Japan Clinical Metabolomics Institute, Kahoku, Ishikawa, 929-1174, Japan.
Department of Child Neurology, Okayama University Hospital, Okayama, 700-8558, Japan.
Anal Biochem. 2020 Sep 1;604:113739. doi: 10.1016/j.ab.2020.113739. Epub 2020 Apr 24.
α-Aminoadipic semialdehyde and its cyclic form (Δ-piperideine-6-carboxylate) accumulate in patients with α-aminoadipic semialdehyde dehydrogenase (AASADH; antiquitin; ALDH7A1) deficiency. Δ-Piperideine-6-carboxylate is known to react with pyridoxal 5'-phosphate (PLP) to form a Knoevenagel condensation product, resulting in pyridoxine-dependent epilepsy. Despite dramatic clinical improvement following pyridoxine supplementation, many patients still suffer some degree of intellectual disability due to delayed diagnosis. In order to expedite the diagnosis of patients with suspected AASADH deficiency and minimize the delay in treatment, we used gas chromatography-mass spectrometry-based metabolomics to search for potentially diagnostic biomarkers in urine from four patients with ALDH7A1 mutations, and identified Δ-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as candidate biomarkers. In a patient at postnatal day six, but before pyridoxine treatment, Δ-piperideine-6-carboxylate and pipecolate were present at very high concentrations, indicating that these compounds may be good biomarkers for untreated AASADH deficiency patients. On the other hand, following pyridoxine/PLP treatment, 6-oxopipecolate was shown to be greatly elevated. We suggest that noninvasive urine metabolomics screening for Δ-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate will be useful for prompt and reliable diagnosis of AASADH deficiency in patients within any age group. The most appropriate combination among Δ-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as biomarkers for AASADH deficiency patients appears to depend on the age of the patient and whether pyridoxine/PLP supplementation has been implemented. We anticipate that the present bioanalytical information will also be useful to researchers studying glutamate, proline, lysine and ornithine metabolism in mammals and other organisms.
α-氨基己二酸半醛及其环状形式（Δ-哌啶-6-羧酸）在α-氨基己二酸半醛脱氢酶（AASADH；抗坏血酸；ALDH7A1）缺乏症患者中积累。已知 Δ-哌啶-6-羧酸与吡哆醛 5'-磷酸（PLP）反应形成 Knoevenagel 缩合产物，导致吡哆醇依赖性癫痫。尽管补充吡哆醇后临床症状明显改善，但由于诊断延迟，许多患者仍存在一定程度的智力残疾。为了加快疑似 AASADH 缺乏症患者的诊断速度，并尽量减少治疗延迟，我们使用基于气相色谱-质谱的代谢组学方法在四名 ALDH7A1 突变患者的尿液中寻找潜在的诊断生物标志物，并鉴定出 Δ-哌啶-6-羧酸、6-氧代哌啶酸和哌啶酸为候选生物标志物。在一名出生后第六天的患者中，但在接受吡哆醇治疗之前，Δ-哌啶-6-羧酸和哌啶酸的浓度非常高，表明这些化合物可能是未经治疗的 AASADH 缺乏症患者的良好生物标志物。另一方面，在接受吡哆醇/PLP 治疗后，6-氧代哌啶酸的浓度大大升高。我们建议，对未经治疗的 AASADH 缺乏症患者进行非侵入性尿液代谢组学筛查，检测 Δ-哌啶-6-羧酸、6-氧代哌啶酸和哌啶酸，将有助于快速可靠地诊断 AASADH 缺乏症。作为 AASADH 缺乏症患者生物标志物，Δ-哌啶-6-羧酸、6-氧代哌啶酸和哌啶酸的最佳组合似乎取决于患者的年龄以及是否已实施吡哆醇/PLP 补充。我们预计，本生物分析信息也将对研究哺乳动物和其他生物体内谷氨酸、脯氨酸、赖氨酸和鸟氨酸代谢的研究人员有用。
