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

琥珀酸半醛脱氢酶缺乏症 (SSADHD) 的自然史，一种 GABA 代谢的遗传性疾病

• 批准号: 10437717
• 负责人: Jean-Baptiste O Roullet
• 金额: $ 60.25万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437717
• 关键词: Acids; Address; Adult; Age; Allopregnanolone; Anatomy; Basic Science; Biochemical; Biochemical Markers; Biological Assay; Biological Markers; Biometry; Blood; Boston; Brain; Brain imaging; Brain scan; Brain-Derived Neurotrophic Factor; Case Study; Cerebrum; Clinical; Clinical Research; Collaborations; Communication impairment; Complement; Cross-Sectional Studies; Data; Data Analyses; Data Collection; Databases; Defect; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Disease Progression; Early Diagnosis; Electroencephalography; Enrollment; Ensure; Epilepsy; Evolution; Florida; Foundations; Frequencies; Functional disorder; Funding; Future; Gene Expression; Goals; Hereditary Disease; Image; Impaired cognition; Impairment; International; Knowledge; Laboratories; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic; Metabolism; MicroRNAs; Molecular; Monitor; Mutation; Natural History; Neonatal Screening; Neurologic; Neurotransmitters; Outcome; Pathogenicity; Patient Care; Patients; Pediatric Hospitals; Plasma; Rare Diseases; Recording of previous events; Registries; Regulation; Reporting; Research; Residual state; Scanning; Severities; Site; Specialist; Spottings; Standardization; Succinate-semialdehyde dehydrogenase deficiency; Testing; Therapeutic; Therapeutic Trials; Time; Transcranial magnetic stimulation; Treatment Efficacy; Universities; Urine; Validation; Visit; biobank; clinical predictors; data management; disease prognosis; efficacy evaluation; gamma hydroxybutyrate; gamma-Aminobutyric Acid; indexing; individual patient; motor impairment; myelination; neurogenesis; neurophysiology; neuropsychiatry; neurotransmission; novel; novel therapeutics; patient advocacy group; prognostic value; rare genetic disorder; screening; screening panel; standard of care; success; treatment strategy; working group

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.

总结——过去 15 年的广泛基础研究极大地扩展了我们对 琥珀半醛脱氢酶缺乏症的病理生理学和潜在治疗策略 （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。 疾病的早​​期检测和预后，以及新疗法疗效的评估。 这些差距包括对自然疾病过程的全面描述、对疾病的理解 该疾病的神经生理学和生化标记物以及经过验证的 GABA 检测的预后价值 适合高通量 NBS 平台因此，我们建议使用 SSADHD 进行自然历史研究。 以下 3 个目标： 1) 综合确定 SSADHD 临床表现的自然过程 我们勇敢地承认疾病的表现会随着年龄的增长而恶化，并建议使用一种新颖的方法。 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进化 SSADHD，包括：脑容量、脑GABA浓度（MRS）、脑髓鞘形成（DTI）、 通过脑电图和经颅磁刺激 (TMS) 测量皮质 GABA 功能，以及血液和 GABA 和 GABA 相关代谢衍生物（例如 GHB 等）的尿液水平就包含在这一目标中。 验证适用于 NBS 的 GABA 干血斑测定法 3) 识别神经生理学和 临床严重程度的生化预测因素，其假设是血浆和大脑中的 GABA 含量较高 首次就诊时的浓度预示着以后几年会出现更严重的临床结果。该研究将跟踪 30 名患者。 年度评估：波士顿儿童医院入组 20 名患者，国外医院入组 10 名患者 参与神经递质相关疾病国际工作组 (iNTD) 的学术网站。 此外，我们将从大约 25 名患者那里收集标准护理数据，然后进行国际调查 也与 iNTD 相关的罕见疾病专家网络累计，我们将从 up 获得纵向数据。 WSU 将在 5 年内对 55 名患者进行分析（约 25% 的报告病例）。 实验室并储存用于未来测试（生物储存库）。 由 BCH 成像核心分析的数据将由 RDCRN 数据管理和协调管理。 南佛罗里达大学中心还将提供在线数据输入表格。 将开发促进相关疾病信息在世界范围内标准化输入，从而创建真正的 国际 SSADHD 登记处将在该研究的资助期限结束后继续存在 该项目受到热烈欢迎。 拟议的研究得到了代表全球超过 125 名患者的多个患者倡导团体的支持。 将提供更好地预测 SSADHD 自然病程、更好地监测成功所需的信息 未来的治疗方法，并将为在现有 NBS 小组中添加 SSADHD 筛查奠定基础。

项目成果

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective.

小鼠和人类的琥珀半醛脱氢酶缺乏症：非靶向代谢组学视角。

• DOI: 10.1002/jimd.12657
• 发表时间: 2023
• 期刊: Journal of inherited metabolic disease
• 影响因子: 4.2
• 作者: Peters,TessaMA;Engelke,UdoFH;deBoer,Siebolt;Reintjes,JorisTG;Roullet,Jean-Baptiste;Broekman,Sanne;deVrieze,Erik;vanWijk,Erwin;Wamelink,MirjamMC;Artuch,Rafael;Barić,Ivo;Merx,Jona;Boltje,ThomasJ;Martens,Jonathan;Wille
• 通讯作者: Wille

Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue.

• DOI: 10.1177/0883073820987742
• 发表时间: 2021-11
• 期刊: Journal of child neurology
• 影响因子: 1.9
• 作者: Walters DC;Lawrence R;Kirby T;Ahrendsen JT;Anderson MP;Roullet JB;Murphy EJ;Gibson KM;SSADH Deficiency Investigators Consortium (SDIC)
• 通讯作者: SSADH Deficiency Investigators Consortium (SDIC)

Longitudinal metabolomics in dried bloodspots yields profiles informing newborn screening for succinic semialdehyde dehydrogenase deficiency.

• DOI: 10.1002/jmd2.12075
• 发表时间: 2020-05-01
• 期刊: JIMD reports
• 作者: Brown, Madalyn;Turgeon, Coleman;Gibson, K Michael
• 通讯作者: Gibson, K Michael

Leveraging expertise and optimizing clinical research: Initial success of a pediatric epilepsy surgery collaborative.

利用专业知识和优化临床研究：小儿癫痫手术合作取得初步成功。

• DOI: 10.1111/epi.17579
• 发表时间: 2023
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Berl,MadisonM;Koop,JenniferI;Ailion,Alyssa;Bearden,DonaldJ;Boyer,Katrina;Cooper,CrystalM;Decrow,AmandaM;Duong,PriscillaH;Espe-Pfeifer,Patricia;Gabriel,Marsha;Hodges,Elise;Marshall,DavidF;McNally,KellyA;Molnar,AndrewE;O
• 通讯作者: O

Allosteric modulation of α1β3γ2 GABAA receptors by farnesol through the neurosteroid sites.

法呢醇通过神经类固醇位点对α1β3γ2 GABAA 受体进行变构调节。

• DOI: 10.1016/j.bpj.2023.01.032
• 发表时间: 2023
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Gc,JeevanB;Szlenk,ChristopherT;Diyaolu,Ayobami;Obi,Peter;Wei,Haiyang;Shi,Xutong;Gibson,KMichael;Natesan,Senthil;Roullet,Jean-Baptiste
• 通讯作者: Roullet,Jean-Baptiste