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.

摘要 - 在过去15年中的广泛基础研究大大扩展了我们对 琥珀酸半脱水酶缺乏症的病理生理学和潜在治疗策略 （SSADHD），一种罕见的GABA代谢障碍。然而，作为障碍仍然存在重大知识差距 疾病的早​​期发现和预后，以及评估新疗法的效率。 这些差距包括对自然疾病过程的全面描述，了解 该疾病的神经生理学和生化标志物的预后价值以及经过验证的GABA测定 适用于高通量NBS平台。那，我们提出了SSADHD的自然历史研究 以下3个目标：1）确定SSADHD临床表现的自然过程 年度评估。我们假设疾病的表现会随着年龄的增长和建议而引起麻烦 半定量临床严重程度评分，以量化该疾病最突出的临床特征； 2）到 确定神经生理学和生化指数的自然演化已知在 SSADHD，包括：脑体积，脑GABA浓度（MRS），脑髓鞘化（DTI），指数 用脑电图和经颅磁刺激（TMS）和血液和血液和血液测量的皮质GABA能功能 GABA和GABA相关的代谢衍生物（例如GHB等）的尿液水平。嵌入此目标 是对适合NB的GABA的干血点测定的验证； 3）确定神经生理学和 临床严重程度的生化预测指标，由较高的血浆和脑GABA的假设构成 初次访问时的浓度预测了后来几年的更严重的临床结果。该研究将跟随30名患者 每年评估：有20名在波士顿儿童医院招收的患者，有10名患者入学 参与国际神经递质相关疾病（INTD）的国际工作组。在 此外，我们将收集大约25名患者的护理标准数据，然后是国际 稀有疾病专家网络也与INTD有关。累积地，我们将从上获得纵向数据 在5年的55名患者中（报告病例的25％）。 WSU将分析生物测量 实验室和储备以进行将来的测试（生物库）。大脑成像扫描，脑电图和TMS录音将是 通过BCH成像核心分析。数据将由RDCRN数据管理和协调管理 南佛罗里达大学中心。 DMCC还将提供生物统计学支持。在线数据输入表格 将开发以促进全球标准化的相关疾病信息的进入，从而真正创建一个真正的 国际SSADHD注册表将超过研究的资金年限。该项目在热情上 由几个代表全球125多名患者的患者倡导组的支持。拟议的研究 将提供更好地预测SSADHD自然过程所需的信息，更好地监控成功 将来的治疗方法，并将为在现有NBS面板中添加SSADHD筛选奠定基础。

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