Pub Date : 2024-10-01DOI: 10.1016/j.nmd.2024.07.015
S. Ramdas
Acquired muscle disorders comprise of a heterogenous group of treatable infectious or inflammatory disorders. Outside the benign self-limiting viral myositis, the most common acquired muscle disorders are Immune mediated myopathies (IIMs) which include juvenile dermatomyositis, juvenile polymyositis and immune-mediated necrotising myopathy. IIMs are rare in paediatric cohorts with an annual incidence of 1.6- 4 cases/million children compared to adult incidence of 0.2-2/100,000 person years, leading to diagnostic delay including misdiagnosis as genetic or para-infectious muscle disorders and consequently morbidity and mortality due to treatment delay. The talk will cover the pathophysiology mechanisms, clinical presentations, current and emerging treatment strategies in management of paediatric acquired muscle disorders focusing particularly on the nuances of the issues which are pertinent to children and young people compared to adults.
{"title":"04INV Acquired muscle disorders - a paediatric perspective","authors":"S. Ramdas","doi":"10.1016/j.nmd.2024.07.015","DOIUrl":"10.1016/j.nmd.2024.07.015","url":null,"abstract":"<div><div>Acquired muscle disorders comprise of a heterogenous group of treatable infectious or inflammatory disorders. Outside the benign self-limiting viral myositis, the most common acquired muscle disorders are Immune mediated myopathies (IIMs) which include juvenile dermatomyositis, juvenile polymyositis and immune-mediated necrotising myopathy. IIMs are rare in paediatric cohorts with an annual incidence of 1.6- 4 cases/million children compared to adult incidence of 0.2-2/100,000 person years, leading to diagnostic delay including misdiagnosis as genetic or para-infectious muscle disorders and consequently morbidity and mortality due to treatment delay. The talk will cover the pathophysiology mechanisms, clinical presentations, current and emerging treatment strategies in management of paediatric acquired muscle disorders focusing particularly on the nuances of the issues which are pertinent to children and young people compared to adults.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.6"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423646","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.2024.07.029
O. Martineau , E. Milev , M. Main , M. Scoto , F. Muntoni , G. Baranello
In recent years, disease-modifying treatments (DMT) for Spinal Muscular Atrophy (SMA) have become readily available on the National Health Service in the UK. Although phenotypes are changing, progressive scoliosis remains common and can affect individuals' quality of life causing a negative impact on mobility, increased pain and worsened respiratory function. Corrective spinal surgery aims to reduce the curvature of the spine with the purpose to improve sitting posture and lung function. Limited data is available on the effects of scoliosis surgery on upper limb function in SMA patients. The revised upper limb module (RULM) is used to monitor changes in the arm function in the SMA cohort assessing both proximal and distal activities. The aim of this study is to review changes in upper limb function of SMA children following spinal surgery identifying possible contributing factors. A single-centre retrospective review has been completed of the current SMA cohort at Great Ormond Street Hospital (GOSH) that underwent corrective spinal surgery (posterior spinal fusion or growth rod insertion). Forty-two patients were identified; 20 were excluded due to insufficient data. Of the remaining 22 patients, 14 were female and 8 male. Nine were classified as type 3, 12 as type 2 and 1 as type 1;12/22 had started on DMT prior to surgery. Scores from 2 RULM assessments taken prior to surgery at least 6 months apart were compared with RULM results post-surgery at two 6-month intervals. Other factors were recorded including age, Cobb angle and time on DMT prior to surgery. Patients receiving DMT post-surgery were used as a control group. At the initial follow-up, 64% showed a decline in RULM score with an average change in score of-2.18. At the second follow-up, 78% had improved or maintained their score with an average score change of 0.09. Comparing the treated and untreated group, there was no significant difference in scores at the initial follow-up, while at the second follow up a significant difference was observed (p=0.018) with an average change of +1 in the DMT group compared to -1 in the untreated group. Our study shows that children with SMA treated with a DMT prior to surgery declined initially however 87% regained or maintained some upper limb function at their second follow-up. We aim to further analyse the data and present the full scope of this study including a larger group across the UK.
近年来，脊髓性肌肉萎缩症（SMA）的改良疾病疗法（DMT）已在英国国民健康服务中普及。虽然表型正在发生变化，但进行性脊柱侧弯仍然很常见，会影响患者的生活质量，导致行动不便、疼痛加剧和呼吸功能恶化。脊柱矫正手术旨在减少脊柱弯曲，从而改善坐姿和肺功能。有关脊柱侧弯手术对 SMA 患者上肢功能影响的数据十分有限。修订后的上肢模块（RULM）用于监测 SMA 患者手臂功能的变化，评估近端和远端活动。本研究旨在回顾脊柱手术后 SMA 儿童上肢功能的变化，找出可能的诱因。大奥蒙德街医院（Great Ormond Street Hospital，GOSH）对目前接受脊柱矫正手术（脊柱后路融合术或生长棒植入术）的 SMA 患者进行了单中心回顾性研究。共确定了 42 例患者，其中 20 例因数据不足而被排除。在剩下的 22 名患者中，14 人为女性，8 人为男性。9人被归为3型，12人被归为2型，1人被归为1型；12/22的患者在手术前已开始服用DMT。将手术前至少间隔 6 个月进行的两次 RULM 评估结果与手术后两次间隔 6 个月进行的 RULM 评估结果进行比较。其他因素包括年龄、Cobb 角和手术前接受 DMT 的时间。手术后接受 DMT 治疗的患者作为对照组。在首次随访中，64%的患者 RULM 评分下降，平均分数变化为 2.18。在第二次随访时，78% 的患者的评分有所改善或保持不变，平均分数变化为 0.09。对比治疗组和未治疗组，初次随访时的得分没有显著差异，而在第二次随访时观察到了显著差异（P=0.018），DMT 组的平均得分变化为 +1，而未治疗组的平均得分变化为 -1。我们的研究表明，在手术前接受 DMT 治疗的 SMA 患儿最初上肢功能有所下降，但 87% 的患儿在第二次随访时恢复或保持了一定的上肢功能。我们的目标是进一步分析数据，并展示这项研究的全部内容，包括英国更大规模的群体。
{"title":"122P A retrospective review of changes in upper limb function following spinal surgery in spinal muscular atrophy","authors":"O. Martineau , E. Milev , M. Main , M. Scoto , F. Muntoni , G. Baranello","doi":"10.1016/j.nmd.2024.07.029","DOIUrl":"10.1016/j.nmd.2024.07.029","url":null,"abstract":"<div><div>In recent years, disease-modifying treatments (DMT) for Spinal Muscular Atrophy (SMA) have become readily available on the National Health Service in the UK. Although phenotypes are changing, progressive scoliosis remains common and can affect individuals' quality of life causing a negative impact on mobility, increased pain and worsened respiratory function. Corrective spinal surgery aims to reduce the curvature of the spine with the purpose to improve sitting posture and lung function. Limited data is available on the effects of scoliosis surgery on upper limb function in SMA patients. The revised upper limb module (RULM) is used to monitor changes in the arm function in the SMA cohort assessing both proximal and distal activities. The aim of this study is to review changes in upper limb function of SMA children following spinal surgery identifying possible contributing factors. A single-centre retrospective review has been completed of the current SMA cohort at Great Ormond Street Hospital (GOSH) that underwent corrective spinal surgery (posterior spinal fusion or growth rod insertion). Forty-two patients were identified; 20 were excluded due to insufficient data. Of the remaining 22 patients, 14 were female and 8 male. Nine were classified as type 3, 12 as type 2 and 1 as type 1;12/22 had started on DMT prior to surgery. Scores from 2 RULM assessments taken prior to surgery at least 6 months apart were compared with RULM results post-surgery at two 6-month intervals. Other factors were recorded including age, Cobb angle and time on DMT prior to surgery. Patients receiving DMT post-surgery were used as a control group. At the initial follow-up, 64% showed a decline in RULM score with an average change in score of-2.18. At the second follow-up, 78% had improved or maintained their score with an average score change of 0.09. Comparing the treated and untreated group, there was no significant difference in scores at the initial follow-up, while at the second follow up a significant difference was observed (p=0.018) with an average change of +1 in the DMT group compared to -1 in the untreated group. Our study shows that children with SMA treated with a DMT prior to surgery declined initially however 87% regained or maintained some upper limb function at their second follow-up. We aim to further analyse the data and present the full scope of this study including a larger group across the UK.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.20"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423723","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.2024.07.049
G. Stimpson , E. O'Reilly , G. Coratti , D. Ridout , T. Chakraborti , R. Mitra , E. Mercuri , M. Scoto , F. Muntoni , G. Baranello
Disease-modifying treatments, such as nusinersen, have significantly improved the disease trajectory of Spinal Muscular Atrophy (SMA) patients. Treatment response is heterogeneous, and predicting response is crucial for clinicians to give realistic guidance to patients and carers when counselling about treatment options. We collected data on 124 patients from the SMA Reach UK and Italian Network studies. Participants were included if they were treated under 4 years and were non-sitters at nusinersen initiation, were randomly allocated to training (80%) and testing cohorts (20%). Tree and regression-based machine learning for survival outcomes were compared, and oblique random forests were selected, with a testing C-Index of 0.74. The features were selected from items of the CHOP and HINE-2, respiratory symptoms and bulbar interventions using mutual information. In total, 62 (50%) have achieved sitting, at a median age of 2.4 years. The predicted median time-to-sitting in those requiring NG or G-Tubes at treatment was 4-months later on average than those without, and this was the most influential factor. The ability to kick at treatment, (≥1 on the HINE-2 item) was also influential in predicting the likelihood of sitting, as was antigravity shoulder movement in supine and ability to reach in side-lying (4 on items 1 and 8), and neck muscle activation in pull to sit (≥2 on item 14) and rolling fully prone from supine when elicited from arms (≥3 on item 7) on the CHOP at treatment. Most notably, those who could roll fully prone from supine had a median predicted time-to-sit 5.8 months earlier than an identical patient who could not. Nusinersen starting and symptom onset age were less influential, whilst SMN2 copy numbers did not improve the model. This work provides a tool to predict treatment response in nusinersen-treated patients and has the potential to be extended to other treatment options, moving clinicians towards personalised treatment plans for each patient.
疾病改变疗法（如纽西奈森）大大改善了脊髓性肌肉萎缩症（SMA）患者的疾病轨迹。治疗反应各不相同，因此预测治疗反应对于临床医生在为患者和护理人员提供治疗方案咨询时提供切合实际的指导至关重要。我们从 SMA Reach UK 和意大利网络研究中收集了 124 名患者的数据。如果参与者接受治疗的时间不足 4 年，并且在开始使用奴西奈森时没有坐位，我们就将其纳入研究，并将其随机分配到训练组（80%）和测试组（20%）。对基于树和回归的生存结果机器学习进行了比较，并选择了斜向随机森林，测试 C 指数为 0.74。使用互信息从 CHOP 和 HINE-2 的项目、呼吸道症状和球部干预中选择特征。共有 62 人（50%）实现了坐位，中位年龄为 2.4 岁。在治疗时需要插 NG 或 G 型管的患者，其坐起时间的预测中位数平均比不需要插 NG 或 G 型管的患者晚 4 个月，这是影响最大的因素。治疗时的踢腿能力（在 HINE-2 项目中≥1）对预测坐起的可能性也有影响，同样有影响的还有仰卧时的反重力肩部运动和侧卧时的伸手能力（在项目 1 和 8 中为 4），以及治疗时的颈部肌肉激活（在项目 14 中为≥2）和从仰卧位完全俯卧翻滚（在项目 7 中为≥3）。最值得注意的是，与不能完全仰卧翻身的相同患者相比，能完全仰卧翻身的患者的中位预测坐位时间提前了 5.8 个月。奴西那生起始年龄和症状发作年龄的影响较小，而SMN2拷贝数并没有改善模型。这项研究提供了一种工具来预测接受奴西尼森治疗的患者的治疗反应，并有可能扩展到其他治疗方案，使临床医生为每位患者制定个性化的治疗计划。
{"title":"142P A preliminary machine learning retrospective observational study to predict treatment response to nusinersen in non-sitter spinal muscular atrophy","authors":"G. Stimpson , E. O'Reilly , G. Coratti , D. Ridout , T. Chakraborti , R. Mitra , E. Mercuri , M. Scoto , F. Muntoni , G. Baranello","doi":"10.1016/j.nmd.2024.07.049","DOIUrl":"10.1016/j.nmd.2024.07.049","url":null,"abstract":"<div><div>Disease-modifying treatments, such as nusinersen, have significantly improved the disease trajectory of Spinal Muscular Atrophy (SMA) patients. Treatment response is heterogeneous, and predicting response is crucial for clinicians to give realistic guidance to patients and carers when counselling about treatment options. We collected data on 124 patients from the SMA Reach UK and Italian Network studies. Participants were included if they were treated under 4 years and were non-sitters at nusinersen initiation, were randomly allocated to training (80%) and testing cohorts (20%). Tree and regression-based machine learning for survival outcomes were compared, and oblique random forests were selected, with a testing C-Index of 0.74. The features were selected from items of the CHOP and HINE-2, respiratory symptoms and bulbar interventions using mutual information. In total, 62 (50%) have achieved sitting, at a median age of 2.4 years. The predicted median time-to-sitting in those requiring NG or G-Tubes at treatment was 4-months later on average than those without, and this was the most influential factor. The ability to kick at treatment, (≥1 on the HINE-2 item) was also influential in predicting the likelihood of sitting, as was antigravity shoulder movement in supine and ability to reach in side-lying (4 on items 1 and 8), and neck muscle activation in pull to sit (≥2 on item 14) and rolling fully prone from supine when elicited from arms (≥3 on item 7) on the CHOP at treatment. Most notably, those who could roll fully prone from supine had a median predicted time-to-sit 5.8 months earlier than an identical patient who could not. Nusinersen starting and symptom onset age were less influential, whilst SMN2 copy numbers did not improve the model. This work provides a tool to predict treatment response in nusinersen-treated patients and has the potential to be extended to other treatment options, moving clinicians towards personalised treatment plans for each patient.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.40"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423505","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.2024.07.020
S. Ribault , P. Rippert , T. Lopinet , L. Le Goff , A. Barrière , M. Morard , J. Theuriet , A. Pegat , F. Boyer , C. Vuillerot
Spinal muscular atrophy is a motoneuron disease caused by a mutation of the SMN1 gene, at the origin of a limb and axial motor deficiency. The specificities of the quality of life of adult patients with SMA remain poorly described, as well as its link with participation as defined by the WHO in the International Classification of Function. This study aims to assess SMA adult patient's quality of life compared to other NMD patients, and to identify determinants of quality of life in SMA patients. Material and Adult individuals with a diagnosis of SMA gave an informed consent and filled an anonymous online questionnaire containing questions about medical and demographic data, the SMA independence scale (SMAIS), the QOLgNMD scale, the Rosenberg self-esteem scale, and questions regarding patients’ participation. 114 individuals were included. QOLgNMD self-perception domain and activities and participation domain were lower in the SMA population compared to the other NMD population (p<0.0001). There was no correlation between quality of life and the Brooke, Vignos or the SMAIS scales. The 3 domains of the QOLgNMD were significantly correlated with the level of stress, the Rosenberg scale and the satisfaction with life scale. SMA patients showed a lower quality of life regarding self-perception and activities and participation compared to other NMDs. However, motor function and independence do not appear to be determinants of quality of life. Assessing the determinants of quality of life is crucial to propose relevant outcomes for the evaluation of therapeutic interventions.
脊髓性肌萎缩症是一种由 SMN1 基因突变引起的运动神经元疾病，是肢体和轴性运动障碍的起源。关于 SMA 成年患者生活质量的特殊性及其与世界卫生组织在《国际功能分类》中定义的参与之间的联系，目前仍鲜有描述。本研究旨在评估 SMA 成年患者与其他 NMD 患者相比的生活质量，并确定 SMA 患者生活质量的决定因素。材料和成人确诊为 SMA 的患者在知情同意的情况下填写了一份匿名在线问卷，其中包含有关医疗和人口统计学数据、SMA 独立性量表 (SMAIS)、QOLgNMD 量表、罗森伯格自尊量表的问题以及有关患者参与的问题。共纳入 114 人。与其他 NMD 患者相比，SMA 患者的 QOLgNMD 自我感知领域以及活动和参与领域较低（p<0.0001）。生活质量与布鲁克量表、维格诺斯量表或 SMAIS 量表之间没有相关性。QOLgNMD 的 3 个领域与压力水平、罗森伯格量表和生活满意度量表显著相关。与其他 NMD 相比，SMA 患者在自我认知、活动和参与方面的生活质量较低。然而，运动功能和独立性似乎并不是生活质量的决定因素。评估生活质量的决定因素对于提出评估治疗干预措施的相关结果至关重要。
{"title":"113P Quality of life and participation of adults with spinal muscular atrophy: QOLSMA","authors":"S. Ribault , P. Rippert , T. Lopinet , L. Le Goff , A. Barrière , M. Morard , J. Theuriet , A. Pegat , F. Boyer , C. Vuillerot","doi":"10.1016/j.nmd.2024.07.020","DOIUrl":"10.1016/j.nmd.2024.07.020","url":null,"abstract":"<div><div>Spinal muscular atrophy is a motoneuron disease caused by a mutation of the SMN1 gene, at the origin of a limb and axial motor deficiency. The specificities of the quality of life of adult patients with SMA remain poorly described, as well as its link with participation as defined by the WHO in the International Classification of Function. This study aims to assess SMA adult patient's quality of life compared to other NMD patients, and to identify determinants of quality of life in SMA patients. Material and Adult individuals with a diagnosis of SMA gave an informed consent and filled an anonymous online questionnaire containing questions about medical and demographic data, the SMA independence scale (SMAIS), the QOLgNMD scale, the Rosenberg self-esteem scale, and questions regarding patients’ participation. 114 individuals were included. QOLgNMD self-perception domain and activities and participation domain were lower in the SMA population compared to the other NMD population (p<0.0001). There was no correlation between quality of life and the Brooke, Vignos or the SMAIS scales. The 3 domains of the QOLgNMD were significantly correlated with the level of stress, the Rosenberg scale and the satisfaction with life scale. SMA patients showed a lower quality of life regarding self-perception and activities and participation compared to other NMDs. However, motor function and independence do not appear to be determinants of quality of life. Assessing the determinants of quality of life is crucial to propose relevant outcomes for the evaluation of therapeutic interventions.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.11"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423567","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.2024.07.023
B. Buchignani , G. Coratti , C. Cutrì , C. Palermo , D. Leone , L. Antonaci , M. Pera , M. Pane , E. Mercuri
The advent of disease modifying therapies in Spinal Muscular Atrophy (SMA) has changed the natural history of the disease, increasing life expectancy and quality of life but, at the same time, raising new clinical challenges. The aim of this study is to explore the neurobehavioral profile in treated individuals with SMA type I and subjects identified by newborn screening (NBS). Twenty-eight individuals aged 2-10 years underwent a comprehensive behavioral assessment using three screening questionnaires (Strengths and Difficulties Questionnaire (SDQ), Social Communication Questionnaire (SCQ), and Sensory Profile (SP)), which provide information regarding the risk of behavioral disorders and autism. A cognitive evaluation, and a clinical observation were performed by two independent observers. Twenty-two individuals with SMA type I and 6 patients identified with NBS were included. None had abnormal clinical scores in the SCQ questionnaire, 4 had borderline scores, but in two of the 4 the scores were normal when the motor items were removed. SDQ showed some abnormal results in 10/28 subjects. The clinical observation confirmed the result of the screening questionnaires in 17/28 subjects and highlighted behavioral issues in 4/28 not detected by the questionnaires. Our findings confirm that neurobehavioral disorders may occur in subjects with SMA and highlight the challenges in choosing the appropriate assessment tools. Questionnaires such as SCQ do not appear to be adequate as they often failed to identify signs detected by other tools. SDQ appeared to be the most appropriate tool in our cohort. In our experience, a structured clinical observation was also helpful to identify behavioral problems, suggesting that, in the absence of disease specific tools, the use of different instruments may help to better identify the type and the frequency of behavioral problems.
脊髓性肌萎缩症（SMA）疾病修饰疗法的出现改变了该病的自然病史，延长了患者的预期寿命，提高了生活质量，但同时也提出了新的临床挑战。本研究旨在探讨接受治疗的 I 型 SMA 患者和通过新生儿筛查（NBS）确定的受试者的神经行为特征。28 名 2-10 岁的患者接受了全面的行为评估，评估中使用了三种筛查问卷（优势与困难问卷 (SDQ)、社会交流问卷 (SCQ) 和感官特征问卷 (SP)），这些问卷可提供有关行为障碍和自闭症风险的信息。认知评估和临床观察由两名独立观察员进行。研究共纳入了 22 名 I 型 SMA 患者和 6 名 NBS 患者。没有人在 SCQ 问卷中出现异常临床得分，4 人的得分处于边缘状态，但其中 2 人在去除运动项目后得分正常。有 10/28 名受试者的 SDQ 结果出现异常。临床观察证实了 17/28 名受试者的筛查问卷结果，并在 4/28 名受试者身上发现了问卷未发现的行为问题。我们的研究结果证实，SMA 患者可能会出现神经行为障碍，并强调了选择适当评估工具的挑战。SCQ 等问卷似乎并不合适，因为它们往往无法识别其他工具所发现的体征。在我们的队列中，SDQ 似乎是最合适的工具。根据我们的经验，结构化临床观察也有助于识别行为问题，这表明，在缺乏特定疾病工具的情况下，使用不同的工具可能有助于更好地识别行为问题的类型和频率。
{"title":"116P Exploring neurobehavioral disorders in type 1 and presymptomatic patients with spinal muscular atrophy","authors":"B. Buchignani , G. Coratti , C. Cutrì , C. Palermo , D. Leone , L. Antonaci , M. Pera , M. Pane , E. Mercuri","doi":"10.1016/j.nmd.2024.07.023","DOIUrl":"10.1016/j.nmd.2024.07.023","url":null,"abstract":"<div><div>The advent of disease modifying therapies in Spinal Muscular Atrophy (SMA) has changed the natural history of the disease, increasing life expectancy and quality of life but, at the same time, raising new clinical challenges. The aim of this study is to explore the neurobehavioral profile in treated individuals with SMA type I and subjects identified by newborn screening (NBS). Twenty-eight individuals aged 2-10 years underwent a comprehensive behavioral assessment using three screening questionnaires (Strengths and Difficulties Questionnaire (SDQ), Social Communication Questionnaire (SCQ), and Sensory Profile (SP)), which provide information regarding the risk of behavioral disorders and autism. A cognitive evaluation, and a clinical observation were performed by two independent observers. Twenty-two individuals with SMA type I and 6 patients identified with NBS were included. None had abnormal clinical scores in the SCQ questionnaire, 4 had borderline scores, but in two of the 4 the scores were normal when the motor items were removed. SDQ showed some abnormal results in 10/28 subjects. The clinical observation confirmed the result of the screening questionnaires in 17/28 subjects and highlighted behavioral issues in 4/28 not detected by the questionnaires. Our findings confirm that neurobehavioral disorders may occur in subjects with SMA and highlight the challenges in choosing the appropriate assessment tools. Questionnaires such as SCQ do not appear to be adequate as they often failed to identify signs detected by other tools. SDQ appeared to be the most appropriate tool in our cohort. In our experience, a structured clinical observation was also helpful to identify behavioral problems, suggesting that, in the absence of disease specific tools, the use of different instruments may help to better identify the type and the frequency of behavioral problems.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.14"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423571","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.2024.07.026
U. Werlauff , L. Busk , P. Drivsholm , B. Heiden , R. Iversen , H. Laustsen , A. Mahoney , L. Olesen , C. Handberg
Medical treatment for 5q spinal muscular atrophy (SMA) is now standard treatment in many countries, and a growing number of studies report on improvement or stabilization in physical function as a result of medical treatment. Different countries have different practices regarding the target group for medical treatment. Age and level of function have been decisive criteria for receiving the treatment. Until July 2023, the Danish medical council had approved initiation of medical treatment for children up to 10 years of age, and during the spring of 2023 it were to be determined whether the patient target group could be expanded. Based on this potential expansion, the aim of the study was to evaluate the current physical functioning in a national cohort of patients > 10 years and – in case treatment was approved – to repeat the evaluation six month after initiation of treatment. Due to the size of the target group (n=136) and the narrow time frame it was decided to narrow the target group to non-ambulant patients and perform the evaluation online. The evaluation included two items from the revised upper limb scale (RULM) (lift hands, pick up and hold coins), the EK2-scale (17 items), Fatigue Severity Scale (7 items), a brief questionnaire on patient expectations before treatment and an online interview about experiences after initiation of treatment. 57 patients accepted the invitation, answered the questionnaire, and were examined online during the spring of 2023. In July 2023, the Danish medical council decided to expand the target group to patients up to 25 years of age. 11/57 patients met the new criteria and accepted treatment. Follow-up examinations of these patients are ongoing. Results will be reported on the poster.
{"title":"119P Evaluation of physical function before and after medical treatment in patients with Spinal Muscular Atrophy aged 11-25 years","authors":"U. Werlauff , L. Busk , P. Drivsholm , B. Heiden , R. Iversen , H. Laustsen , A. Mahoney , L. Olesen , C. Handberg","doi":"10.1016/j.nmd.2024.07.026","DOIUrl":"10.1016/j.nmd.2024.07.026","url":null,"abstract":"<div><div>Medical treatment for 5q spinal muscular atrophy (SMA) is now standard treatment in many countries, and a growing number of studies report on improvement or stabilization in physical function as a result of medical treatment. Different countries have different practices regarding the target group for medical treatment. Age and level of function have been decisive criteria for receiving the treatment. Until July 2023, the Danish medical council had approved initiation of medical treatment for children up to 10 years of age, and during the spring of 2023 it were to be determined whether the patient target group could be expanded. Based on this potential expansion, the aim of the study was to evaluate the current physical functioning in a national cohort of patients > 10 years and – in case treatment was approved – to repeat the evaluation six month after initiation of treatment. Due to the size of the target group (n=136) and the narrow time frame it was decided to narrow the target group to non-ambulant patients and perform the evaluation online. The evaluation included two items from the revised upper limb scale (RULM) (lift hands, pick up and hold coins), the EK2-scale (17 items), Fatigue Severity Scale (7 items), a brief questionnaire on patient expectations before treatment and an online interview about experiences after initiation of treatment. 57 patients accepted the invitation, answered the questionnaire, and were examined online during the spring of 2023. In July 2023, the Danish medical council decided to expand the target group to patients up to 25 years of age. 11/57 patients met the new criteria and accepted treatment. Follow-up examinations of these patients are ongoing. Results will be reported on the poster.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.17"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423574","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.2024.07.080
R. Ramesh Babu , I. Kinimi , S. Shinde , N. Mohan Rao , A. Sahoo , M. Maganthi , A. Agnes Mathew
<div><div>Neuromuscular disorders (NMD) have seen a revolution in the availability of novel disease-modifying therapies (DMT) in the last few years. Yet affected individuals often gain suboptimal improvement despite these, due to the paucity of robust allied supportive specialities such as sleep medicine. Sleep Disordered Breathing (SDB) is fairly common in NMD and is the leading cause of death in them. Hence, non-invasive ventilation (NIV) is a crucial part of SDB management. This is often challenging where resources are limited. Here we describe the approach of our referral neuromuscular centre in establishing home mechanical ventilation (HMV) and respiratory care including cough assist. Clinical details of children with neuromuscular diseases attending our centre between January 2018 and August 2022 with SDB were collected by retrospective data review. Level 1 polysomnography (PSG) results of those who underwent the test were retrieved and analysed. 296 children (male: 67.2%, female: 22.8%) with NMD were thus included. The majority of our cohort had spinal muscular atrophy (SMA,165/296), followed by Duchenne muscular dystrophy (DMD, 67/296) and the remaining had other NMD (64/296). 164/296 (55.4%) subjects underwent a PSG. The median Apnoea Hypopnea Index (AHI) was 8.0 (0.3 - 78) per hour of total sleep time. Interestingly, 59.14% of our cohort had moderate to severe OSA. PSG could not be carried out for all individuals with clinical symptoms of SDB due to economic constraints, lack of resources and availability in carrying out PSG in children at a tertiary care unit with its attendant waiting times. Hence we initiated HMV in all subjects with NMD either when they had clinically overt symptoms of SDB or when the PSG supported it or both. HMV was initiated in 243/296 (82.1%) of the subjects included in our cohort. 14 of these individuals underwent a tracheostomy, 32 used cough assist, 22 were on nasogastric tube feeds and 20 underwent gastrostomy with fundoplication. In the subset with SMA: 69/165 (41.87%) children had received one of the DMTs like gene therapy (32/69) or Risdiplam (17/69) or Spinraza (20/69). Initiation of HMV reduced hospital admissions and improved quality of life. 15 children succumbed due to respiratory failure. The use of HMV and cough assist is well established in resource-equipped settings, but is extremely challenging in resource-limited ones, where affected individuals often receive DMT, due to various charitable initiatives without the benefit of adequate respiratory support. But even with these challenges such as long waiting times for PSG, the financial and logistical challenges including those for BiPAP (Bilevel Positive Airway pressure) as well as the cough assistive devices, it is still possible to ensure that subjects have access to them to gain meaningful outcomes from DMTs. In the long run, early initiation reduces the economic burden, both in terms of morbidity and mortality. A low threshold for initiation o
{"title":"229P Home mechanical ventilation in paediatric neuromuscular disorders in a resource limited setting","authors":"R. Ramesh Babu , I. Kinimi , S. Shinde , N. Mohan Rao , A. Sahoo , M. Maganthi , A. Agnes Mathew","doi":"10.1016/j.nmd.2024.07.080","DOIUrl":"10.1016/j.nmd.2024.07.080","url":null,"abstract":"<div><div>Neuromuscular disorders (NMD) have seen a revolution in the availability of novel disease-modifying therapies (DMT) in the last few years. Yet affected individuals often gain suboptimal improvement despite these, due to the paucity of robust allied supportive specialities such as sleep medicine. Sleep Disordered Breathing (SDB) is fairly common in NMD and is the leading cause of death in them. Hence, non-invasive ventilation (NIV) is a crucial part of SDB management. This is often challenging where resources are limited. Here we describe the approach of our referral neuromuscular centre in establishing home mechanical ventilation (HMV) and respiratory care including cough assist. Clinical details of children with neuromuscular diseases attending our centre between January 2018 and August 2022 with SDB were collected by retrospective data review. Level 1 polysomnography (PSG) results of those who underwent the test were retrieved and analysed. 296 children (male: 67.2%, female: 22.8%) with NMD were thus included. The majority of our cohort had spinal muscular atrophy (SMA,165/296), followed by Duchenne muscular dystrophy (DMD, 67/296) and the remaining had other NMD (64/296). 164/296 (55.4%) subjects underwent a PSG. The median Apnoea Hypopnea Index (AHI) was 8.0 (0.3 - 78) per hour of total sleep time. Interestingly, 59.14% of our cohort had moderate to severe OSA. PSG could not be carried out for all individuals with clinical symptoms of SDB due to economic constraints, lack of resources and availability in carrying out PSG in children at a tertiary care unit with its attendant waiting times. Hence we initiated HMV in all subjects with NMD either when they had clinically overt symptoms of SDB or when the PSG supported it or both. HMV was initiated in 243/296 (82.1%) of the subjects included in our cohort. 14 of these individuals underwent a tracheostomy, 32 used cough assist, 22 were on nasogastric tube feeds and 20 underwent gastrostomy with fundoplication. In the subset with SMA: 69/165 (41.87%) children had received one of the DMTs like gene therapy (32/69) or Risdiplam (17/69) or Spinraza (20/69). Initiation of HMV reduced hospital admissions and improved quality of life. 15 children succumbed due to respiratory failure. The use of HMV and cough assist is well established in resource-equipped settings, but is extremely challenging in resource-limited ones, where affected individuals often receive DMT, due to various charitable initiatives without the benefit of adequate respiratory support. But even with these challenges such as long waiting times for PSG, the financial and logistical challenges including those for BiPAP (Bilevel Positive Airway pressure) as well as the cough assistive devices, it is still possible to ensure that subjects have access to them to gain meaningful outcomes from DMTs. In the long run, early initiation reduces the economic burden, both in terms of morbidity and mortality. A low threshold for initiation o","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.71"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423583","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.2024.07.014
J. Vencovský, H. Mann
The idiopathic inflammatory myopathies are a heterogeneous group of acquired diseases comprising dermatomyositis (DM), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis (IBM) and myositis occurring in overlap syndromes with other autoimmune systemic diseases. Drug-induced myositis is increasingly seen in association with treatment with statins or checkpoint inhibitors. International collaboration projects in the last decade resulted in better understanding of the genetic predisposition and etiopathogenetic pathways leading to disease initiation and progression, in development of the new disease classification and treatment response criteria, and in a number of large-scale clinical trials with several biologic or targeted synthetic drugs. The new recommendations for cancer screening in myositis are an important clinical aid. In addition to more refined characterisation of the association with HLA molecules, the relationship of IIM to other non-HLA genes or to low gene copy number of complement has been demonstrated. Further evidence is emerging for an important role of autoantibodies, not only in relation to clinical manifestations and prognosis, but also in terms of a possible pathogenic effect in the disease. Attention is now also being paid to organ involvement in myositis, particularly the lungs, as new therapeutic options for interstitial lung disease became available. Several new clinical trials with biologics have generally failed to demonstrate sufficient efficacy in the treatment of IIM, although there are signals of a possible benefit in some subtypes of IIM. A landmark clinical trial with intravenous immunoglobulins has provided evidence of significant efficacy in patients with DM leading to a new regulatory approval in many years. A number of other clinical trials are currently underway in various subtypes of IIM, including notoriously resistant IBM, with drugs that have very intriguing mechanisms of action and some have already been shown to be effective in similar immune-mediated diseases. Results will be known in the coming months/years.
{"title":"03INV Idiopathic inflammatory myopathies: current state of the field, new insights and treatment","authors":"J. Vencovský, H. Mann","doi":"10.1016/j.nmd.2024.07.014","DOIUrl":"10.1016/j.nmd.2024.07.014","url":null,"abstract":"<div><div>The idiopathic inflammatory myopathies are a heterogeneous group of acquired diseases comprising dermatomyositis (DM), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis (IBM) and myositis occurring in overlap syndromes with other autoimmune systemic diseases. Drug-induced myositis is increasingly seen in association with treatment with statins or checkpoint inhibitors. International collaboration projects in the last decade resulted in better understanding of the genetic predisposition and etiopathogenetic pathways leading to disease initiation and progression, in development of the new disease classification and treatment response criteria, and in a number of large-scale clinical trials with several biologic or targeted synthetic drugs. The new recommendations for cancer screening in myositis are an important clinical aid. In addition to more refined characterisation of the association with HLA molecules, the relationship of IIM to other non-HLA genes or to low gene copy number of complement has been demonstrated. Further evidence is emerging for an important role of autoantibodies, not only in relation to clinical manifestations and prognosis, but also in terms of a possible pathogenic effect in the disease. Attention is now also being paid to organ involvement in myositis, particularly the lungs, as new therapeutic options for interstitial lung disease became available. Several new clinical trials with biologics have generally failed to demonstrate sufficient efficacy in the treatment of IIM, although there are signals of a possible benefit in some subtypes of IIM. A landmark clinical trial with intravenous immunoglobulins has provided evidence of significant efficacy in patients with DM leading to a new regulatory approval in many years. A number of other clinical trials are currently underway in various subtypes of IIM, including notoriously resistant IBM, with drugs that have very intriguing mechanisms of action and some have already been shown to be effective in similar immune-mediated diseases. Results will be known in the coming months/years.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.5"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423645","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.2024.07.098
S. Tamura, I. Sidhu, J. Ilagan, A. Yu, A. Byer, S. Kamath, L. Staskus, C. Russell, A. Melton, K. Larimore
BMN 351, a next-generation antisense oligonucleotide (ASO), is being developed for the treatment of people with Duchenne muscular dystrophy (DMD) who have mutations amenable to exon 51 skipping. Out-of-frame dystrophin mRNA transcripts are converted by exon 51 skipping to in-frame, near-full–length, functional dystrophin transcripts. In-frame dystrophin mRNA expression is an early pharmacodynamic marker of BMN 351 activity. Current standard methods measure mRNA skipping by calculating the percentage of in-frame (exon skipped) dystrophin transcripts over total dystrophin transcripts. However, the relationship between exon skip percentage and dystrophin protein expression is unclear, as measurement of exon skip percentage does not account for reduced total dystrophin mRNA in DMD muscle. Here, we propose a novel assay strategy that quantifies functional in-frame dystrophin mRNA as a percentage of normal in-frame dystrophin transcripts from control muscle. This enhances the value of dystrophin mRNA measurements and better aligns with and predicts protein expression. Using in silico data mining and experimental verification, we identified both ubiquitously expressed and muscle-specific normalizer transcripts that can be measured in a multiplex ddPCR method with in-frame and total dystrophin mRNA. Ubiquitously expressed normalizers enable reporting of in-frame dystrophin mRNA levels normalized to total cellular content, compensating for varying RNA quantity and quality between samples. Muscle-specific normalizers provide insight into in-frame dystrophin mRNA expression per muscle cell in biopsies that may contain inflammatory infiltrate and adipocyte cells that vary with disease state and across individual biopsies. In this next-generation multiplex approach we propose a strategy to provide a more comprehensive and clinically relevant evaluation of mRNA expression that may be more predictive of functional dystrophin protein levels following ASO treatment for DMD.
{"title":"361P Development of a next-generation multiplex ddPCR assay for measurement of in-frame dystrophin mRNA in people with DMD treated with BMN 351","authors":"S. Tamura, I. Sidhu, J. Ilagan, A. Yu, A. Byer, S. Kamath, L. Staskus, C. Russell, A. Melton, K. Larimore","doi":"10.1016/j.nmd.2024.07.098","DOIUrl":"10.1016/j.nmd.2024.07.098","url":null,"abstract":"<div><div>BMN 351, a next-generation antisense oligonucleotide (ASO), is being developed for the treatment of people with Duchenne muscular dystrophy (DMD) who have mutations amenable to exon 51 skipping. Out-of-frame dystrophin mRNA transcripts are converted by exon 51 skipping to in-frame, near-full–length, functional dystrophin transcripts. In-frame dystrophin mRNA expression is an early pharmacodynamic marker of BMN 351 activity. Current standard methods measure mRNA skipping by calculating the percentage of in-frame (exon skipped) dystrophin transcripts over total dystrophin transcripts. However, the relationship between exon skip percentage and dystrophin protein expression is unclear, as measurement of exon skip percentage does not account for reduced total dystrophin mRNA in DMD muscle. Here, we propose a novel assay strategy that quantifies functional in-frame dystrophin mRNA as a percentage of normal in-frame dystrophin transcripts from control muscle. This enhances the value of dystrophin mRNA measurements and better aligns with and predicts protein expression. Using in silico data mining and experimental verification, we identified both ubiquitously expressed and muscle-specific normalizer transcripts that can be measured in a multiplex ddPCR method with in-frame and total dystrophin mRNA. Ubiquitously expressed normalizers enable reporting of in-frame dystrophin mRNA levels normalized to total cellular content, compensating for varying RNA quantity and quality between samples. Muscle-specific normalizers provide insight into in-frame dystrophin mRNA expression per muscle cell in biopsies that may contain inflammatory infiltrate and adipocyte cells that vary with disease state and across individual biopsies. In this next-generation multiplex approach we propose a strategy to provide a more comprehensive and clinically relevant evaluation of mRNA expression that may be more predictive of functional dystrophin protein levels following ASO treatment for DMD.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.89"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423992","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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