Assessment of urinary 6-oxo-pipecolic acid as a biomarker for ALDH7A1 deficiency.

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Youssef Khalil, Emma Footitt, Reddy Vootukuri, Michael F Wempe, Curtis R Coughlin, Spyros Batzios, Matthew P Wilson, Viktor Kožich, Peter T Clayton, Philippa B Mills
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引用次数: 0

Abstract

ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.

评估尿液中作为 ALDH7A1 缺乏症生物标志物的 6-oxo-pipecolic 酸。
ALDH7A1 缺乏症是一种癫痫性脑病,其发作对超生理剂量的吡哆醇治疗有反应。α-氨基己二酸半醛(α-AASA)和Δ1-哌啶-6-羧酸盐(P6C)因赖氨酸分解途径受阻而积聚,是这种疾病的诊断生物标志物。最近有报道称,6-氧代-1-哌啶-6-羧酸(6-oxo-PIP)也会在 ALDH7A1 缺乏症患者的尿液、脑脊液和血浆中蓄积,而且由于其稳定性更好,可能更适合作为这种疾病的生物标记物。这项研究测量了α-AASA升高的30名患者尿液中的6-oxo-PIP,结果显示,所有6个月以上的患者尿液中的6-oxo-PIP均高于正常范围。然而,在 6 个月以下的患者中,有 33% 的 6-oxo-PIP 水平在正常范围内。随着年龄的增长,6-oxo-PIP 的水平也随之升高,并与α-AASA 水平的下降相关。对ALDH7A1缺陷患者的尿样进行纵向分析后发现,6-oxo-PIP水平保持升高,而α-AASA水平下降。与 α-AASA 类似,我们发现钼辅助因子缺乏症患者的尿液中也会出现 6-oxo-PIP 排泄物升高的现象。这项研究表明,尿液中的 6-oxo-PIP 可能不是新生儿 ALDH7A1 缺乏症的合适生物标志物。不过,还需要进一步研究,以了解导致其积累的生物化学过程及其潜在的长期副作用。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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