Nutrition and Health Sciences, Laney Graduate School, Emory University, Atlanta, GA, USA.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
Am J Clin Nutr. 2022 Mar 4;115(3):811-821. doi: 10.1093/ajcn/nqab400.
There remains a limited understanding of the metabolic perturbations, beyond phenylalanine (Phe) metabolism, that contribute to phenotypic variability in phenylketonuria (PKU).
This study aimed to characterize changes in the PKU plasma metabolome following a 5-d metabolic camp intervention and to compare PKU profiles with those of matched healthy controls.
In 28 females (aged 12-57 y), fasting plasma samples were collected on the first (day 1) and final (day 5) days of camp to measure metabolic control and to complete untargeted metabolomic profiling. Three-day dietary records were collected to assess changes in dietary adherence and composition. Univariate (Wilcoxon signed-rank and Mann-Whitney U test) and multivariate (random forest, hierarchical clustering) analyses were performed to identify clinical and metabolic features that were associated with the intervention and disease state.
Relative to healthy controls, Phe catabolites, ketones, and carnitine- and glycine-conjugated fatty acids were elevated in females with PKU at baseline, whereas fatty acylcholine metabolites were substantially lower. After the camp intervention, plasma Phe concentrations decreased [median change: -173 µmol/L (IQR: -325, -28 µmol/L)] and 70% of PKU participants demonstrated improved dietary adherence by decreasing Phe intake and/or increasing medical food consumption. This was accompanied by a shift in abundance for 223 metabolites (q < 0.05). Compounds associated with the metabolism of Phe, fatty acids, and choline contributed most to profile differences between camp days 1 and 5.
In females with PKU, untargeted metabolomics identified prominent perturbations in amino acid and lipid metabolites associated with bioenergetic impairment and oxidative stress. Choline-conjugated lipids could have fundamental roles in these pathways and they have not been previously evaluated in PKU. A short-term camp intervention was effective for improving or fully normalizing the abundance of the identified discriminatory metabolites.
除了苯丙氨酸（Phe）代谢之外，人们对导致苯丙酮尿症（PKU）表型变异的代谢改变仍知之甚少。
本研究旨在描述 5 天代谢营干预后 PKU 患者的血浆代谢组学变化，并将 PKU 谱与匹配的健康对照组进行比较。
在 28 名女性（年龄 12-57 岁）中，在营地的第一天（第 1 天）和最后一天（第 5 天）空腹采集血浆样本，以测量代谢控制情况并完成非靶向代谢组学分析。收集三天的饮食记录以评估饮食依从性和成分的变化。使用单变量（Wilcoxon 符号秩和检验和 Mann-Whitney U 检验）和多变量（随机森林、层次聚类）分析来识别与干预和疾病状态相关的临床和代谢特征。
与健康对照组相比，PKU 女性在基线时苯丙氨酸代谢产物、酮体、肉碱和甘氨酸结合的脂肪酸升高，而脂肪酸胆碱代谢物则显著降低。在营地干预后，血浆 Phe 浓度降低[中位数变化：-173μmol/L（IQR：-325，-28μmol/L）]，70%的 PKU 患者通过减少 Phe 摄入和/或增加医学食品的摄入来提高饮食依从性。这伴随着 223 种代谢物丰度的变化（q<0.05）。与 Phe、脂肪酸和胆碱代谢相关的化合物对营地第 1 天和第 5 天之间的轮廓差异贡献最大。
在 PKU 女性中，非靶向代谢组学确定了与生物能量损伤和氧化应激相关的氨基酸和脂质代谢物的显著改变。胆碱结合脂质在这些途径中可能具有根本作用，而它们在 PKU 中尚未得到评估。短期营地干预对改善或完全正常化所识别的区分代谢物的丰度是有效的。
