المؤلفون: Mary Chesshyre, Deborah Ridout, Yasumasa Hashimoto, Yoko Ookubo, Silvia Torelli, Kate Maresh, Valeria Ricotti, Lianne Abbott, Vandana Ayyar Gupta, Marion Main, Giulia Ferrari, Anna Kowala, Yung‐Yao Lin, Francesco Saverio Tedesco, Mariacristina Scoto, Giovanni Baranello, Adnan Manzur, Yoshitsugu Aoki, Francesco Muntoni

المصدر: Journal of Cachexia, Sarcopenia and Muscle, Vol 13, Iss 2, Pp 1360-1372 (2022)

مصطلحات موضوعية: Duchenne muscular dystrophy, Isoform, Motor function, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695

الوصف: Abstract Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full‐length Dp427 is the primary dystrophin isoform expressed in muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS comorbidities is well known, relationships between mutations expected to disrupt Dp140 and Dp71 and motor outcomes are not. Methods Functional outcome data from 387 DMD boys aged 4–15 years were subdivided by DMD mutation expected effects on dystrophin isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n = 201); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 152); and Group 3 (Dp427/Dp140/Dp71 absent, n = 34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10 m walk/run velocities and rise time velocities were explored using regression analysis. Western blot analysis was used to study Dp427, Dp140 and Dp71 production in myogenic cells (control and DMD human), control skeletal muscle, DMD skeletal muscle from the three isoform groups and cerebral cortex from mice (wild‐type and DMD models). Grip strength and rotarod running test were studied in wild‐type mice and DMD mouse models. DMD mouse models were mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD‐null (lacking all isoforms). Results In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in Group 3 than Group 1 (P

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2190-5991Test; https://doaj.org/toc/2190-6009Test

الوصول الحر: https://doaj.org/article/f0e9fb8a39b84e67b80fc0751fc0cab9Test

المؤلفون: Vandana Ayyar Gupta, Jacqueline M Pitchforth, Joana Domingos, Deborah Ridout, Mario Iodice, Catherine Rye, Mary Chesshyre, Amy Wolfe, Victoria Selby, Anna Mayhew, Elena S Mazzone, Valeria Ricotti, Jean-Yves Hogrel, Erik H Niks, Imelda de Groot, Laurent Servais, Volker Straub, Eugenio Mercuri, Adnan Y Manzur, Francesco Muntoni, iMDEX Consortium and the U.K. NorthStar Clinical Network

المصدر: PLoS ONE, Vol 18, Iss 4, p e0283669 (2023)

مصطلحات موضوعية: Medicine, Science

الوصف: The North Star ambulatory assessment (NSAA) is a functional motor outcome measure in Duchenne muscular dystrophy (DMD), widely used in clinical trials and natural history studies, as well as in clinical practice. However, little has been reported on the minimal clinically important difference (MCID) of the NSAA. The lack of established MCID estimates for NSAA presents challenges in interpreting the significance of the results of this outcome measure in clinical trials, natural history studies and clinical practice. Combining statistical approaches and patient perspectives, this study estimated MCID for NSAA using distribution-based estimates of 1/3 standard deviation (SD) and standard error of measurement (SEM), an anchor-based approach, with six-minute walk distance (6MWD) as the anchor, and evaluation of patient and parent perception using participant-tailored questionnaires. The MCID for NSAA in boys with DMD aged 7 to 10 years based on 1/3 SD ranged from 2.3-2.9 points, and that on SEM ranged from 2.9-3.5 points. Anchored on the 6MWD, the MCID for NSAA was estimated as 3.5 points. When the impact on functional abilities was considered using participant response questionnaires, patients and parent perceived a complete loss of function in a single item or deterioration of function in one to two items of the assessment as an important change. Our study examines MCID estimates for total NSAA scores using multiple approaches, including the impact of patient and parent perspective on within scale changes in items based on complete loss of function and deterioration of function, and provides new insight on evaluation of differences in these widely used outcome measure in DMD.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/21885a505e0b4afe9114a65409bbe906Test

المؤلفون: Georgia Stimpson, Sarah Raquq, Mary Chesshyre, Mary Fewtrell, Deborah Ridout, Anna Sarkozy, Adnan Manzur, Vandana Ayyar Gupta, Ramona De Amicis, Francesco Muntoni, Giovanni Baranello, the NorthStar Network

المصدر: Orphanet Journal of Rare Diseases, Vol 17, Iss 1, Pp 1-11 (2022)

مصطلحات موضوعية: Duchenne muscular dystrophy, Growth, Isoforms, Glucocorticoids, Prednisolone, Deflazacort, Medicine

الوصف: Abstract Objectives The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5–12 years with Duchenne muscular dystrophy (DMD). Background We considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003–2020) on one of five regimes: “GC naïve”, “deflazacort daily” (DD), “deflazacort intermittent” (DI), “prednisolone daily” (PD) and “prednisolone intermittent” (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90). Results The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI − 0.30, − 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation. Conclusion These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1750-1172Test

الوصول الحر: https://doaj.org/article/9839128fa22d4b0f98c61ed228c910e7Test

المؤلفون: Georgia Stimpson, Mary Chesshyre, Giovanni Baranello, Francesco Muntoni

المصدر: Frontiers in Genetics, Vol 12 (2021)

مصطلحات موضوعية: spinal muscular atrophy, duchenne and becker muscular dystrophy, translational research, trial design, inclusion criteria, matching criteria, Genetics, QH426-470

الوصف: Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), two of the most common, child onset, rare neuromuscular disorders, present a case study for the translation of preclinical research into clinical work. Over the past decade, well-designed clinical trials and innovative methods have led to the approval of several novel therapies for SMA and DMD, with many more in the pipeline. This review discusses several features that must be considered during trial design for neuromuscular diseases, as well as other rare diseases, to maximise the possibility of trial success using historic examples. These features include well-defined inclusion criteria, matching criteria, alternatives to placebo-controlled trials and the selection of trial endpoints. These features will be particularly important in the coming years as the investigation into innovative therapy approaches for neuromuscular diseases continues.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fgene.2021.759994/fullTest; https://doaj.org/toc/1664-8021Test

الوصول الحر: https://doaj.org/article/3eef4adc91d2442cbee9b941935f8fa9Test

المؤلفون: Giorgia Coratti, Marika Pane, Claudia Brogna, Valeria Ricotti, Sonia Messina, Adele D'Amico, Claudio Bruno, Gianluca Vita, Angela Berardinelli, Elena Mazzone, Francesca Magri, Federica Ricci, Tiziana Mongini, Roberta Battini, Luca Bello, Elena Pegoraro, Giovanni Baranello, Stefano C Previtali, Luisa Politano, Giacomo P Comi, Valeria A Sansone, Alice Donati, Jean Yves Hogrel, Volker Straub, Silvana De Lucia, Erik Niks, Laurent Servais, Imelda De Groot, Mary Chesshyre, Enrico Bertini, Nathalie Goemans, Francesco Muntoni, Eugenio Mercuri, on behalf on the International DMD Group and the iMDEX Consortium

المصدر: PLoS ONE, Vol 16, Iss 6, p e0253882 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: IntroductionThe aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53.Materials and methodsWe included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52.ResultsThe difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001).DiscussionMutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up.ConclusionOur results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/be2f7562560244a9a2a56400fc1fd6e8Test

المؤلفون: E. Mercuri, A.M. Seferian, L. Servais, N. Deconinck, H. Stevenson, X. Ni, W. Zhang, L. East, S. Yonren, F. Muntoni, Nicolas Deconinck, Rudy Van Coster, Arnaud Vanlander, Andreea Seferian, Silvana De Lucia, Teresa Gidaro, Laura Vanden Brande, Laurent Servais, Janbernd Kirschner, Sabine Borell, Eugenio Mercuri, Claudia Brogna, Marika Pane, Lavinia Fanelli, Giulia Norcia, Francesco Muntoni, Chiara Brusa, Mary Chesshyre, Kate Maresh, Jaqueline Pitchforth, Lucia Schottlaender, Mariacristina Scoto, Arpana Silwal, Fedrica Trucco

المصدر: Neuromuscular Disorders. 33:476-483

مصطلحات موضوعية: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::010c398abc3705355c31db1d1dedc9efTest
https://doi.org/10.1016/j.nmd.2023.03.008Test

المؤلفون: Federica Trucco, Deborah Ridout, Joana Domingos, Kate Maresh, Mary Chesshyre, Pinki Munot, Anna Sarkozy, Stephanie Robb, Rosaline Quinlivan, Mollie Riley, Colin Wallis, Elaine Chan, Francois Abel, Silvana De Lucia, Jean‐Yves Hogrel, Erik H. Niks, Imelda de Groot, Laurent Servais, Volker Straub, Valeria Ricotti, Adnan Manzur, Francesco Muntoni

المساهمون: Trucco, Federica, Ridout, Deborah, Domingos, Joana, Maresh, Kate, Chesshyre, Mary, Munot, Pinki, Sarkozy, Anna, Robb, Stephanie, Quinlivan, Rosaline, Riley, Mollie, Wallis, Colin, Chan, Elaine, Abel, Francoi, De Lucia, Silvana, Hogrel, Jean‐yve, Niks, Erik H., de Groot, Imelda, Servais, Laurent, Straub, Volker, Ricotti, Valeria, Manzur, Adnan, Muntoni, Francesco

مصطلحات موضوعية: Duchenne muscular dystrophy, exon skipping, forced vital capacity, genotype, respiratory function

الوصف: Introduction/Aims Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long-term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon-skipping therapeutic strategies. Methods This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid-naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53). Results We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow-up was 3 (range, 0.3-8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age. Discussion The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon-skipping therapies.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/34606104; info:eu-repo/semantics/altIdentifier/wos/WOS:000711484700001; volume:65; firstpage:67; lastpage:74; numberofpages:8; journal:MUSCLE & NERVE; https://hdl.handle.net/11567/1155339Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85118321421

الإتاحة: https://doi.org/10.1002/mus.27427Test
https://hdl.handle.net/11567/1155339Test

المؤلفون: Yasumasa Hashimoto, Marion Main, Yoshitsugu Aoki, Deborah Ridout, Mariacristina Scoto, Francesco Muntoni, K. Maresh, Silvia Torelli, Giovanni Baranello, Valeria Ricotti, Adnan Y. Manzur, Yoko Ookubo, Lianne Abbott, Vandana Ayyar Gupta, Mary Chesshyre

مصطلحات موضوعية: Gene isoform, medicine.medical_specialty, biology, business.industry, Duchenne muscular dystrophy, Central nervous system, Skeletal muscle, medicine.disease, Phenotype, Grip strength, Endocrinology, medicine.anatomical_structure, Internal medicine, biology.protein, Medicine, Muscular dystrophy, business, Dystrophin

الوصف: BackgroundDuchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full length Dp427 is the primary dystrophin isoform expressed in skeletal muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS co-morbidities is well known, relationships between lack of Dp140 and Dp71 and DMD motor outcomes are not. We have conducted a series of investigations addressing this.MethodsFunctional outcome data from 387 DMD boys aged 4.0-15.4 years was subdivided by DMD mutation expected effect on isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n=201); group 2 (Dp427/Dp140 absent, Dp71 present, n=152); and group 3 (Dp427/Dp140/Dp71 absent, n=34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10m walk/run and rise times were explored using regression analysis. We used Capillary Western immunoassay (Wes) analysis to study Dp427, Dp140 and Dp71 production in wild-type and DMD skeletal muscle and myogenic cultures. Grip strength was studied in wild-type, mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD-null (lacking all isoforms) mice.ResultsIn DMD boys, we found a strong association between isoform group and motor function. In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in group 3 than group 1 (ppp=0.09) and 1.6 points lower in group 2 than group 1 (p=0.04).Average grip strength in peak force at 3 months of age was higher in mdx than mdx52 mice (p=0.01).Dp427, but not Dp71, was produced in normal skeletal muscle; low levels of Dp71 were detected in DMD skeletal muscle. High Dp71 levels were present in wild-type and DMD myogenic cultures.ConclusionsDMD boys lacking Dp140 and Dp140/Dp71 displayed worse motor function with a cumulative effect of isoform loss. DMD mouse models lacking Dp427 and Dp140 had lower grip strength than those lacking Dp427 but not Dp140. Our results highlight the importance of considering the effects of dystrophin isoform loss on DMD motor impairment, with important implications for understanding the complex relationship between brain and muscle function in DMD and patient stratification for clinical trials.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7d68df556d4c4d29335f762e13be0a33Test
https://doi.org/10.1101/2021.07.27.21261120Test

المؤلفون: Sonia Messina, Claudio Bruno, E. Mazzone, Eugenio Mercuri, Valeria A. Sansone, Claudia Brogna, Gianluca Vita, Francesco Muntoni, Marika Pane, Tiziana Mongini, Giovanni Baranello, Erik H. Niks, Mary Chesshyre, Francesca Magri, Volker Straub, Enrico Bertini, Elena Pegoraro, Luca Bello, Alice Donati, Silvana De Lucia, Stefano C. Previtali, Valeria Ricotti, Adele D'Amico, Jean-Yves Hogrel, Nathalie Goemans, Roberta Battini, Giacomo P. Comi, Laurent Servais, Giorgia Coratti, Federica Ricci, Imelda J. M. de Groot, Luisa Politano, Angela Berardinelli

المصدر: PLoS ONE, 16(6). PUBLIC LIBRARY SCIENCE
PLoS ONE
PLoS ONE, Vol 16, Iss 6, p e0253882 (2021)

مصطلحات موضوعية: Male, Heredity, Genetic Linkage, Epidemiology, Physiology, Duchenne muscular dystrophy, Walking, Duchenne Muscular Dystrophy, Severity of Illness Index, Muscular Dystrophies, Dystrophin, Exon, 0302 clinical medicine, Medical Conditions, Medicine and Health Sciences, 030212 general & internal medicine, Muscular Dystrophy, Longitudinal Studies, Child, Baseline values, Multidisciplinary, Settore MED/48 - SCIENZE INFERMIERISTICHE E TECNICHE NEURO-PSICHIATRICHE E RIABILITATIVE, Organic Compounds, Men, Exons, Multidisciplinary Sciences, Chemistry, Deletion Mutation, Neurology, X-Linked Traits, Sex Linkage, Ambulatory, Physical Sciences, Disease Progression, Medicine, Science & Technology - Other Topics, Steroids, exon skipping, Research Article, medicine.medical_specialty, Science, Natural history of disease, 03 medical and health sciences, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Internal medicine, medicine, Genetics, Humans, Clinical Genetics, Science & Technology, business.industry, Biological Locomotion, Organic Chemistry, Chemical Compounds, Biology and Life Sciences, Human Genetics, medicine.disease, Duchenne, Human genetics, Exon skipping, Follow-Up Studies, Muscular Dystrophy, Duchenne, Mutation, Clinical trial, Natural History of Disease, Medical Risk Factors, business, 030217 neurology & neurosurgery

الوصف: Introduction The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. Materials and methods We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52. Results The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001). Discussion Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up. Conclusion Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.

وصف الملف: application/pdf; Electronic-eCollection

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::de7208ef0a5c3984e1eb8d2853199ed7Test
http://hdl.handle.net/1887/3249481Test

المؤلفون: Amy Wolfe, Mariacristina Scoto, Mary Chesshyre, Lianne Abbott, Vandana Ayyar Guptar, Stephanie Wadsworth, Adnan Y. Manzur, Victoria Selby, Giovanni Baranello, Francesco Muntoni, Marion Main

المصدر: Digital poster presentations.

مصطلحات موضوعية: musculoskeletal diseases, education.field_of_study, medicine.medical_specialty, business.industry, Duchenne muscular dystrophy, Population, Functional skills, Retrospective cohort study, medicine.disease, Ambulatory, Physical therapy, Medicine, education, business, Hypermobility (travel)

الوصف: On average children with hypermobility achieve motor milestones later than peers without. This study looked at the prevalence of hypermobility in a sample of Duchenne Muscular Dystrophy (DMD) and aimed to determine if hypermobility has an impact on walking age and delays attainment of functional skills assessed by the North Star Ambulatory Assessment (NSAA). This is a retrospective study of 158 boys with DMD aged 3 to 8 years (±3 months). During clinical appointments each boy was assessed using the NSAA, joint ranges measured and age of walking noted. Hypermobility was determined using the revised Beighton scale where a score above 4 is considered hypermobile. The young DMD population had a higher percentage, 18%, of hypermobility compared to healthy controls, 7%. The pattern of hypermobility in DMD differed as well; knees and elbows were more commonly hypermobile compared to the expected ankles and thumbs. In DMD only 5% had hypermobile ankles compared to 22%. Hypermobility in DMD ankles often quickly tightened. Non hypermobile DMD boys walked on average at 17.8 mths (range 10–36 mths). This was similar to hypermobile boys; average 19 mths (range 13–36 mths). Hypermobile DMD boys were found to have a lower average NSAA at each age point than those who weren’t hypermobile, approximately 6 months behind. Both DMD groups gained functional skills with increased age until 6.5 (non hypermobile) and 7 years (hypermobile). Both groups subsequently declined. Hypermobility is more common in DMD and impacts development of later functional skills, however doesn’t dramatically influence age of walking started. Hypermobility should be therefore be considered when predicting the development of later skills. There are however other factors which can alter progression of NSAA including behaviour. More research is needed to further understand the impact of hypermobility in the DMD population especially for later years and loss of ambulation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7a6aac726e751a9670ea7b2963a816efTest
https://doi.org/10.1136/archdischild-2020-gosh.74Test