Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective.
Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective.
复制标题
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
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发表时间：
2023
影响因子：
4.2
通讯作者：
Wille
中科院分区：
文献类型：
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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
琥珀酸半醛脱氢酶缺乏症（SSADHD）是一种罕见的神经代谢紊乱，由γ-氨基丁酸（GABA）通路中断引起。更详细地了解其病理生理学，除了GABA和γ-羟基丁酸（GHB）的积累，将增加我们对疾病的理解，并可能支持新的治疗方法的开发。为此，我们使用下一代代谢筛查（NGMS）比较了SSADHD患者与对照组的生化体液特征。脑脊液（CSF）NGMS数据的目标分析显示，SSADHD样本中天冬氨酸、谷氨酸、乙醇酸、4-胍基丁酸和2-羟基谷氨酸中度增加，GHB和4，5-二羟基己酸（4，5-DHHA）显著升高。值得注意的是，4，5-DHHA和GHB的强度在对照CSF中显示出显著的正相关性，但在患者CSF中不存在。在一个已建立的斑马鱼癫痫模型中，4，5-DHHA显示出活动性增加，这可能反映了有限的癫痫发生。使用非靶向代谢组学，我们确定了CSF中具有高生物标志物潜力的12个特征。这些具有与GHB和4，5-DHHA相当的增加倍数变化。对于这些特征中的10个，与对照相比，在SSADHD的血浆、尿液和/或小鼠脑组织中发现了类似的增加。其中之一被确定为新的生物标志物4，5-二羟基庚酸。SSADHD患者血浆和尿液中选定特征的强度与患者癫痫临床严重程度评分和精神症状呈正相关，并且也显示出高度的相互相关性。我们的研究结果为SSADHD的（神经）代谢紊乱提供了新的见解，并为进一步研究SSADHD的病理生理学提供了线索。
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma‐aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma‐hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next‐generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4‐guanidinobutanoic acid, and 2‐hydroxyglutaric acid, and prominent elevations of GHB and 4,5‐dihydroxyhexanoic acid (4,5‐DHHA) in SSADHD samples. Remarkably, the intensities of 4,5‐DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5‐DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5‐DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5‐dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology.