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Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation.
Orphanet Journal of Rare Diseases ( IF 3.7 ) Pub Date : 2020-02-27 , DOI: 10.1186/s13023-020-1329-5
Claire Cannet 1 , Andrea Pilotto 2, 3, 4 , Júlio César Rocha 5, 6 , Hartmut Schäfer 1 , Manfred Spraul 1 , Daniela Berg 7 , Peter Nawroth 8 , Christian Kasperk 8 , Gwendolyn Gramer 9 , Dorothea Haas 9 , David Piel 10 , Stefan Kölker 9 , Georg Hoffmann 9 , Peter Freisinger 10 , Friedrich Trefz 9, 11
Affiliation  

BACKGROUND Phenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, microcephaly, motor deficits, eczematous rash, autism, seizures, and developmental problems. There is a controversial discussion of whether patients with PKU have an additional risk for atherosclerosis due to interference of Phe with cholesterol synthesis and LDL-cholesterol regulation. Since cholesterol also plays a role in membrane structure and myelination, better insight into the clinical significance of the impact of Phe on lipoprotein metabolism is desirable. In 22 treated PKU patients (mean age 38.7 years) and 14 healthy controls (mean age 35.2 years), we investigated plasma with NMR spectroscopy and quantified 105 lipoprotein parameters (including lipoprotein subclasses) and 24 low molecular weight parameters. Analysis was performed on a 600 MHz Bruker AVANCE IVDr spectrometer as previously described. RESULTS Concurrent plasma Phe in PKU patients showed a wide range with a mean of 899 μmol/L (50-1318 μmol/L). Total cholesterol and LDL-cholesterol were significantly lower in PKU patients versus controls: 179.4 versus 200.9 mg/dL (p < 0.02) and 79.5 versus 104.1 mg/dL (p < 0.0038), respectively. PKU patients also had lower levels of 22 LDL subclasses with the greatest differences in LDL2 Apo-B, LDL2 Particle Number, LDL2-phospholipids, and LDL2-cholesterol (p < 0.0001). There was a slight negative correlation of total cholesterol and LDL-cholesterol with concurrent Phe level. VLDL5-free cholesterol, VLDL5-cholesterol, VLDL5-phospholipids, and VLDL4-free cholesterol showed a significant (p < 0.05) negative correlation with concurrent Phe level. There was no difference in HDL and their subclasses between PKU patients and controls. Tyrosine, glutamine, and creatinine were significantly lower in PKU patients compared to controls, while citric and glutamic acids were significantly higher. CONCLUSIONS Using NMR spectroscopy, a unique lipoprotein profile in PKU patients can be demonstrated which mimics a non-atherogenic profile as seen in patients treated by statins.

中文翻译:

与健康对照组相比,成人苯丙酮尿症(PKU)患者的血浆胆固醇,LDL-胆固醇和LDL-脂蛋白亚类较低:NMR代谢组学研究的结果。

背景技术苯丙酮尿症(PKU; OMIM#261600)是由苯丙氨酸羟化酶(PAH)基因突变导致血液和大脑中高苯丙氨酸(Phe)引起的罕见代谢疾病。如果不及早治疗,将导致智力残疾,行为和精神病问题,小头畸形,运动障碍,湿疹,自闭症,癫痫发作和发育问题。关于PKU患者是否由于Phe干扰胆固醇合成和LDL-胆固醇调节而引起动脉粥样硬化的额外风险存在争议。由于胆固醇在膜结构和髓鞘形成中也起作用,因此需要更好地洞察Phe对脂蛋白代谢的临床意义。在22名接受治疗的PKU患者中(平均年龄38.7岁)和14名健康对照者(平均年龄35岁)。2年),我们用NMR光谱法研究了血浆,并量化了105个脂蛋白参数(包括脂蛋白亚类)和24个低分子量参数。如前所述,分析是在600 MHz Bruker AVANCE IVDr光谱仪上进行的。结果PKU患者的并发血浆Phe值范围很广,平均为899μmol/ L(50-1318μmol/ L)。与对照组相比,PKU患者的总胆固醇和LDL-胆固醇显着降低:分别为179.4和200.9 mg / dL(p <0.02)和79.5和104.1 mg / dL(p <0.0038)。PKU患者还具有较低的22种LDL亚类水平,其中LDL2 Apo-B,LDL2颗粒数,LDL2-磷脂和LDL2-胆固醇差异最大(p <0.0001)。总胆固醇和低密度脂蛋白胆固醇与同时存在的苯丙氨酸水平略有负相关。不含VLDL5的胆固醇,VLDL5-胆固醇,VLDL5-磷脂和不含VLDL4的胆固醇与并发Phe水平呈显着负相关(p <0.05)。在PKU患者和对照组之间,HDL及其亚类没有差异。与对照组相比,PKU患者的酪氨酸,谷氨酰胺和肌酐明显较低,而柠檬酸和谷氨酸明显较高。结论使用NMR光谱法,可以证明PKU患者具有独特的脂蛋白谱,该谱模拟了他汀类药物治疗患者的非动脉粥样硬化谱。与对照组相比,PKU患者的酪氨酸,谷氨酰胺和肌酐明显较低,而柠檬酸和谷氨酸明显较高。结论使用NMR光谱法,可以证明PKU患者具有独特的脂蛋白谱,该谱可模拟他汀类药物治疗患者的非动脉粥样硬化谱。与对照组相比,PKU患者的酪氨酸,谷氨酰胺和肌酐明显较低,而柠檬酸和谷氨酸明显较高。结论使用NMR光谱法,可以证明PKU患者具有独特的脂蛋白谱,该谱可模拟他汀类药物治疗患者的非动脉粥样硬化谱。
更新日期:2020-04-22
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