Body Composition and Energy Utilization in Spinal Muscular Atrophy

描述(申请人提供)：脊髓性肌萎缩症(SMA)是一种遗传性的儿童神经肌肉疾病，其特征是进行性虚弱和肌肉萎缩，原因是脊髓运动神经元的丧失。SMA的临床表现广泛，从预后极差的极其虚弱的婴儿(Werdnig-Hoffmann，SMA 1型)到受轻微影响的门诊儿童和成人(Kugelberg-Welander，SMA 3型)。尽管缺乏有效的治疗方法，但积极的营养管理(包括胃造瘘术)以及机械通气支持的广泛使用，在最近几年极大地改变了该病的自然病史。1型脊髓性肌萎缩症患儿的存活率尤其提高。不幸的是，尽管营养和身体成分是影响SMA患者最佳临床治疗的潜在重要因素，但几乎没有数据或同行评议的研究可以为这一领域的临床护理提供信息。我们建议使用最先进的方法和技术，研究患有SMA的儿童和成人的能量消耗、卡路里摄入量(因此卡路里平衡)和身体组成。我们的目标是促进目前对脊髓性肌萎缩症营养方面有限的了解。制定针对患者的饮食建议将对受影响的患者具有潜在的临床益处，并可能有意义地改善SMA患者的生活。我们还将研究肌肉成像方法，如MRI和双能X射线吸收法，以及电阻抗肌图术，作为SMA疾病进展的潜在生物标志物。疾病进展(和治疗效果)的生物标记物的开发对加速早期临床试验至关重要。我的目标是建立一个研究SMA的营养和身体成分的临床研究努力，最终目的是通过改善临床护理来影响SMA和其他儿科神经肌肉疾病患者的功能和预后。为此，我正在通过纽约肥胖营养研究中心(NYONRC)和哥伦比亚大学欧文临床与翻译研究所和人类营养研究所，与越来越多的同事在身体成分和能量消耗方面进行合作，并在营养方面进行合作。我的提案包含一套全面的指导和培训课程，其中包括：1)NYONRC高级研究员Dympna Gallagher博士和儿科神经肌肉疾病资深研究员Darryl de Vivo医学博士的积极指导；2)通过NYONRC举办正式的教育研讨会、杂志俱乐部和实验室培训；3)通过营养研究所开展课程活动，4)补充临床和临床研究责任；5)完成拟议的研究项目，从而成功申请独立资助。 公共卫生相关性：我们的目标是推进脊髓性肌萎缩症(SMA)的循证营养管理，SMA是一种以脊髓运动神经元丧失为特征的无法治疗的遗传性儿科神经肌肉疾病。我们将研究疾病严重程度、身体成分和能量消耗之间的关系，目的是为临床治疗提供信息，以及营养调节对疾病自然病程的潜在作用。我们还将研究肌肉成像和电阻抗作为疾病进展的潜在生物标记物；此类生物标记物的开发对于加快SMA临床试验至关重要。

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a hereditary pediatric neuromuscular disease marked by progressive weakness and muscle atrophy resulting from the loss of spinal cord motor neurons. SMA presents across a clinical spectrum, ranging from extremely weak infants with a historically dismal prognosis (Werdnig-Hoffmann, SMA type 1) to mildly affected, ambulatory children and adults (Kugelberg-Welander, SMA type 3). Despite the absence of an effective therapy, aggressive nutritional management (including gastrostomy placement) along with widespread use of mechanical ventilatory support has greatly altered the "natural history" of the disease in recent years. Survival has been particularl improved among children with spinal muscular atrophy type 1. Unfortunately, although nutrition and body composition are a modifiable factors of potential importance in the optimal clinical management of patients with SMA, there is almost no data or peer- reviewed study available to inform this area of clinical care. We propose to study energy expenditure, caloric intake (and therefore caloric balance), and body composition, using state-of-the-art approaches and technology, among children and adults with SMA. We aim to advance the presently limited understanding of nutrition in spinal muscular atrophy. The development of patient- specific dietary recommendations would be of potential clinical benefit to affected patients, and could meaningfully improve the lives of people with SMA. We will also study muscle imaging approaches such as MRI and dual energy x-ray absorptiometry, and electrical impedance myography, for potential use as biomarkers of disease progression in SMA. The development of biomarkers of disease progression (and treatment effect) is critical in the acceleration of early stage clinical trials. My goal is to build a clinical research effort studying nutrition and body composition in SMA, with the ultimate aim of impacting function and outcome of patients with SMA and other pediatric neuromuscular diseases through improvements in clinical care. To this end, I am working with a growing network of colleagues in body composition and energy expenditure, through the New York Obesity Nutrition Research Center (NYONRC), and nutrition, through the Irving Institute for Clinical and Translational Research and Institute of Human Nutrition at Columbia University. My proposal incorporates a comprehensive mentoring and training curriculum that includes: 1) active mentorship from Dr. Dympna Gallagher, Ph.D., a senior researcher with the NYONRC, and Dr. Darryl De Vivo, M.D., an experienced researcher in pediatric neuromuscular disease; 2) formal educational seminars and journal clubs and laboratory training through the NYONRC; 3) coursework activities through the Institute of Nutrition, 4) complementary clinical and clinical research responsibilities; and 5) completion of the proposed research project leading to successful application for independent funding. PUBLIC HEALTH RELEVANCE: We aim to advance evidence-based nutritional management in spinal muscular atrophy (SMA), an untreatable hereditary pediatric neuromuscular disease marked by the loss of spinal cord motor neurons. We will study the relationship between disease severity, body composition and energy expenditure with the goal of informing clinical management and the potential role of nutritional modulation to affect the natural course of the disease. We will also study muscle imaging and electrical impedance as potential biomarkers of disease progression; the development of such biomarkers is of critical importance in the acceleration of clinical trials in SMA.