Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Molecular genetics and metabolism Pub Date : 2024-05-03 DOI:10.1016/j.ymgme.2024.108489
Christian Posern , Benjamin Dreyer , Sarah L. Maier , Florian Eichler , Michael H. Gelb , René Santer , Annette Bley , Simona Murko
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Abstract

Background

Canavan disease is a devastating neurometabolic disorder caused by accumulation of N acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (ASPA). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective.

Methods

We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample.

Results

Measuring N-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6–13.6 μmol/L [n = 45] vs 0.44; 0.24–0.99 μmol/L [n = 59] (p < 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1–9.9 μmol/L [n = 8]) and neonatal controls (0.93; 0.4–1.8 μmol/L [n = 784]) (p < 0.05).

Conclusions

We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.

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干血斑中 N-acetyl-l-aspartate 的定量:用于诊断卡纳万病的简单快速的 LC-MS/MS 新生儿筛查方法
背景卡那万病是一种破坏性神经代谢疾病,由于天冬氨酸氨酰基酶基因(ASPA)的遗传缺陷,导致脑部和体液中的天冬氨酸氨酰基蓄积。因此,我们开发了一种快速、高灵敏度的液相色谱质谱法(LC-MS/MS),用于定量检测干血斑中的 N-乙酰天冬氨酸,并确定了新生儿和老年对照组的参考范围。通过该检测方法,我们对 25 名卡纳万患者的 45 份样本进行了检测,其中包括 8 份新生儿样本:5.7; 1.6-13.6 μmol/L [n = 45] vs 0.44; 0.24-0.99 μmol/L [n = 59] (p < 0.05))。结论我们开发了一种新的基于 LC-MS/MS 的筛查检测方法,用于卡纳万病的产后早期诊断,一旦出现有前途的治疗方法,就应在基于人群的研究中对该方法进行进一步评估。该方法符合新生儿筛查的一般要求,适合与其他结合色谱和质谱技术的筛查方法进行多重分析。
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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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