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

 描述(申请人提供)：拟议的研究项目将集中在脊髓肌萎缩症(SMA)患者运动能力下降的病理生理学基础上。患有SMA的门诊患者的氧化能力显著降低，对运动的条件性反应迟钝。相比之下，其他神经肌肉疾病尽管有相似的临床表现和功能限制，但从有氧调节的运动计划中获得了显著的好处。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。氧化能力的降低与瘦体重和疾病严重程度不成比例，这将进一步支持SMA中线粒体耗竭的证据。替代的运动训练策略和/或伴随的有针对性的治疗干预可能是实现有氧调节效果所必需的。了解腿部肌肉群之间在成分和氧化能力方面的潜在差异，将有助于利用最容易产生训练效果的肌肉群进行定向运动训练。这项建议将集中于(1)使用近红外光谱估计运动中特定肌肉群的氧化能力，以及(2)描述身体成分，以更好地了解动态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个月的观察研究，包括14名动态SMA患者、14名动态线粒体肌病患者和14名健康对照。线粒体肌病患者是理想的疾病控制人群，因为虽然线粒体与疾病和表型都有关，但它们可能呈现相似的表现，但导致运动耐受的机制不同。在临床上，线粒体患者是理想的疾病比较对象，因为(1)他们代表了广泛的表型谱，(2)包括儿童和成人，(3)在先前的周期测功法研究中证明了对有氧适应的好处。所有参与者将接受两次访问，每隔6个月进行评估和数据收集。访问评估将包括在次极量运动期间对腿部肌肉群进行近红外光谱分析，以确定氧化能力。将使用相同肌肉群的双能X射线吸收法(DEXA)和节段性生物电阻抗分析(BIA)来评估身体成分。其他临床评估将包括运动耐量测试、带有步态分析的6分钟步行测试(6MWT)、计时起跳测试以及腿部肌肉组的手动和定量力量评估。对力量和功能的临床评估对于量化疾病严重程度以及与疾病负担的生理学评估相比较是必要的。SMA是最常见的遗传决定的神经肌肉疾病之一，影响儿童，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，该项目致力于解决与疾病相关的重要残疾问题，并将有助于指导未来的医疗康复计划。

 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.