Abstract:
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a deficiency of the arylsulfatase A (ARSA). ARSA deficiency leads to an accumulation of sulfatides primarily in the nervous system ultimately causing demyelination. With evolving therapeutic options, there is an increasing need for indicators to evaluate disease progression. Here, we report targeted metabolic urine profiling of 56 MLD patients including longitudinal sampling, using 1H (proton) nuclear magnetic resonance (NMR) spectroscopy. 1H-NMR urine spectra of 119 MLD samples and 323 healthy controls were analyzed by an in vitro diagnostics research (IVDr) tool, covering up to 50 endogenous and 100 disease-related metabolites on a 600-MHz IVDr NMR spectrometer. Quantitative data reports were analyzed regarding age of onset, clinical course, and therapeutic intervention. The NMR data reveal metabolome changes consistent with a multiorgan affection in MLD patients in comparison to controls. In the MLD cohort, N-acetylaspartate (NAA) excretion in urine is elevated. Early onset MLD forms show a different metabolic profile suggesting a metabolic shift toward ketogenesis in comparison to late onset MLD and controls. In samples of juvenile MLD patients who stabilize clinically after hematopoietic stem cell transplantation (HSCT), the macrophage activation marker neopterin is elevated. We were able to identify different metabolic patterns reflecting variable organ disturbances in MLD, including brain and energy metabolism and inflammatory processes. We suggest NAA in urine as a quantitative biomarker for neurodegeneration. Intriguingly, elevated neopterin after HSCT supports the hypothesis that competent donor macrophages are crucial for favorable outcome.
摘要:
异染性脑白质营养不良(MLD)是由芳基硫酸酯酶A(ARSA)缺乏引起的溶酶体贮积病。ARSA缺乏导致硫苷脂主要在神经系统中积累,最终导致脱髓鞘。随着治疗选择的不断发展,越来越需要评估疾病进展的指标.这里,我们报告了56名MLD患者的有针对性的代谢尿液分析,包括纵向采样,使用1H(质子)核磁共振(NMR)光谱。通过体外诊断研究(IVDr)工具分析了119个MLD样品和323个健康对照的1H-NMR尿液光谱,在600MHzIVDrNMR光谱仪上覆盖多达50种内源性和100种疾病相关代谢物。定量数据报告分析了发病年龄,临床课程,和治疗干预。NMR数据显示,与对照组相比,MLD患者的代谢组变化与多器官病变一致。在MLD队列中,尿液中N-乙酰天冬氨酸(NAA)的排泄量升高。与晚发作MLD和对照相比,早发作MLD形式显示出不同的代谢谱,表明代谢向生酮发生转变。在造血干细胞移植(HSCT)后临床稳定的青少年MLD患者样本中,巨噬细胞激活标记新蝶呤升高。我们能够识别反映MLD中可变器官紊乱的不同代谢模式,包括大脑和能量代谢和炎症过程。我们建议尿液中的NAA作为神经变性的定量生物标志物。有趣的是,HSCT后新蝶呤升高支持以下假设:有能力的供体巨噬细胞对于有利的结果至关重要.