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

摘要-在过去的15年里，广泛的基础研究极大地扩展了我们对 琥珀酸半醛脱氢酶缺乏症的病理生理及可能的治疗策略 (SSADHD)，一种罕见的GABA代谢遗传性疾病。然而，巨大的知识差距仍然是障碍。 对疾病的早期发现和预后，以及对新疗法的疗效的评估。 这些差距包括对自然疾病过程的全面描述，对 神经生理和生化标记物对该病预后的预测价值及验证的GABA测定 适用于高吞吐量的NBS平台。因此，我们建议对SSADHD的自然历史进行研究 目的：1)确定SSADHD临床表现的自然病程 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 半定量的临床严重程度评分，以量化疾病最显著的临床特征；2) 确定已知异常的神经生理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)、 脑电和经颅磁刺激(TMS)测定皮质GABA能功能，血和 尿中GABA和GABA相关代谢衍生物的水平，如GHB和其他。植根于这一目标 干血斑法检测GABA是否适用于NBS；3)以确定神经生理学和 临床严重程度的生化预测因子，基于较高的血浆和脑内GABA的假设 首次就诊时的浓度预示着未来几年会出现更严重的临床结果。这项研究将跟踪调查30名患者 年度评估：20名患者在波士顿儿童医院登记，10名病人在外国登记 国际神经递质相关疾病工作组(INTD)的学术网站。在……里面 此外，我们将收集大约25名患者的标准护理数据，随后是一项国际 罕见疾病专家网络也与iNTD有关。累积起来，我们将从UP获得纵向数据 到5年内的55例(约占报告病例的25%)。生物制品将由WSU进行分析 实验室和银行以备将来测试(生物储存库)。脑成像扫描，EEG和TMS记录将是 由BCH成像核心进行分析。数据将由RDCRN数据管理和协调中心管理 南佛罗里达大学的研究中心。DMCC还将提供生物统计支持。网上数据录入表格 将被开发为便于在世界范围内标准化地输入相关疾病信息，从而创造一个真正的 国际SSADHD登记册的有效期将超过研究的供资年限。这个项目进行得很热烈。 由代表全球超过125名患者的几个患者权益倡导团体提供支持。拟议的研究 将提供所需信息，以更好地预测SSADHD的自然进程，更好地监测成功 并将为将SSADHD筛查添加到现有的国家统计局小组奠定基础。

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.