Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
Clin Chim Acta. 2023 Mar 1;542:117295. doi: 10.1016/j.cca.2023.117295. Epub 2023 Mar 11.
Plasmalogens are glycerophospholipids characterized by a vinyl-ether bond with a fatty alcohol at the sn-1 position, a polyunsaturated fatty acid at the sn-2 position, and a polar head at the sn-3 position, commonly phosphoethanolamine. Plasmalogens play crucial roles in several cellular processes. Reduced levels have been associated with Alzheimer's and Parkinson's disease progression. Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders (PBD) because plasmalogen synthesis requires functional peroxisomes. Particularly, severe plasmalogen deficiency is the biochemical hallmark of rhizomelic chondrodysplasia punctata (RCDP). Traditionally, plasmalogens are evaluated in red blood cells (RBCs) by gas-chromatography/mass-spectrometry (GC-MS), which cannot distinguish individual species. We developed a liquid-chromatography/tandem mass-spectrometry (LC-MS/MS) method to quantify eighteen phosphoethanolamine plasmalogens in RBCs to diagnose PBD patients, especially RCDP. Validation results showed a specific, robust, and precise method with broad analytical range. Age-specific reference intervals were established; control medians were used to assess plasmalogen deficiency in patients' RBCs. Clinical utility was also confirmed in Pex7 deficient mouse models recapitulating severe and milder RCDP clinical phenotypes. To our knowledge, this is the first attempt to replace the GC-MS method in the clinical laboratory. In addition to diagnosing PBDs, structure-specific plasmalogen quantitation could help understand disease pathogenesis and monitor therapy.
磷脂酶是甘油磷脂的一种，其特征是在 sn-1 位有一个乙烯醚键与脂肪醇相连，在 sn-2 位有一个多不饱和脂肪酸，在 sn-3 位有一个极性头，通常是磷酸乙醇胺。磷脂酶在几个细胞过程中发挥着关键作用。水平降低与阿尔茨海默病和帕金森病的进展有关。明显减少的磷脂酶是过氧化物酶体生物发生障碍（PBD）的一个典型特征，因为磷脂酶合成需要功能性过氧化物酶体。特别是，严重的磷脂酶缺乏症是根骨软骨发育不良点状（RCDP）的生化特征。传统上，通过气相色谱/质谱（GC-MS）在红细胞（RBC）中评估磷脂酶，该方法无法区分单个物种。我们开发了一种液相色谱/串联质谱（LC-MS/MS）方法来定量 RBC 中的十八种磷酸乙醇胺磷脂酶，以诊断 PBD 患者，尤其是 RCDP。验证结果表明该方法具有特异性、稳健性和精确性，分析范围广泛。建立了年龄特异性参考区间；使用对照中位数评估患者 RBC 中的磷脂酶缺乏症。该方法在模拟严重和较轻 RCDP 临床表型的 Pex7 缺陷小鼠模型中也得到了临床应用的确认。据我们所知，这是首次尝试在临床实验室中替代 GC-MS 方法。除了诊断 PBD 之外，结构特异性磷脂酶定量还可以帮助了解疾病的发病机制并监测治疗效果。
