recruited 197 patients with genetically confirmed dysferlinopathy. COS aims to identify the most relevant outcome measures for this heterogeneous degenerative disease to facilitate trial readiness. We report findings in a subset of 49 subjects at Newcastle and Paris. Lower limbs were imaged using gradient-echo 3-point Dixon with site-specific optimized echo times (Newcastle 3T Philips: E1/TE2/TE3 = 3.45/4.6/5.75 ms; Paris 3T Siemens: TE1/TE2/TE3=2.75/3.95/5.15 ms). Thigh and leg muscles were manually delineated to obtain mean Fat Fraction (FF) value per muscle per year. We examined the relationship between change in functional motor performance as measured by the North Star for Dysferlinopathy (NSAD) and weighted FF per segment (one for leg and one for thigh). We stratified the cohort at baseline using the NSAD to identify different trajectories of disease progression. Weighted FF at baseline does not predict clinical severity, with overlap between mild, moderate and severe disease. At above 60% FF, most of the subset are noted to have severe disease. Below 10% FF, most are defined clinically as mild. There is considerable overlap between severity groupings using a mean FF for weighted segments. A more detailed analysis evaluating individual muscles will be presented. After three years, a rapid clinical decline in motor ability measured by NSAD was observed in 13 subjects compared to whole COS cohort average change. Analysis of 2 and 3 year MRI data is ongoing. We will report on the further examination of the cohort 's FF change over three years and the interaction between pathology on MRI and motor performance. Progression in dysferlinopathy can be demonstrated using functional outcomes measured by Physiotherapists and quantitative MRI over three years. The relationship appears to be non-linear between muscle pathology and functional motor performance.

P.171A clinical outcome study for dysferlinopathy: biobanking samples collected through a collaborative international multisite study

The Jain clinical outcome study (COS) is an international study-evaluating patients with genetically confirmed dysferlinopathy. COS aims to develop understanding of disease progression and support future scientific research 197 patients were recruited across 15 sites and in 8 countries. All sites completed year 3 visits. Further to the COS data collection allowing the characterization of the disease (results reported elsewhere), patients also had the option to donate biobank samples to the MRC biobank for rare and neuromuscular diseases curated at Newcastle. Standardised protocols for collection, processing and shipment were provided to each site. Blood for DNA and RNA was collected at one time point only. Plasma and serum were collected annually. Patients could opt to provide a skin sample to generate fibroblast cell lines. Samples have been shipped to the Newcastle MRC Centre Biobank for rare and neuromuscular disease. 12 sites of 15 sites provided samples. 97% patients opted to donate blood samples. 43% patients opted to donate skin samples for fibroblasts. Samples currently at Newcastle are as follows: blood for RNA n164; DNA n161; baseline plasma n147; year 1 plasma n151; year 2 plasma n134; year 3 plasma n132 (pending final shipments); baseline serum n145; year 1 serum n150; year 2 serum n133; year 3 serum n87 (pending final shipments); limited year 4 and year 5 samples are also available. This is a valuable resource for scientists worldwide to develop understanding of potential biomarkers for dysferlinopathies necessary to support design of future clinical trials. Samples can be requested from the Newcastle MRC center for rare and neuromuscular disease. The Jain COS steering group will consider requests for study data to support the analysis of results generated by research using these samples. The COS study has been extended for two further years. COS2 will also collect urine across all participating sites.

Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

ObjectiveTo assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.MethodsOne 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.ResultsThe 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.ConclusionCertain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.ClinicalTrials.gov identifier:NCT01676077.

D02 - Is cardiac dysfunction a feature of dysferlinopathy? Data from the Clinical Outcome Study of Dysferlinopathy

D02 - Is cardiac dysfunction a feature of dysferlinopathy? Data from the Clinical Outcome Study of Dysferlinopathy

D03 - Clinical Outcome Study of Dysferlinopathy: what are the best outcome measures for dysferlinopathy patients?

D03 - Clinical Outcome Study of Dysferlinopathy: what are the best outcome measures for dysferlinopathy patients?

The clinical outcome study of dysferlinopathy: Muscle MRI pattern at baseline and longitudinal changes over one year

Background: The Clinical Outcome Study in Dysferlinopathy is an international natural history study. 203 genetically confirmed adults have been recruited across 15 sites in 8 countries.

P.161 - North Star Assessment for dysferlinopathy: Longitudinal performance in the clinical outcome study of dysferlinopathy

The North Star Assessment for dysferlinopathy (NSAD) was developed to measure motor performance in ambulant and non-ambulant subjects as part of the clinical outcome study of dysferlinopathy. The clinical outcome study of dysferlinopathy is an international study evaluating 203 patients with genetically confirmed dysferlinopathy with the intention of improving trial readiness in dysferlinopathy. This novel scale comprises clinically relevant items from the adapted North Star Ambulatory Assessment and motor function measure-20. The NSAD was developed following examination of the year 1 data, and was introduced at the year 2 study visit. The scale was reviewed for suitability and robustness using modern psychometric measures (RUMM2030). This Rasch analysis performed on data from 143 individuals at the year 2 visit demonstrated the items of the NSAD represent the construct of motor performance for dysferlinopathy and demonstrate good item fit, logical scoring progression and appropriate targeting as well as measuring ambulant and non-ambulant patients on a single scale. We will describe the longitudinal performance of the NSAD through examination of over 100 available year 3 visit data using modern psychometric measures.

P.437 - Clinical outcome study of dysferlinopathy: what are the best outcome measures for dysferlinopathy patients?

P.437 - Clinical outcome study of dysferlinopathy: what are the best outcome measures for dysferlinopathy patients?

P.160 - Is cardiac dysfunction a feature of dysferlinopathy? Data from the clinical outcome study of dysferlinopathy

P.160 - Is cardiac dysfunction a feature of dysferlinopathy? Data from the clinical outcome study of dysferlinopathy

D12 - Clinical outcome study for dysferlinopathy: Sensitivity of outcome measures over one-year

D12 - Clinical outcome study for dysferlinopathy: Sensitivity of outcome measures over one-year