AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice

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Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever Study to Assess Risk Tolerance in the SMA Patient Community

PurposePatients’ perceptions of benefit–risk are essential to informing the regulatory process and the context in which potential therapies are evaluated. To bring this critical information to regulators, Cure SMA launched a first-ever Benefit-Risk Survey for spinal muscular atrophy (SMA) to characterize decision-making and benefit–risk trade-offs in SMA associated with a potential therapy. We hypothesized that risk tolerance would be correlated with SMA type/severity and disease progression. This article presents the results of a benefit–risk survey to enhance understanding of how patients with SMA and caregivers evaluate specific benefits and risks associated with potential therapies.MethodsAffected adults, representing all SMA types (I–IV) within the Cure SMA database, and caregivers of affected individuals of all ages/types were invited via e-mail to participate. Best–worst scaling (BWS) was used to assess participants’ priorities on benefit–risk trade-offs, as it provides higher discrimination and importance scaling among tested attributes. Twelve potentially clinically meaningful treatment benefits and 11 potential risks (ranging in severity and immediacy) were tested. Multiple factors were correlated with individual responses, including: SMA type/disease severity, stage of disease, respondent type, sex, and quality of life/level of independence (current and expected). Survey respondents were also evaluated for "risk-taking attitudes."FindingsA total of 298 responses were evaluated (28% affected adults and 72% caregivers, mostly parents). Most respondents were diagnosed >5 years ago (67.3%), with 22.1% SMA type I, 45.6% SMA type II, and 27.9% SMA type III. No strong correlation was found between risk tolerance and SMA type, stage of disease progression, respondent type, sex, quality of life assessment, or rated levels of independence. Irrespective of SMA type, respondents consistently rated the following risks, associated with a potential treatment, as "least tolerable": life-threatening allergic reactions; 1 in 1000 risk of life-threatening side effects leading to possible organ failure; or worsening quality of life. Furthermore, all SMA type respondents rated these risks as "most tolerable": invasive mode of treatment administration (including need for general anesthesia); side effect of dizziness; and other common side effects such as nausea, vomiting, loss of appetite, headaches, back pain, or fatigue.ImplicationsWith the approval of the first SMA treatment, these findings offer a unique opportunity to assess and characterize baseline risk-tolerance in SMA against which to evaluate future SMA treatment options. Although differences had been expected in risk tolerance among respondents based on disease baseline and certain patient attributes, this was not observed. Survey results should inform future SMA drug development and benefit–risk assessments.     

聚合酶链反应用于进行性脊髓性肌萎缩的诊断

目的了解儿童期发作的进行性脊髓性肌萎缩（ＳＭＡ）患者的运动神经元存活基因（ＳＭＮ）的缺失，探讨聚合酶链反应限制性片段长度多态性（ＰＣＲＲＦＬＰ）技术用于检测ＳＭＡ疾病的诊断价值。方法应用ＰＣＲＲＦＬＰ技术对１０例拟诊为ＳＭＡ患者、６个家系的２０例非ＳＭＡ成员及３０例正常人的ＳＭＮ基因外显子７和８进行了检测。结果１０例ＳＭＡ可疑患者中９例（９０％）有ＳＭＮ基因缺失，其中仅外显子７或８缺失各为１例。家系其他成员及对照组均无ＳＭＮ端粒基因缺失。结论用ＰＣＲＲＦＬＰ法对高度可疑ＳＭＡ的病例进行诊断，具有较高敏感性和特异性，简便易行     

应用多重连接依赖探针扩增技术对脊髓性肌萎缩患者及致病基因携带者进行基因诊断

目的探讨多重连接依赖探针扩增（MLPA）技术对脊髓性肌萎缩（SMA）患者及携带者基因检测的临床应用价值,为进一步创建可靠的SMA产前诊断技术平台奠定基础。方法运用MLPA技术对6例SMA患者及双亲进行运动神经元生存基因（survival of motor neuron gene,SMN）检测,用PCR限制性内切酶片段长度多态性技术（PCR-RFLP）和DNA测序技术对MLPA检测结果进行验证。结果 MLPA试剂盒P021-A1检测6个患者中4个患者为SMN1的外显子7和外显子8缺失纯合子,2个患者为SMN1外显子7缺失纯合子;6例患者的12名双亲的SMN信号值均明显比正常对照组低30%～50%。同时还检测出部分患者及携带者GTF2H2（BTF2p44）和BIRC1（NAIP）基因存在病变。P060-A2检测出12名携带者SMN1信号比正常对照组降低30%～50%,其中3名合并BIRC1基因信号降低。PCR-RFLP和DNA测序技术支持MLPA有关SMN基因检测结果。结论 MLPA技术能对SMA患者及携带者进行快速可靠的基因诊断。通过MLPA技术分析SMN邻近基因的基因突变和（或）缺失情况,为SMA患者基因型和临床分型诊断提供依据。     

Muscle Ultrasound Changes Correlate With Functional Impairment in Spinal Muscular Atrophy

ObjectiveWe investigated ultrasound patterns of muscle involvement in different types of spinal muscular atrophy (SMA) and their correlation with functional status to determine the pattern of muscle compromise in patients with SMA and the potential role of ultrasound to evaluate disease progression.MethodsWe examined muscles (biceps brachii, rectus femoris, diaphragm, intercostals and thoracic multifidus) of 41 patients with SMA (types 1 to 4) and 46 healthy age- and sex-matched control individuals using B-mode ultrasound for gray-scale analysis (GSA), area (biceps brachii and rectus femoris) and diaphragm thickening ratio. Functional scales were applied to patients only. We analyzed ultrasound abnormalities in specific clinical subtypes and correlated findings with functional status.ResultsCompared with controls, patients had reduced muscle area and increased mean GSA for all muscles (p < 0.001), with an established correlation between the increase in GSA and the severity of SMA for biceps brachii, rectus femoris and intercostals (p = 0.03, 0.01 and 0.004 respectively) when using the Hammersmith Functional Motor Scale Expanded. Diaphragm thickening ratio was normal in the majority of patients, and intercostal muscles had higher GSA than diaphragm in relation to the controls.ConclusionUltrasound is useful for quantifying muscular changes in SMA and correlates with functional status. Diaphragm thickening ratio can be normal even with severe compromise of respiratory muscles in quantitative analysis, and intercostal muscles were more affected than diaphragm.     

减重平板步行训练对完全性脊髓损伤患者下肢骨骼肌萎缩与步行能力的影响

目的研究减重平板步行训练对完全性脊髓损伤患者下肢骨骼肌萎缩与步行能力的影响。方法20例胸段完全性脊髓损伤患者分为对照组与减重组各10例。所有患者均采用综合康复治疗方法,减重组在身体条件许可的情况下及早接受减重平板步行训练3个月。在训练前后对患者进行大腿周经测量、功能独立性评定(FIM)步行能力评定、10m步行速度、日常生活活动能力(ADL)评定。减重组患者还在减重平板步行训练前后进行下肢大腿中部肌肉MRI检查。结果减重组患者训练后,MRI示下肢肌肉均较训练前相对肥大。减重组步行能力、10m步行速度的恢复优于对照组(P<0.05)。治疗前后减重组与对照组大腿周经、ADL评分无显著性差异(P>0.05)。结论减重平板步行训练不仅能够改善脊髓损伤引起的下肢骨骼肌萎缩,而且能够提高脊髓损伤患者的步行能力。     

产褥期妇女自我护理需求的质性分析

目的探讨产褥期妇女对自我护理的本质需求,识别产妇自护需求及自护缺陷。方法采用质性研究中的现象学研究,对15位产妇进行半结构访谈,收集产妇自我护理需求的相关资料,并进行分析整理提炼主题。结果提炼出4个主题:自护观念转变的需求,自护知识学习的需求,自护技能实践的需求,自护能力随访评估的需求。结论通过质性研究可以深入了解产褥期妇女自我护理的需求和缺陷,为医护人员采取相应的自我护理系统和针对性的护理措施提供依据,从而促进母婴健康。     

Molecular Therapeutic Strategies for Spinal Muscular Atrophies: Current and Future Clinical Trials

Background

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the survival motor neuron gene (SMN1) and the leading genetic cause of infant mortality. Currently, there is no effective treatment other than supportive care.

Objective

This article provides a general overview of the main aspects that need to be taken into account to design a more efficient clinical trial and to summarize the most promising molecular trials that are currently in development or are being planned for the treatment of SMA.

Methods

A systematic review of the literature was performed, identifying key clinical trials involving novel molecular therapies in SMA. In addition, abstracts presented at the meetings of the Families of Spinal Muscular Atrophy were searched and the Families of Spinal Muscular Atrophy Web site was carefully analyzed. Finally, a selection of SMA clinical trials registered at clinical- trials.gov has been included in the article.

Results

The past decade has seen a marked advancement in the understanding of both SMA genetics and molecular mechanisms. New molecules targeting SMN have shown promise in preclinical studies, and various clinical trials have started to test the drugs that were discovered through basic research.

Conclusions

Both preclinical and early clinical trial results involving novel molecular therapies suggest that the clinical care paradigm in SMA will soon change.     

Electrical Impedance Myography in the Assessment of Disuse Atrophy

Tarulli AW, Duggal N, Esper GJ, Garmirian LP, Fogerson PM, Lin CH, Rutkove SB. Electrical impedance myography in the assessment of disuse atrophy.

Objective

To quantify disuse atrophy using electrical impedance myography (EIM), a noninvasive technique that we have used successfully to study neurogenic and myopathic atrophy.

Design

We performed EIM of the tibialis anterior of subjects with disuse atrophy secondary to cast immobilization and in their contralateral normal leg. Subjects were studied shortly after cast removal and again several weeks to months after the cast was removed and normal mobility was restored.

Setting

Outpatient neurology and orthopedic practices at a tertiary care medical center.

Participants

Otherwise healthy subjects (N=10) with unilateral leg fracture.

Interventions

Not applicable.

Main Outcome Measures

Resistance, reactance, and phase measured at 50kHz.

Results

The main EIM outcome parameter, phase at 50kHz, was lower in the immobilized leg in 9 of 10 cases. Additionally, when normal mobility was restored, the phase of the casted leg increased relative to its initial measurement in all 10 cases, while it increased inconsistently in the contralateral leg.

Conclusions

EIM may be a powerful tool for the assessment of disuse atrophy.     

儿童进行性肌营养不良误诊为病毒性肝炎五例临床分析

目的分析进行性肌营养不良的临床特点,以提高诊断水平。方法凹顾性分析2008年1月-2011年12月在我院诊断为假性肥大型肌营养不良的5例患儿的临床资料。结果本组5例为男性患儿,均误诊为病毒性肝炎,误诊时间为10d～4年。临床表现为运动发育落后或障碍5例,腓肠肌肥大3例,Gower,止阳性3例,母系阳性家族史1例;查血清肌酸激酶6060～21200U／L,丙氨酸转氨酶216～375U／L,天冬氨酸转氨酶202～415U／L;肌电图显示肌源性损害5例。临床均诊断为似性肥大型肌营养不良,予营养、支持治疗,随访3～40个月临床症状、体征硬缸清肌酶仍无明显改善、结论临床接诊原因不明的持续性且经治疗效果仍不佳的转氨酶升高的男性患儿应想到进行性肌营养不良的呵能,及时进行肌酶、肌电图检查或基因检测,以利于及早诊治。     

Orem自理理论在胰岛素泵治疗患者中的临床应用

目的 有效控制血糖,提高糖尿病患者生活质量.方法 60例糖尿病患者随机分为实验组(30例)及对照组(30例).两组患者采用不同的护理系统及健康教育,比较带泵后7 d不同时间点(空腹,早餐后2 h,午餐后2 h,晚餐后2 h,22:00,03:00)血糖,低血糖发生率,皮下红肿、硬结发生率,病人的满意度.结果 实验组病人不同时间点血糖、低血糖发生率、皮下红肿、硬结发生率、病人的满意度明显优于对照组(P＜0.01,P＜0.05).结论 应用Orem自理理论能帮助糖尿病胰岛素泵治疗患者有效控制血糖,减少和延缓糖尿病各种并发症,提高患者生活质量.     

Almost Normal: Experiences of Adolescents With Implantable Cardioverter Defibrillators

PURPOSE.  The purpose of this study was to describe the experiences of adolescents with implantable cardioverter defibrillators (ICDs).
DESIGN AND METHODS.  This qualitative study explored the lived experiences of 14 adolescents with ICDs using face-to-face, semistructured interviews.
RESULTS.  Six themes were identified: life interrupted; still the same, except; sometimes it's tough; it cuts both ways; unique joule; and living life regular.
PRACTICE IMPLICATIONS.  These findings suggest that nurses could make a significant impact on the lives of adolescents with ICDs by focusing their efforts away from viewing the adolescent through an illness lens and more toward a normalization lens.     

自我护理训练对脊髓损伤患者情绪及生活活动能力的影响

目的探讨自我护理训练对脊髓损伤患者情绪及生活活动能力的影响。方法 2014年6月至2015年6月,便利抽样选取本院收治的84例脊髓损伤患者为研究对象,根据抽签法将患者分为观察组及对照组各42例,对照组应用常规护理,观察组应用自我护理训练,对比分析两组患者干预前后负性情绪及生活活动能力的变化。结果观察组干预1个月、3个月、6个月时康复评分均高于对照组(均P0.05);观察组干预后焦虑自评量表、抑郁自评量表评分均低于对照组(均P0.05),而总体健康、生理功能、生理职能、社会功能、健康精神、情感职能等方面评分均高于对照组(均P0.05)。结论自我护理训练能有效改善脊髓损伤患者负性情绪,促进患者康复,提高患者生活质量。     

门诊青少年癫痫患儿自我管理需求的质性研究

目的了解门诊青少年癫痫患儿自我管理需求,为构建癫痫患儿的照护模式提供理论依据。方法采用目的抽样法,选取2020年6月1日—12月31日在江苏省某医科大学附属三级甲等医院神经内科门诊就诊的10例青少年癫痫患儿为研究对象,采用质性研究设计,应用半结构访谈法对研究对象进行深度访谈,采用Nvivo 10.0软件进行资料分析。结果通过资料分析门诊青少年癫痫患儿自我管理需求,提炼出3个主题,分别为信息需求、心理支持需求、社会支持需求。结论根据门诊青少年癫痫患儿自我管理需求分析,医护人员应该注重满足患儿的信息需求,支持患儿心理需求,加强社会支持,应重视家庭以及学校的作用,适应新形势,拓展服务领域,构建适合青少年癫痫患儿自我管理照护模式。