Pub Date : 2024-10-18DOI: 10.1016/j.nmd.2024.105213
Rahul Gaini , Gregory Chamberlin , Shih-Hsiu J. Wang , Jonathan Morena
A 72-year-old woman on sertraline and levothyroxine (Levoxyl) presented to clinic with progressive proximal > distal and left > right upper and lower extremity weakness. She had length-dependent paresthesias and sensory deficits. Aldolase was elevated but CK was normal. EMG/NCS showed myopathic motor units. Muscle biopsy revealed numerous muscle fibers with markedly increased lipid content. Additional bloodwork showed elevated plasma acylcarnitine species of all chain lengths, concerning for multiple acyl-CoA dehydrogenase deficiency (MADD), along with elevated Growth Differentiation Factor 15 (GDF-15). Metabolic and mitochondrial genetic testing followed by whole exome sequencing was negative. The patient started riboflavin 400 mg daily and improved from requiring a wheelchair to independent ambulation. She was diagnosed with very-late-onset riboflavin-responsive MADD. This case adds to the growing literature on the clinical heterogeneity of VLO-MADD, comments on the potential for non-genetic, pharmacologic triggers like sertraline, and highlights that GDF-15 and aldolase can be elevated with normal CK.
{"title":"Very-late-onset multiple Acyl-coenzyme a dehydrogenase deficiency with elevated GDF-15 and Aldolase: a case report","authors":"Rahul Gaini , Gregory Chamberlin , Shih-Hsiu J. Wang , Jonathan Morena","doi":"10.1016/j.nmd.2024.105213","DOIUrl":"10.1016/j.nmd.2024.105213","url":null,"abstract":"<div><div>A 72-year-old woman on sertraline and levothyroxine (Levoxyl) presented to clinic with progressive proximal > distal and left > right upper and lower extremity weakness. She had length-dependent paresthesias and sensory deficits. Aldolase was elevated but CK was normal. EMG/NCS showed myopathic motor units. Muscle biopsy revealed numerous muscle fibers with markedly increased lipid content. Additional bloodwork showed elevated plasma acylcarnitine species of all chain lengths, concerning for multiple acyl-CoA dehydrogenase deficiency (MADD), along with elevated Growth Differentiation Factor 15 (GDF-15). Metabolic and mitochondrial genetic testing followed by whole exome sequencing was negative. The patient started riboflavin 400 mg daily and improved from requiring a wheelchair to independent ambulation. She was diagnosed with very-late-onset riboflavin-responsive MADD. This case adds to the growing literature on the clinical heterogeneity of VLO-MADD, comments on the potential for non-genetic, pharmacologic triggers like sertraline, and highlights that GDF-15 and aldolase can be elevated with normal CK.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"45 ","pages":"Article 105213"},"PeriodicalIF":2.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1016/j.nmd.2024.104470
Lei Zhao , Chaoping Hu , Shirang Pan , Depeng Wang , Yi Wang , Xihua Li
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness, due to mutations in the DMD gene, which encodes the dystrophin protein. While mutations within the coding regions of DMD have been extensively studied, recent focus has shifted to deep intronic variants for their potential impact on disease severity. Here, we characterize two deep intronic variants, c.8669-19_8669-24del and c.6439-1016_6439-3376del, in unrelated DMD patients. These variants were identified using targeted long-read sequencing on patients' DNA. RNA sequencing/reverse transcription polymerase chain reaction on RNA extracted from muscle biopsies revealed the presence of a pseudoexon or retention of part of the intron in the transcript, resulting in the introduction of premature termination codons. This study enhances our understanding of pseudoexon activation mechanisms in DMD and underscores the diverse genetic abnormalities contributing to the disease's complexity.
{"title":"Two novel deep intronic variants cause Duchenne muscular dystrophy by splice-altering mechanism","authors":"Lei Zhao , Chaoping Hu , Shirang Pan , Depeng Wang , Yi Wang , Xihua Li","doi":"10.1016/j.nmd.2024.104470","DOIUrl":"10.1016/j.nmd.2024.104470","url":null,"abstract":"<div><div>Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness, due to mutations in the DMD gene, which encodes the dystrophin protein. While mutations within the coding regions of DMD have been extensively studied, recent focus has shifted to deep intronic variants for their potential impact on disease severity. Here, we characterize two deep intronic variants, c.8669-19_8669-24del and c.6439-1016_6439-3376del, in unrelated DMD patients. These variants were identified using targeted long-read sequencing on patients' DNA. RNA sequencing/reverse transcription polymerase chain reaction on RNA extracted from muscle biopsies revealed the presence of a pseudoexon or retention of part of the intron in the transcript, resulting in the introduction of premature termination codons. This study enhances our understanding of pseudoexon activation mechanisms in DMD and underscores the diverse genetic abnormalities contributing to the disease's complexity.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"45 ","pages":"Article 104470"},"PeriodicalIF":2.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142586085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.nmd.2024.104468
Amelia Evoli , Jacqueline Palace , Gregorio Spagni , Marta Cheli , Annabel Ruiter , Jan Verschuuren , Lorenzo Maggi
The 275th ENMC workshop on the diagnosis and management of seronegative myasthenia gravis (SNMG) was held on February 9–11, 2024. The participants included experts in the field of adult and pediatric MG together with patient representatives. This workshop aimed to redefine SNMG in view of recent diagnostic and therapeutic updates and to identify patient unmet needs. The workshop has highlighted considerable challenges in the SNMG diagnostic work-up. To date, SNMG confirmation is often controversial, given the absence of specific diagnostic tests; no recommendations from international panels of experts are available in literature; myopathies, congenital myasthenic syndromes and functional disorders are the commonest misdiagnoses. Improving the disease diagnosis is crucial to avoid long delays in receiving appropriate treatment. To this purpose, a comprehensive diagnostic algorithm achieved consensus. Moreover, a remarkable variability in SNMG response to therapy and long-term prognosis has also been highlighted.
{"title":"275th ENMC international workshop: Seronegative myasthenia gravis: An update paradigm for diagnosis and management, 9–11 February 2024, Hoofddorp, the Netherlands","authors":"Amelia Evoli , Jacqueline Palace , Gregorio Spagni , Marta Cheli , Annabel Ruiter , Jan Verschuuren , Lorenzo Maggi","doi":"10.1016/j.nmd.2024.104468","DOIUrl":"10.1016/j.nmd.2024.104468","url":null,"abstract":"<div><div>The 275th ENMC workshop on the diagnosis and management of seronegative myasthenia gravis (SNMG) was held on February 9–11, 2024. The participants included experts in the field of adult and pediatric MG together with patient representatives. This workshop aimed to redefine SNMG in view of recent diagnostic and therapeutic updates and to identify patient unmet needs. The workshop has highlighted considerable challenges in the SNMG diagnostic work-up. To date, SNMG confirmation is often controversial, given the absence of specific diagnostic tests; no recommendations from international panels of experts are available in literature; myopathies, congenital myasthenic syndromes and functional disorders are the commonest misdiagnoses. Improving the disease diagnosis is crucial to avoid long delays in receiving appropriate treatment. To this purpose, a comprehensive diagnostic algorithm achieved consensus. Moreover, a remarkable variability in SNMG response to therapy and long-term prognosis has also been highlighted.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"44 ","pages":"Article 104468"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.nmd.2024.105211
Eleonora S D'Ambrosio , Matti D Allen , Burcak Ozes , Zarife Sahenk
Localized painful nodules associated with focal myositis have been previously documented, either as isolated occurrences or in conjunction with systemic illnesses, such as polymyositis [[1], [2], [3], [4]]. These nodules typically manifest over the course of 2-8 weeks and exhibit histological features consistent with inflammatory myositis. Here we present a unique case of a patient with a history of myasthenia gravis, who experienced exacerbation of myasthenic symptoms, accompanied by the development of palpable, tender nodules on her thighs and proximal weakness. Muscle biopsy revealed circumscribed mononuclear infiltrates predominantly composed of CD3+ and CD4+ lymphocytes. Furthermore, we detail the patient's rapid and sustained response to treatment with steroids (both intravenous pulse and maintenance therapy) and methotrexate. To the best of our knowledge, this represents the first documented case of nodular lymphocytic myositis concurrent with an exacerbation of myasthenia gravis, in a patient with no prior history of significant immunosuppression or chronic infection.
{"title":"Concurrent nodular lymphocytic myositis and myasthenia gravis. A case report","authors":"Eleonora S D'Ambrosio , Matti D Allen , Burcak Ozes , Zarife Sahenk","doi":"10.1016/j.nmd.2024.105211","DOIUrl":"10.1016/j.nmd.2024.105211","url":null,"abstract":"<div><div>Localized painful nodules associated with focal myositis have been previously documented, either as isolated occurrences or in conjunction with systemic illnesses, such as polymyositis [<span><span>[1]</span></span>, <span><span>[2]</span></span>, <span><span>[3]</span></span>, <span><span>[4]</span></span>]. These nodules typically manifest over the course of 2-8 weeks and exhibit histological features consistent with inflammatory myositis. Here we present a unique case of a patient with a history of myasthenia gravis, who experienced exacerbation of myasthenic symptoms, accompanied by the development of palpable, tender nodules on her thighs and proximal weakness. Muscle biopsy revealed circumscribed mononuclear infiltrates predominantly composed of CD3+ and CD4+ lymphocytes. Furthermore, we detail the patient's rapid and sustained response to treatment with steroids (both intravenous pulse and maintenance therapy) and methotrexate. To the best of our knowledge, this represents the first documented case of nodular lymphocytic myositis concurrent with an exacerbation of myasthenia gravis, in a patient with no prior history of significant immunosuppression or chronic infection.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"45 ","pages":"Article 105211"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142531655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1016/j.nmd.2024.104452
Jos Hendriksen , Pien Weerkamp , Ruben Miranda , Anna Kolesnik , Daniela Chieffo , David Skuse , Elizabeth Vroom , Chloe Geagan , Francesco Muntoni , Eugenio Mercuri , BIND WP5 working group
As part of an international project aimed at improving the characterization of brain involvement in Duchenne and Becker Muscular Dystrophies, a group of clinicians, researchers and family associations held multiple meetings between March 2021 and March 2024 to identify and reach a consensus on the possible tools that could assess the spectrum of neurocognitive and neurobehavioral brain comorbidities in dystrophinopathies. Consensus was achieved on which of these tools should be used across different settings, ranging from screening to clinical practice and scientific research. Screening questionnaires were found to be valuable not only for providing epidemiological data but also for raising awareness among the Duchenne community and professionals. More standardised and detailed online questionnaires, combined with in-depth clinical assessments can help better identify the profile of brain comorbidities and plan appropriate interventions. Additionally, the information gathered from assessing multiple features of brain involvement can be used to explore correlations with other aspects, such as the regional expression of the different dystrophin isoforms, brain imaging, and the animal models deficient in these isoforms.
{"title":"Towards harmonization of clinical tools for assessing Brain Involvement in Dystrophinopathies (BIND); report of four expert workshops: Newcastle, Leiden, Rome, Paris","authors":"Jos Hendriksen , Pien Weerkamp , Ruben Miranda , Anna Kolesnik , Daniela Chieffo , David Skuse , Elizabeth Vroom , Chloe Geagan , Francesco Muntoni , Eugenio Mercuri , BIND WP5 working group","doi":"10.1016/j.nmd.2024.104452","DOIUrl":"10.1016/j.nmd.2024.104452","url":null,"abstract":"<div><div>As part of an international project aimed at improving the characterization of brain involvement in Duchenne and Becker Muscular Dystrophies, a group of clinicians, researchers and family associations held multiple meetings between March 2021 and March 2024 to identify and reach a consensus on the possible tools that could assess the spectrum of neurocognitive and neurobehavioral brain comorbidities in dystrophinopathies. Consensus was achieved on which of these tools should be used across different settings, ranging from screening to clinical practice and scientific research. Screening questionnaires were found to be valuable not only for providing epidemiological data but also for raising awareness among the Duchenne community and professionals. More standardised and detailed online questionnaires, combined with in-depth clinical assessments can help better identify the profile of brain comorbidities and plan appropriate interventions. Additionally, the information gathered from assessing multiple features of brain involvement can be used to explore correlations with other aspects, such as the regional expression of the different dystrophin isoforms, brain imaging, and the animal models deficient in these isoforms.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"44 ","pages":"Article 104452"},"PeriodicalIF":2.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1016/j.nmd.2024.104453
Werner Stenzel , Andrew L Mammen , Laure Gallay , Marie-Therese Holzer , Felix Kleefeld , Olivier Benveniste , Yves Allenbach
Among the idiopathic inflammatory myopathies, patients harbouring an Antisynthetase syndrome exhibit a unique clinical picture, with characteristic signs such as myositis, interstitial lung disease, arthritis, rash, and/or fever. Characteristic morphological features on skeletal muscle biopsies differentiate Antisynthetase syndrome from other forms of myositis. Autoantibodies typically recognizing one of the members of the aminoacyl-tRNA synthetase family of proteins can be detected in the serum of such patients, with anti-Jo1 being most frequent. Until now, an international consensus definition of the Antisynthetase syndrome is lacking, hence this workshop has undertaken the task to inform about the clinical, morphological and autoantibody profiles of Antisynthetase syndrome. The authors also expand their aims by giving management and therapeutic strategies, and finally provide precise classification criteria for Antisynthetase syndrome.
{"title":"273rd ENMC International workshop: Clinico-Sero-morphological classification of the Antisynthetase syndrome. Amsterdam, The Netherlands, 27-29 October 2023","authors":"Werner Stenzel , Andrew L Mammen , Laure Gallay , Marie-Therese Holzer , Felix Kleefeld , Olivier Benveniste , Yves Allenbach","doi":"10.1016/j.nmd.2024.104453","DOIUrl":"10.1016/j.nmd.2024.104453","url":null,"abstract":"<div><div>Among the idiopathic inflammatory myopathies, patients harbouring an Antisynthetase syndrome exhibit a unique clinical picture, with characteristic signs such as myositis, interstitial lung disease, arthritis, rash, and/or fever. Characteristic morphological features on skeletal muscle biopsies differentiate Antisynthetase syndrome from other forms of myositis. Autoantibodies typically recognizing one of the members of the aminoacyl-tRNA synthetase family of proteins can be detected in the serum of such patients, with anti-Jo1 being most frequent. Until now, an international consensus definition of the Antisynthetase syndrome is lacking, hence this workshop has undertaken the task to inform about the clinical, morphological and autoantibody profiles of Antisynthetase syndrome. The authors also expand their aims by giving management and therapeutic strategies, and finally provide precise classification criteria for Antisynthetase syndrome.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"45 ","pages":"Article 104453"},"PeriodicalIF":2.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142532226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1016/j.nmd.2024.104467
M. Lorentzos , JA. Parsons , KJ. Jones , L. Servais , The Treat NMD Early Diagnosis Workshop Participants
The diagnosis of Duchenne muscular dystrophy (DMD) is significant at any stage, however an early diagnosis in a presymptomatic or very early phase of DMD, offers unique opportunities and challenges for families and health care providers. Currently, there is limited evidence as to the optimal models of care during this stage of the condition.. To address this, in 2023, Treat-NMD facilitated the Early Diagnosis for DMD project; bringing together 42 experts from across Europe, the US and Australasia, including health care professionals, researchers, and people with lived experience to discuss the complexities of an early or newborn diagnosis of DMD, and provide recommendations regarding approaches to multidisciplinary care. A series of virtual meetings followed by a hybrid workshop resulted in broad recommendations to support clinicians in caring for children and families following an early diagnosis of DMD. The workshop did not define a cut-off for early diagnosis, however much of the discussion focused on diagnoses that occurred prior to 2 years. There is recognition that boys may first present with non-motor symptoms, such as speech delay or neurodevelopmental issues that are secondary to their dystrophinopathy, and therefore this report refers reflects that infants with DMD may be presymptomatic or early symptomatic.
{"title":"Early diagnosis of Duchenne muscular dystrophy - A Treat-NMD international workshop","authors":"M. Lorentzos , JA. Parsons , KJ. Jones , L. Servais , The Treat NMD Early Diagnosis Workshop Participants","doi":"10.1016/j.nmd.2024.104467","DOIUrl":"10.1016/j.nmd.2024.104467","url":null,"abstract":"<div><div>The diagnosis of Duchenne muscular dystrophy (DMD) is significant at any stage, however an early diagnosis in a presymptomatic or very early phase of DMD, offers unique opportunities and challenges for families and health care providers. Currently, there is limited evidence as to the optimal models of care during this stage of the condition.. To address this, in 2023, Treat-NMD facilitated the Early Diagnosis for DMD project; bringing together 42 experts from across Europe, the US and Australasia, including health care professionals, researchers, and people with lived experience to discuss the complexities of an early or newborn diagnosis of DMD, and provide recommendations regarding approaches to multidisciplinary care. A series of virtual meetings followed by a hybrid workshop resulted in broad recommendations to support clinicians in caring for children and families following an early diagnosis of DMD. The workshop did not define a cut-off for early diagnosis, however much of the discussion focused on diagnoses that occurred prior to 2 years. There is recognition that boys may first present with non-motor symptoms, such as speech delay or neurodevelopmental issues that are secondary to their dystrophinopathy, and therefore this report refers reflects that infants with DMD may be presymptomatic or early symptomatic.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"45 ","pages":"Article 104467"},"PeriodicalIF":2.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.nmd.2024.07.089
V. Sian , J. Sarparanta , A. Hentschel , P. Jonson , A. Roos , S. Natraj Gayathri , B. Udd , M. Savarese , A. Nebbioso
Skeletal muscle differentiation is a tightly controlled and elaborated process, that consists of alignment and fusion of myoblasts to form mature myotubes. A growing interest for epigenetics involvement in guiding muscle differentiation raised the attention on epi-modulators as pivotal regulators in this process. Our in vitro study aimed to investigate the potential effects of Remodelin in muscle differentiation. Remodelin is the inhibitor of N-acetyltransferase 10, the key-player of RNA acetylation. We used the well-consolidated model of murine C2C12 cells cultivated on ultra-compliant gelatin hydrogels for long-term studies. The newly developed hydrogel scaffold promotes myotube alignment and maturation, mimicking the skeletal muscle biology observed in vivo. We differentiated C2C12 cells in low-serum conditions up to 16 days and treated them with the epi-drug Remodelin. At day 7 of differentiation, confocal images revealed that Remodelin prompted a lack of organization, proper morphology, and maturation of myotubes compared to the control. Marked twitching was neither visible upon Remodelin treatment, even in the late stage of differentiation. Remodelin downregulated the expression of protein markers of differentiation, but without any significant epi-modulation. Both transcriptomics and proteomics analyses confirmed that Remodelin effectively slowed down the process of myotube formation. RNAseq analysis revealed that the epi-drug down-regulated 749 genes, predominantly encoding proteins involved in muscle contraction, sarcomere organization, muscle structure development, and calcium ion binding. Proteomics analysis further unveiled that 37 significantly down-regulated proteins were related to extracellular matrix, cell-matrix adhesion, positive regulation of muscle cell differentiation, and calcium ion binding. Taken together, these results suggest that Remodelin exerts a broad effect on the regulatory networks of skeletal muscle differentiation.
{"title":"271P Exploring the effects of the epi-drug Remodelin on murine myoblasts differentiation","authors":"V. Sian , J. Sarparanta , A. Hentschel , P. Jonson , A. Roos , S. Natraj Gayathri , B. Udd , M. Savarese , A. Nebbioso","doi":"10.1016/j.nmd.2024.07.089","DOIUrl":"10.1016/j.nmd.2024.07.089","url":null,"abstract":"<div><div>Skeletal muscle differentiation is a tightly controlled and elaborated process, that consists of alignment and fusion of myoblasts to form mature myotubes. A growing interest for epigenetics involvement in guiding muscle differentiation raised the attention on epi-modulators as pivotal regulators in this process. Our in vitro study aimed to investigate the potential effects of Remodelin in muscle differentiation. Remodelin is the inhibitor of N-acetyltransferase 10, the key-player of RNA acetylation. We used the well-consolidated model of murine C2C12 cells cultivated on ultra-compliant gelatin hydrogels for long-term studies. The newly developed hydrogel scaffold promotes myotube alignment and maturation, mimicking the skeletal muscle biology observed in vivo. We differentiated C2C12 cells in low-serum conditions up to 16 days and treated them with the epi-drug Remodelin. At day 7 of differentiation, confocal images revealed that Remodelin prompted a lack of organization, proper morphology, and maturation of myotubes compared to the control. Marked twitching was neither visible upon Remodelin treatment, even in the late stage of differentiation. Remodelin downregulated the expression of protein markers of differentiation, but without any significant epi-modulation. Both transcriptomics and proteomics analyses confirmed that Remodelin effectively slowed down the process of myotube formation. RNAseq analysis revealed that the epi-drug down-regulated 749 genes, predominantly encoding proteins involved in muscle contraction, sarcomere organization, muscle structure development, and calcium ion binding. Proteomics analysis further unveiled that 37 significantly down-regulated proteins were related to extracellular matrix, cell-matrix adhesion, positive regulation of muscle cell differentiation, and calcium ion binding. Taken together, these results suggest that Remodelin exerts a broad effect on the regulatory networks of skeletal muscle differentiation.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.80"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.nmd.2024.07.052
T. Dangouloff , L. De Waele , D. Beysen , N. Smeets , A. Vanlander , N. Benmhammed , C. Tychon , A. Daron , N. Deconinck , P. Dontaine , L. Servais
Several newborn screening (NBS) programs for Spinal Muscular Atrophy (SMA) have demonstrated feasibility-reliability and short-term efficacy of PCR-based universal SMA NBS, but longer-term data are needed to precise the benefit of this intervention. In addition, the comparison with external control groups can reinforce the level of evidence and support robust health economic assessment. The aim of this study is to compare the medical, quality of life and economic data for SMA patients diagnosed by NBS and those identified by symptoms, in the same country, during the same time period. We collected data on all SMA patients born in Flanders and the Wallonia-Brussels Federation (FWB) between January 1, 2019 (the date on which the entire FWB began screening for SMA) and 30 November 2022 (the date on which Flanders began screening). We compared the median age of diagnosis and initiation of treatment, the treatment, scores on motor development scales, and the age of acquisition of sitting and walking. We also collected quality of life data for parents, utility data for children, and costs associated with the disease. A total of 30 patients were included in the analysis: 16 patients in FWB (7 with 2 SMN2 copies, 4 with 3 copies and 5 with 4 copies) and 13 in Flanders. One patient with a point mutation was not identified by NBS in FWB. Patients in FWB were initially treated by nusinersen (n = 5) risdiplam (n = 3) and onasemnogene abeparvovec (n = 7) at 36 days of life on average (29, 37, and 44 days respectively for patients with 2, 3 and 4 SMN2 copies of SMN2). Two patients shifted from nusinersen to risdiplam, one from nusinersen to onasemnogene abeparvovec and one from risdiplam to onasemnogene abeparvovec. One patient with 4 SMN2 copies was still untreated at 26 months. Median follow up was 32 months (9-54 months). All patients over 18 months with 3 and 4 SMN2 copies acquired ambulation (median age: 17 months, 13-24 months). Of the 7 patients with 2 SMN2 copies, 2 are not yet 18 months old, 4 are walking, and one aged 24 months is not yet walking. One child with 2 SMN2 copies have non-invasive nocturnal ventilation. None of the children needed nutritional support at the time of the last follow-up. Data in Flanders, where NBS was not implemented in the studied time, are currently collected, and will be presented during the congress. Our data shows that middle term outcome of patients identified by NBS is very good so far. Estimation of health care cost saving will be presented.
{"title":"145P Efficacy of SMA NBS: 4-year comparative study with control group","authors":"T. Dangouloff , L. De Waele , D. Beysen , N. Smeets , A. Vanlander , N. Benmhammed , C. Tychon , A. Daron , N. Deconinck , P. Dontaine , L. Servais","doi":"10.1016/j.nmd.2024.07.052","DOIUrl":"10.1016/j.nmd.2024.07.052","url":null,"abstract":"<div><div>Several newborn screening (NBS) programs for Spinal Muscular Atrophy (SMA) have demonstrated feasibility-reliability and short-term efficacy of PCR-based universal SMA NBS, but longer-term data are needed to precise the benefit of this intervention. In addition, the comparison with external control groups can reinforce the level of evidence and support robust health economic assessment. The aim of this study is to compare the medical, quality of life and economic data for SMA patients diagnosed by NBS and those identified by symptoms, in the same country, during the same time period. We collected data on all SMA patients born in Flanders and the Wallonia-Brussels Federation (FWB) between January 1, 2019 (the date on which the entire FWB began screening for SMA) and 30 November 2022 (the date on which Flanders began screening). We compared the median age of diagnosis and initiation of treatment, the treatment, scores on motor development scales, and the age of acquisition of sitting and walking. We also collected quality of life data for parents, utility data for children, and costs associated with the disease. A total of 30 patients were included in the analysis: 16 patients in FWB (7 with 2 SMN2 copies, 4 with 3 copies and 5 with 4 copies) and 13 in Flanders. One patient with a point mutation was not identified by NBS in FWB. Patients in FWB were initially treated by nusinersen (n = 5) risdiplam (n = 3) and onasemnogene abeparvovec (n = 7) at 36 days of life on average (29, 37, and 44 days respectively for patients with 2, 3 and 4 SMN2 copies of SMN2). Two patients shifted from nusinersen to risdiplam, one from nusinersen to onasemnogene abeparvovec and one from risdiplam to onasemnogene abeparvovec. One patient with 4 SMN2 copies was still untreated at 26 months. Median follow up was 32 months (9-54 months). All patients over 18 months with 3 and 4 SMN2 copies acquired ambulation (median age: 17 months, 13-24 months). Of the 7 patients with 2 SMN2 copies, 2 are not yet 18 months old, 4 are walking, and one aged 24 months is not yet walking. One child with 2 SMN2 copies have non-invasive nocturnal ventilation. None of the children needed nutritional support at the time of the last follow-up. Data in Flanders, where NBS was not implemented in the studied time, are currently collected, and will be presented during the congress. Our data shows that middle term outcome of patients identified by NBS is very good so far. Estimation of health care cost saving will be presented.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.43"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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