Natural History of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD), a Heritable Disorder of GABA Metabolism

总结-在过去的15年里，广泛的基础研究大大扩展了我们对 琥珀酸半醛脱氢酶缺乏症的病理生理学和潜在的治疗策略 （SSADHD），一种罕见的GABA代谢遗传性疾病。然而，重大的知识差距仍然是障碍， 涉及疾病的早期检测和预后，以及评价新疗法的功效。 这些差距包括对自然病程的全面描述，对疾病的理解， 疾病的神经生理学和生化标志物的预后价值以及经验证的GABA测定 适用于高通量NBS平台。因此，我们建议对SSADHD进行自然史研究， 以下3个目的：1）确定SSADHD临床表现的自然过程， 年度评估。我们假设疾病表现会随着年龄的增长而恶化，并建议使用一种新的 半定量临床严重程度评分，以量化疾病最突出的临床特征; 2） 确定已知异常的神经生理学和生化指标的自然演变， SSADHD，包括：脑体积、脑GABA浓度（MRS）、脑髓鞘形成（DTI）、 用EEG和经颅磁刺激（TMS）测量皮质GABA能功能， GABA和GABA相关代谢衍生物（如GHB等）的尿液水平。在这一目标中， 是对适用于NBS的GABA干血斑试验的验证; 3）鉴定神经生理学和 临床严重程度的生化预测因子，由较高的血浆和脑GABA 第一次就诊时的浓度预测了以后几年更严重的临床结果。该研究将跟踪30名患者 每年评估：20名患者在波士顿儿童医院入组，10名患者在国外医院入组。 参与神经递质相关疾病国际工作组（iNTD）的学术网站。在 此外，我们将收集约25例患者的标准治疗数据，然后进行国际 罕见病专家网络也与iNTD有关。累积起来，我们将获得纵向数据， 55例患者（约占报告病例的25%）。生物样本将由WSU进行分析 实验室和库存用于未来的测试（生物储存库）。脑成像扫描，脑电图和TMS记录将被 由BCH成像核心分析。数据将由RDCRN数据管理和协调部门管理 南佛罗里达大学中心。DMCC还将提供生物统计支持。在线数据输入表格 将开发一个标准化的全球疾病信息输入系统，从而建立一个真正的 国际SSADHD登记，将超过研究的资助年。该项目热情 得到了代表全球125多名患者的多个患者倡导团体的支持。拟议研究 将提供所需的信息，以更好地预测SSADHD的自然过程，更好地监测成功与否， 的未来治疗，并将奠定基础，增加SSADHD筛查现有的NBS面板。

SUMMARY – Extensive basic research in the last 15 years has significantly extended our understanding of the pathophysiology and potential treatment strategies for succinic semialdehyde dehydrogenase deficiency (SSADHD), a rare heritable disorder of GABA metabolism. Yet, significant knowledge gaps remain as barriers to early detection and prognosis of the disease, and to the assessment of the efficacy of novel therapeutics. These gaps include a comprehensive description of the natural disease course, an understanding of the prognostic value of neurophysiological and biochemical markers of the disease and a validated GABA assay suitable for high-throughput NBS platforms. Thus, we propose a natural history study of SSADHD with the following 3 aims: 1) to determine the natural course of the clinical presentation of SSADHD with comprehensive yearly assessments. We hypothesize that disease presentation will worsen with age and propose to use a novel semi-quantitative clinical severity score to quantify the most prominent clinical features of the disease; 2) to determine the natural evolution of neurophysiological and biochemical indices known to be abnormal in SSADHD, including: cerebral volume, brain GABA concentration (MRS), brain myelination (DTI), indices of cortical GABAergic function measured with EEG and transcranial magnetic stimulation (TMS), and blood and urine levels of GABA and GABA-related metabolic derivatives such as GHB and others. Embedded in this aim is the validation of a dried bloodspot assay for GABA suitable for NBS; 3) to identify neurophysiological and biochemical predictors of clinical severity, framed by the hypothesis that higher plasma and brain GABA concentrations at first visit predict more severe clinical outcomes in later years. The study will follow 30 patients with yearly assessments: 20 patients enrolled at Boston Children's Hospital, and 10 patients enrolled at foreign academic sites participating in the International Working Group of Neurotransmitter Related Diseases (iNTD). In addition, we will collected standard-of-care data from approximately 25 patients followed by an international network of rare disease specialists also related to iNTD. Cumulatively, we will obtain longitudinal data from up to 55 patients over the course of 5 years (~25% of reported cases). Biospecimens will be analyzed by the WSU laboratory and banked for future testing (biorepository). Brain imaging scans, EEG and TMS recordings will be analyzed by the BCH Imaging Core. Data will be managed by the RDCRN Data Management & Coordinating Center at University of South Florida. The DMCC will also provide biostatistics support. On-line data entry forms will be developed to facilitate standardized world-wide entry of relevant disease information, thus creating a truly international SSADHD registry that will outlive the funding years of the study. The project is enthusiastically supported by several patient advocacy groups representing over 125 patients worldwide. The proposed research will provide the information needed to better predict the natural course of SSADHD, better monitor the success of future therapeutics, and will lay the foundation for addition of SSADHD screening to existing NBS panels.