Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Institute for Molecules and Materials, FELIX Laboratory and.
J Clin Invest. 2021 Aug 2;131(15). doi: 10.1172/JCI148272.
BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC).
吡哆醇依赖性癫痫（PDE-ALDH7A1）是一种赖氨酸分解代谢的先天性错误，在新生儿中表现为难治性癫痫。双等位基因 ALDH7A1 变体导致 α-氨基己二酸半醛脱氢酶/抗坏血酸缺乏，导致哌啶-6-羧酸（P6C）积累，并通过与 P6C 结合导致重要辅因子吡哆醛-5'-磷酸（PLP，活性维生素 B6）的继发性缺乏。维生素 B6 补充可使患者的癫痫得到缓解，但智力残疾仍可能发生。早期诊断和治疗，最好基于新生儿筛查，可优化长期临床结局。然而，目前尚无合适的 PDE-ALDH7A1 新生儿筛查生物标志物。
我们结合创新的分析方法非靶向代谢组学和红外离子光谱学，在血浆中发现并鉴定出可用于 PDE-ALDH7A1 新生儿筛查诊断的生物标志物。
我们鉴定出 2S,6S-/2S,6R-氧代丙基哌啶-2-羧酸（2-OPP）作为 PDE-ALDH7A1 的生物标志物，并证实 6-氧代哌啶-2-羧酸（6-oxoPIP）是一种生物标志物。在干血斑中，2-OPP 作为潜在 PDE-ALDH7A1 新生儿筛查生物标志物的适用性得到了证实。此外，我们发现 2-OPP 在患者和 Aldh7a1 基因敲除小鼠的脑组织中积累，并在斑马鱼模型系统中诱导癫痫样行为。
本研究为 PDE-ALDH7A1 的新生儿筛查开辟了道路。我们推测 2-OPP 可能导致持续的神经毒性，即使在治疗后的 PDE-ALDH7A1 患者中也是如此。由于 2-OPP 的形成似乎会随着酮症而增加，因此我们强调在 PDE-ALDH7A1 患者中避免分解代谢的重要性。
荷兰和比利时遗传性代谢疾病学会（ESN）、代谢疾病联合会（UMD）、Stofwisselkracht、拉德堡德大学、加拿大卫生研究院、荷兰科学研究组织（NWO）和欧洲研究理事会（ERC）。
