The Experts below are selected from a list of 726 Experts worldwide ranked by ideXlab platform
U Moore - One of the best experts on this subject based on the ideXlab platform.
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deep phenotyping of an international series of patients with late onset Dysferlinopathy
2021Co-Authors: Gorka Fernandezeulate, Guillaume Bassez, U Moore, Pascal Laforêt, Giorgia Querin, Anthony Behin, Marion Masingue, Sarah Leonardlouis, T Maisonobe, Philippeedouard MerleAbstract:Late‐onset Dysferlinopathy patients show a higher frequency of atypical presentations, including camptocormia, and are less severely affected compared with early‐onset patients. Furthermore, they present less necrosis and inflammation in muscle biopsy.
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assessing Dysferlinopathy patients over three years with a new motor scale
2021Co-Authors: Marni B Jacobs, U Moore, Laura E Rufibach, Jia Feng, Meredoith K James, L Lowes, L Alfano, Michelle Eagle, Robert Muni Lofra, Kristy RoseAbstract: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.
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miyoshi myopathy and limb girdle muscular dystrophy r2 are the same disease
2021Co-Authors: U Moore, Heather Gordish, Jordi Diazmanera, M James, A Mayhew, Michela Guglieri, Roberto Fernandez Torron, Laura E Rufibach, Jia Feng, Andrew M BlamireAbstract:ABSTRACT 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.
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intensive teenage activity is associated with greater muscle hyperintensity on t1w magnetic resonance imaging in adults with Dysferlinopathy
2020Co-Authors: U Moore, M James, A Mayhew, Laura E Rufibach, Marni Jacobs, Roberto Fernandeztorron, Jaume Llauger Rossello, Fiona E Smith, Pierre G Carlier, Andrew M BlamireAbstract: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.
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assessment of disease progression in Dysferlinopathy a 1 year cohort study
2019Co-Authors: U Moore, Jia Feng, Anna Mayhew, K Bettinson, Michelle Eagle, Marni Jacobs, Meredith K James, Roberto Fernandeztorron, Avital Cnaan, Laura E RufibachAbstract: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 Foundation9s 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. ClinicalTrials.gov identifier: NCT01676077.
M James - One of the best experts on this subject based on the ideXlab platform.
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miyoshi myopathy and limb girdle muscular dystrophy r2 are the same disease
2021Co-Authors: U Moore, Heather Gordish, Jordi Diazmanera, M James, A Mayhew, Michela Guglieri, Roberto Fernandez Torron, Laura E Rufibach, Jia Feng, Andrew M BlamireAbstract:ABSTRACT 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.
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intensive teenage activity is associated with greater muscle hyperintensity on t1w magnetic resonance imaging in adults with Dysferlinopathy
2020Co-Authors: U Moore, M James, A Mayhew, Laura E Rufibach, Marni Jacobs, Roberto Fernandeztorron, Jaume Llauger Rossello, Fiona E Smith, Pierre G Carlier, Andrew M BlamireAbstract: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.
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examining longitudinal functional changes in Dysferlinopathy the jain clinical outcome study p5 429
2018Co-Authors: L Lowes, M James, Anna Mayhew, Simone Spuler, L Alfano, Marni Jacobs, Kristi J Jones, John W Day, Diana Bharuchagoebel, Emmanuelle CampanasalortAbstract:Objective: To describe changes in functional outcome measures and muscle strength over a 2 year period in individuals with Dysferlinopathy. Background: Dysferlinopathy, a form of limb girdle muscular dystrophy, clinically presents with a variable spectrum of muscle weakness. The Clinical Outcome Study is an international 3 year natural history study of Dysferlinopathy patients, which aims to gain a better understanding of the disease and to improve clinical trial readiness. Design/Methods: 197 subjects across 15 sites in 8 countries underwent physiotherapy assessments including muscle strength (manual muscle testing, MMT; hand held dynamometry, HHD); and functional performance using the North Star Assessment for Dysferlinopathy (NSAD), Brooke score and Performance of Upper Limb, as well as timed tests (rise from floor, 10 meter walk / run, four stair climb and descend; Timed Up and Go, TUG; Six Minute Walk Distance), and respiratory function testing (forced vital capacity, FVC). Change was defined as significant difference in paired medians by Wilcoxon Signed Rank-Sum test (p Results: Change is captured in this population consistently from baseline to year 1 and from year 1 to year 2 across a range of functional outcome measures. Motor performance assessed by NSAD demonstrated slow but consistent and significant deterioration in scores and confirmed NSAD as a dysferlin specific scale. All timed tests except rise from floor showed significant consistent decline between year 1 and year 2. Muscle groups assessed by HHD showed change, the plantar flexors were the muscles with the highest mean differences (3.14 lbs, SD: 8.22). We detected a mild but significant decrease in FVC (mean difference 0.09L) Conclusions: Progression in Dysferlinopathy can be demonstrated using functional outcomes and dynamometry as measured by Physiotherapists over two years. Change between baseline, year 1 and year 2 were slow but relatively consistent and significant. Results will help to power future clinical trials. Study Supported by: The estimated $4 million USD needed to fund this study is being provided by the Jain Foundation. Disclosure: Dr. Lowes has nothing to disclose. Dr. James has nothing to disclose. Dr. Mayhew has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Jacobs has nothing to disclose. Dr. Spuler has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Bharucha-Goebel has nothing to disclose. Dr. Campana-Salort has nothing to disclose. Dr. Pestronk has nothing to disclose. Dr. Walter has nothing to disclose. Dr. Paradas Lopez has nothing to disclose. Dr. Stojkovic has nothing to disclose. Dr. Mori-Yoshimura has nothing to disclose. Dr. Bravver has nothing to disclose. Dr. Pegoraro has nothing to disclose. Dr. Diaz Manera has nothing to disclose. Dr. Duong has nothing to disclose. Dr. Rose has nothing to disclose. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc. Dr. Bushby has nothing to disclose. Dr. Straub has nothing to disclose.
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teenage exercise is associated with earlier symptom onset in Dysferlinopathy a retrospective cohort study
2018Co-Authors: U Moore, M James, Laura E Rufibach, Anna Mayhew, Michelle Eagle, Marni Jacobs, Roberto Fernandeztorron, Jiji Jang, Plavi Mittal, Avital CnaanAbstract:Dysferlinopathy, an autosomal recessive muscular dystrophy caused by DYSF mutations, demonstrates a variable phenotype and progression rate, with symptom onset ranging from first to eighth decade and some patients requiring wheelchairs for mobility within 10 years, with others remaining minimally affected.1 Dysferlinopathy populations have previously been described as having an unusually high level of presymptomatic sporting ability.2 We hypothesised that this activity could be related to subsequent disease progression and investigated the hypothesis using data from the Jain Foundation’s Clinical Outcomes Study (COS) of 202 patients with Dysferlinopathy.1 Data were used from 182 of the 202 patients enrolled in the Jain COS; 10 dropped out and did not give permission to use their data and 10 did not fully complete the exercise questionnaire. The questionnaire used in the screening visits (online supplementary information) between 6 November 2012 and 19 March 2015 asked about the type, level and frequency of all physical activity prior to symptom onset. Self-reported age of first symptoms, first wheelchair use and full-time wheelchair use was taken from screening questionnaires. Exercises were classified based on metabolic equivalents (METs) as moderate (MET 3–6) or vigorous (MET >6) (online supplementary table 1).3 Participants were coded, based on the maximum frequency of activity reported between ages 10 and 18 years, as 0—no physical activity; 1—vigorous activity occasionally/monthly, or moderate activity once weekly; 2— moderate activity multiple times per week or vigorous activity once weekly; and 3—vigorous activity multiple times per week. ### Supplementary file 1 [jnnp-2017-317329-SP1.pdf] ### Statistical analysis Age of symptom onset was compared by analysis of variance (ANOVA) with least squares means for individual group differences. Risk of symptom onset, occasional wheelchair use and full-time wheelchair requirement over time were compared for exercise groups 1, 2 and 3 against group 0 using Cox proportional hazards regression. Proportional hazards assumption was violated …
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p71 international clinical outcomes study in Dysferlinopathy cos results of screening questionnaires in uk patients
2014Co-Authors: E Harris, M James, M Eagle, Anna Mayhew, K Bettinson, K BushbyAbstract:Mutations in dysferlin cause a variety of phenotypes collectively known as dysferlinopathies, including Limb Girdle Muscular Dystrophy type 2B and Myoshi Myopathy. Although there is currently no treatment for dysferlinopathies there is a need to develop clinically validated outcome measures in Dysferlinopathy in preparation for future clinical trials. The International Clinical Outcomes Study for Dysferlinopathy (COS) is a multicentre international study, funded by The Jain Foundation and sponsored by Newcastle upon Tyne NHS Foundation Trust, which aims to develop and validate clinical outcome measures in addition to collecting natural history data. The recruitment target of 150 patients has now been successfully achieved, with a total of 193 patients recruited in 14 centres worldwide, including 38 UK patients. Data will be collected over 3 years, including physiotherapy and medical assessments, MRI and questionnaires. In this poster we present data from screening questionnaires, including mutations identified and patient-reported details of disease presentation in all 38 UK patients. In total 49 different mutations were identified. Mean age at symptom onset was 22.3 years and mean time to subsequent diagnosis was 6.1 years. Polymyositis was initially incorrectly diagnosed in 6/38 patients. Lower limbs were the most common first affected area (23/38), and muscle weakness the most frequent first symptom (20/38). This data confirms that dysferlinopathies primarily present in young adulthood, often initially with lower limb symptoms, and are associated with significant allelic heterogeneity. Completion of this study and subsequent analyses will enhance our understanding of the natural history this variable condition.
Laura E Rufibach - One of the best experts on this subject based on the ideXlab platform.
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assessing Dysferlinopathy patients over three years with a new motor scale
2021Co-Authors: Marni B Jacobs, U Moore, Laura E Rufibach, Jia Feng, Meredoith K James, L Lowes, L Alfano, Michelle Eagle, Robert Muni Lofra, Kristy RoseAbstract: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.
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miyoshi myopathy and limb girdle muscular dystrophy r2 are the same disease
2021Co-Authors: U Moore, Heather Gordish, Jordi Diazmanera, M James, A Mayhew, Michela Guglieri, Roberto Fernandez Torron, Laura E Rufibach, Jia Feng, Andrew M BlamireAbstract:ABSTRACT 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.
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intensive teenage activity is associated with greater muscle hyperintensity on t1w magnetic resonance imaging in adults with Dysferlinopathy
2020Co-Authors: U Moore, M James, A Mayhew, Laura E Rufibach, Marni Jacobs, Roberto Fernandeztorron, Jaume Llauger Rossello, Fiona E Smith, Pierre G Carlier, Andrew M BlamireAbstract: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.
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assessment of disease progression in Dysferlinopathy a 1 year cohort study
2019Co-Authors: U Moore, Jia Feng, Anna Mayhew, K Bettinson, Michelle Eagle, Marni Jacobs, Meredith K James, Roberto Fernandeztorron, Avital Cnaan, Laura E RufibachAbstract: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 Foundation9s 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. ClinicalTrials.gov identifier: NCT01676077.
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teenage exercise is associated with earlier symptom onset in Dysferlinopathy a retrospective cohort study
2018Co-Authors: U Moore, M James, Laura E Rufibach, Anna Mayhew, Michelle Eagle, Marni Jacobs, Roberto Fernandeztorron, Jiji Jang, Plavi Mittal, Avital CnaanAbstract:Dysferlinopathy, an autosomal recessive muscular dystrophy caused by DYSF mutations, demonstrates a variable phenotype and progression rate, with symptom onset ranging from first to eighth decade and some patients requiring wheelchairs for mobility within 10 years, with others remaining minimally affected.1 Dysferlinopathy populations have previously been described as having an unusually high level of presymptomatic sporting ability.2 We hypothesised that this activity could be related to subsequent disease progression and investigated the hypothesis using data from the Jain Foundation’s Clinical Outcomes Study (COS) of 202 patients with Dysferlinopathy.1 Data were used from 182 of the 202 patients enrolled in the Jain COS; 10 dropped out and did not give permission to use their data and 10 did not fully complete the exercise questionnaire. The questionnaire used in the screening visits (online supplementary information) between 6 November 2012 and 19 March 2015 asked about the type, level and frequency of all physical activity prior to symptom onset. Self-reported age of first symptoms, first wheelchair use and full-time wheelchair use was taken from screening questionnaires. Exercises were classified based on metabolic equivalents (METs) as moderate (MET 3–6) or vigorous (MET >6) (online supplementary table 1).3 Participants were coded, based on the maximum frequency of activity reported between ages 10 and 18 years, as 0—no physical activity; 1—vigorous activity occasionally/monthly, or moderate activity once weekly; 2— moderate activity multiple times per week or vigorous activity once weekly; and 3—vigorous activity multiple times per week. ### Supplementary file 1 [jnnp-2017-317329-SP1.pdf] ### Statistical analysis Age of symptom onset was compared by analysis of variance (ANOVA) with least squares means for individual group differences. Risk of symptom onset, occasional wheelchair use and full-time wheelchair requirement over time were compared for exercise groups 1, 2 and 3 against group 0 using Cox proportional hazards regression. Proportional hazards assumption was violated …
Anna Mayhew - One of the best experts on this subject based on the ideXlab platform.
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assessment of disease progression in Dysferlinopathy a 1 year cohort study
2019Co-Authors: U Moore, Jia Feng, Anna Mayhew, K Bettinson, Michelle Eagle, Marni Jacobs, Meredith K James, Roberto Fernandeztorron, Avital Cnaan, Laura E RufibachAbstract: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 Foundation9s 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. ClinicalTrials.gov identifier: NCT01676077.
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examining longitudinal functional changes in Dysferlinopathy the jain clinical outcome study p5 429
2018Co-Authors: L Lowes, M James, Anna Mayhew, Simone Spuler, L Alfano, Marni Jacobs, Kristi J Jones, John W Day, Diana Bharuchagoebel, Emmanuelle CampanasalortAbstract:Objective: To describe changes in functional outcome measures and muscle strength over a 2 year period in individuals with Dysferlinopathy. Background: Dysferlinopathy, a form of limb girdle muscular dystrophy, clinically presents with a variable spectrum of muscle weakness. The Clinical Outcome Study is an international 3 year natural history study of Dysferlinopathy patients, which aims to gain a better understanding of the disease and to improve clinical trial readiness. Design/Methods: 197 subjects across 15 sites in 8 countries underwent physiotherapy assessments including muscle strength (manual muscle testing, MMT; hand held dynamometry, HHD); and functional performance using the North Star Assessment for Dysferlinopathy (NSAD), Brooke score and Performance of Upper Limb, as well as timed tests (rise from floor, 10 meter walk / run, four stair climb and descend; Timed Up and Go, TUG; Six Minute Walk Distance), and respiratory function testing (forced vital capacity, FVC). Change was defined as significant difference in paired medians by Wilcoxon Signed Rank-Sum test (p Results: Change is captured in this population consistently from baseline to year 1 and from year 1 to year 2 across a range of functional outcome measures. Motor performance assessed by NSAD demonstrated slow but consistent and significant deterioration in scores and confirmed NSAD as a dysferlin specific scale. All timed tests except rise from floor showed significant consistent decline between year 1 and year 2. Muscle groups assessed by HHD showed change, the plantar flexors were the muscles with the highest mean differences (3.14 lbs, SD: 8.22). We detected a mild but significant decrease in FVC (mean difference 0.09L) Conclusions: Progression in Dysferlinopathy can be demonstrated using functional outcomes and dynamometry as measured by Physiotherapists over two years. Change between baseline, year 1 and year 2 were slow but relatively consistent and significant. Results will help to power future clinical trials. Study Supported by: The estimated $4 million USD needed to fund this study is being provided by the Jain Foundation. Disclosure: Dr. Lowes has nothing to disclose. Dr. James has nothing to disclose. Dr. Mayhew has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Jacobs has nothing to disclose. Dr. Spuler has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Bharucha-Goebel has nothing to disclose. Dr. Campana-Salort has nothing to disclose. Dr. Pestronk has nothing to disclose. Dr. Walter has nothing to disclose. Dr. Paradas Lopez has nothing to disclose. Dr. Stojkovic has nothing to disclose. Dr. Mori-Yoshimura has nothing to disclose. Dr. Bravver has nothing to disclose. Dr. Pegoraro has nothing to disclose. Dr. Diaz Manera has nothing to disclose. Dr. Duong has nothing to disclose. Dr. Rose has nothing to disclose. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc. Dr. Bushby has nothing to disclose. Dr. Straub has nothing to disclose.
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teenage exercise is associated with earlier symptom onset in Dysferlinopathy a retrospective cohort study
2018Co-Authors: U Moore, M James, Laura E Rufibach, Anna Mayhew, Michelle Eagle, Marni Jacobs, Roberto Fernandeztorron, Jiji Jang, Plavi Mittal, Avital CnaanAbstract:Dysferlinopathy, an autosomal recessive muscular dystrophy caused by DYSF mutations, demonstrates a variable phenotype and progression rate, with symptom onset ranging from first to eighth decade and some patients requiring wheelchairs for mobility within 10 years, with others remaining minimally affected.1 Dysferlinopathy populations have previously been described as having an unusually high level of presymptomatic sporting ability.2 We hypothesised that this activity could be related to subsequent disease progression and investigated the hypothesis using data from the Jain Foundation’s Clinical Outcomes Study (COS) of 202 patients with Dysferlinopathy.1 Data were used from 182 of the 202 patients enrolled in the Jain COS; 10 dropped out and did not give permission to use their data and 10 did not fully complete the exercise questionnaire. The questionnaire used in the screening visits (online supplementary information) between 6 November 2012 and 19 March 2015 asked about the type, level and frequency of all physical activity prior to symptom onset. Self-reported age of first symptoms, first wheelchair use and full-time wheelchair use was taken from screening questionnaires. Exercises were classified based on metabolic equivalents (METs) as moderate (MET 3–6) or vigorous (MET >6) (online supplementary table 1).3 Participants were coded, based on the maximum frequency of activity reported between ages 10 and 18 years, as 0—no physical activity; 1—vigorous activity occasionally/monthly, or moderate activity once weekly; 2— moderate activity multiple times per week or vigorous activity once weekly; and 3—vigorous activity multiple times per week. ### Supplementary file 1 [jnnp-2017-317329-SP1.pdf] ### Statistical analysis Age of symptom onset was compared by analysis of variance (ANOVA) with least squares means for individual group differences. Risk of symptom onset, occasional wheelchair use and full-time wheelchair requirement over time were compared for exercise groups 1, 2 and 3 against group 0 using Cox proportional hazards regression. Proportional hazards assumption was violated …
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the international clinical outcome study in Dysferlinopathy
2017Co-Authors: Roula Ghaoui, U Moore, Jordi Diazmanera, James Meredith, Anna Mayhew, Roberto Fernandeztorron, Fiona E Smith, Kristi J Jones, Kate Bushby, Volker StraubAbstract:Objectives The Jain Clinical Outcome Study (COS) is the largest international natural history study in patients with genetically confirmed Dysferlinopathy. We recruited 203 participants across 15 sites in 8 countries. The aim of the study was to analyse longitudinal clinical data over the first year of the study, describe the muscle MRI pattern and longitudinal changes in quantitative muscle MRI. Methods An adapted North Star Ambulatory Assessment (aNSAA), MFM-20 and timed tests (rise from floor, 10 metre walk/run, four stair climb and descend, Timed Up and Go (TUG) and 6MWD) were completed at baseline, six months and year 1. A semi-quantitative MRI analysis was performed on T1-weighted axial sequences at baseline in 182 patients using the Mercuri scale modified by Fisher. Hierarchical analysis was performed to define the selective pattern of involvement. Results of the T1-weighted were correlated with appropriate functional tests. Quantitative muscle MRI is made annually based on fat/water separation (Dixon techniques) and muscle water T2 mapping (Multi-Slice Multi-Echo, MSME). Results aNSAA, MFM-20, 10m walk test, and TUG demonstrated consistent deterioration in scores or time taken over each 6 months window, although variation in the change scores was wide. The rise from floor, stair climb and stair descend detected significant change over one year. On muscle MRI scans, gastrocnemius medialis and soleus were most frequently affected. A similar pattern of involvement was identified regardless of clinical phenotype. The increase of fat replacement on MRI correlated positively with disease duration and functional tests. MRI fat fraction showed significant change over a year. However water T2 did not change significantly. Conclusions Functional tests showed changes at 6 months and 1 year. Semi-quantitative MRI can help define the muscle pattern of fat replacement. We detected significant changes in thigh and calf muscles using muscle MRI quantitative Dixon sequences.
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p71 international clinical outcomes study in Dysferlinopathy cos results of screening questionnaires in uk patients
2014Co-Authors: E Harris, M James, M Eagle, Anna Mayhew, K Bettinson, K BushbyAbstract:Mutations in dysferlin cause a variety of phenotypes collectively known as dysferlinopathies, including Limb Girdle Muscular Dystrophy type 2B and Myoshi Myopathy. Although there is currently no treatment for dysferlinopathies there is a need to develop clinically validated outcome measures in Dysferlinopathy in preparation for future clinical trials. The International Clinical Outcomes Study for Dysferlinopathy (COS) is a multicentre international study, funded by The Jain Foundation and sponsored by Newcastle upon Tyne NHS Foundation Trust, which aims to develop and validate clinical outcome measures in addition to collecting natural history data. The recruitment target of 150 patients has now been successfully achieved, with a total of 193 patients recruited in 14 centres worldwide, including 38 UK patients. Data will be collected over 3 years, including physiotherapy and medical assessments, MRI and questionnaires. In this poster we present data from screening questionnaires, including mutations identified and patient-reported details of disease presentation in all 38 UK patients. In total 49 different mutations were identified. Mean age at symptom onset was 22.3 years and mean time to subsequent diagnosis was 6.1 years. Polymyositis was initially incorrectly diagnosed in 6/38 patients. Lower limbs were the most common first affected area (23/38), and muscle weakness the most frequent first symptom (20/38). This data confirms that dysferlinopathies primarily present in young adulthood, often initially with lower limb symptoms, and are associated with significant allelic heterogeneity. Completion of this study and subsequent analyses will enhance our understanding of the natural history this variable condition.
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treatment of Dysferlinopathy with deflazacort a double blind placebo controlled clinical trial
2013Co-Authors: Maggie C Walter, Simone Thiele, J Schessl, Herbert Schreiber, Karlheinz Reiners, Peter Reilich, Clemens Mullerreible, Matthias Vorgerd, Wolfram Kress, Peter UrbanAbstract:Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). We assessed the one-year-natural course of Dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined Dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. During one year of natural course, muscle strength declined about 2% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with Dysferlinopathy, who may be often misdiagnosed as polymyositis. This clinical trial was registered at http://www.ClincalTrials.gov , identifier: NCT00527228 , and was always freely accessible to the public.