Evaluation of Oxidative Capacity and Exercise Tolerance in Ambulatory Patients with Spinal Muscular Atrophy

 描述（由申请方提供）：拟定的研究项目将侧重于脊髓性肌萎缩症（SMA）患者运动能力降低的病理生理学基础。不卧床的SMA患者氧化能力显着降低，对运动的条件反射减弱。相比之下，其他神经肌肉疾病从有氧训练的运动计划中获得显着的益处，尽管具有类似的临床表现和功能限制。有实验室证据表明，线粒体生物发生的分子机制可能容易受到SMN缺乏的影响。与瘦体重和疾病严重程度不成比例的氧化能力降低将进一步支持SMA中线粒体耗竭的证据。替代运动训练策略和/或伴随的靶向治疗干预可能是必要的，以实现有氧条件作用。了解腿部肌肉群之间的组成和氧化能力的潜在差异将允许定向运动训练范式利用最适合引起训练效果的肌肉群。 该提案将重点关注（1）使用近红外光谱法估计运动期间特定肌群的氧化能力，以及（2）描述身体成分，以更好地了解非卧床SMA患者和疾病对照组的运动能力和线粒体功能。这是一项为期6个月的观察性研究，包括14例非卧床SMA患者、14例非卧床线粒体肌病患者和14例健康对照。线粒体肌病患者作为理想的疾病控制人群，因为虽然线粒体与这两种疾病有关，并且它们可能表现出相似的表型，但导致运动不耐受的机制是不同的。在临床上，线粒体患者是理想的疾病比较，因为（1）他们代表了广泛的表型谱，（2）包括儿童和成人，（3）在先前使用踏车测力计的研究中已经证明了有氧调节的益处。所有参与者将接受两次访视，间隔6个月，以进行评估和数据收集。访视评估将包括次极量运动期间腿部肌肉群的近红外光谱，以确定氧化能力。将使用相同肌肉群的双能X线吸收测定法（DEXA）和节段性生物电阻抗分析（BIA）评价身体成分。其他临床评估将包括运动耐量测试、6分钟步行测试（6 MWT）和步态分析、定时起身和行走测试以及腿部肌肉群的手动和定量力量评估。强度和功能的临床评估是必要的，以量化疾病的严重程度，并与疾病负担的生理评估进行比较。 SMA是影响儿童的最常见的遗传决定的神经肌肉疾病之一，导致发育障碍。与尤尼斯·肯尼迪施里弗国家儿童健康和发展研究所的使命一致，该项目处理与疾病有关的重要残疾问题，并将有助于指导未来的医疗康复方案。

 DESCRIPTION (provided by applicant): The proposed research project will focus on the pathophysiological underpinnings of reduced exercise capacity in patients with Spinal Muscular Atrophy (SMA). Ambulatory patients with SMA have a marked reduction in oxidative capacity and a blunted conditioning response to exercise. In contrast, other neuromuscular conditions derive significant benefit from exercise programs of aerobic conditioning despite having similar clinical presentations and functional limitations. There has been laboratory evidence to suggest that the molecular mechanisms underlying mitochondrial biogenesis may be vulnerable to SMN deficiency. A reduction in oxidative capacity disproportionate to lean mass and disease severity would further support evidence of mitochondrial depletion in SMA. Alternative exercise training strategies and/ or concomitant targeted therapeutic intervention may be necessary to achieve an aerobic conditioning effect. Understanding potential differences in composition and oxidative capacity among leg muscle groups will permit directed exercise training paradigms exploiting muscle groups most amenable to elicit a training effect. This proposal will focus on (1) estimating oxidative capacity of specific muscle groups during exercise using near infrared spectroscopy and (2) describing body composition to better understand exercise capacity and mitochondrial function in ambulatory SMA patients and disease controls. It is a 6-month observational study including 14 ambulatory SMA patients, 14 ambulatory patients with mitochondrial myopathy, and 14 healthy controls. Mitochondrial myopathy patients serve as the ideal disease control population because while the mitochondria is implicated in both disorders and phenotypically they may present similarly, the mechanism causing exercise intolerance is different. Clinically, mitochondrial patients are the ideal disease comparison because (1) they represent a broad phenotypic spectrum, (2) include children and adults, and (3) have demonstrated benefit to aerobic conditioning in previous studies using cycle ergometry. All participants will undergo two visits, 6 months apart, for assessment and data collection. Visit assessments will include near infra-red spectroscopy of leg muscle groups during submaximal exercises to determine oxidative capacity. Dual energy x-ray absorptiometry (DEXA) and segmental bioelectrical impedance analysis (BIA) of the same muscle groups will be used to evaluate body composition. Additional clinical assessments will include exercise tolerance testing, the six minute walk test (6MWT) with gait analysis, timed up and go test, and manual and quantitative strength assessments of leg muscle groups. Clinical assessments of strength and function are necessary to quantify disease severity and for comparison to physiological assessments of disease burden. SMA is one of the most common genetically determined neuromuscular disorders affecting children resulting in developmental disability. Consistent with the mission of the Eunice Kennedy Schriever National Institute of Child Health and Development, this project addresses important disease related disabilities and will help direct future medical rehabilitation programs.