Vera Dobelmann, Andreas Roos, Andreas Hentschel, Adela Della Marina, Markus Leo, Linda-Isabell Schmitt, Lorenzo Maggi, Ulrike Schara-Schmidt, Tim Hagenacker, Tobias Ruck, Heike Kölbel
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引用次数: 0
摘要
背景和目的：脊髓性肌萎缩症（SMA）是儿童期第二大常见的神经退行性疾病，其特点是运动神经元（SMN）蛋白的存活能力不足，主要导致α运动神经元变性，从而导致进行性肌无力和萎缩。除了一些生物标志物（如 SMN2 拷贝数）外，目前还缺乏已知的与神经肌肉传导相关的 SMA 治疗生物标志物。在此，我们研究了血栓软骨素-4（TSP4）作为脑脊液（CSF）生物标志物的潜力，这也可能表明治疗反应：方法：我们使用非靶向蛋白质组分析法确定小儿症状前（6 例）和症状期（4 例）SMA 患者脑脊液样本中的生物标记物。然后通过酶联免疫吸附试验（ELISA）作为一种额外的分析方法，在另外68份CSF样本（9名成人和24名小儿SMA患者、5名成人和13名小儿非疾病对照组以及17名小儿疾病对照组）中验证了已确定的生物标志物TSP4：结果：CSF的非靶向蛋白质组分析发现了TSP4的失调，并揭示了症状前SMA患者与首发症状后发现的患者之间的差异。随后的 ELISA 分析表明，TSP4 在小儿 SMA 患者中减少，而在成人 SMA 患者中没有减少。患有其他神经系统疾病的小儿患者的脑脊液中的 TSP4 水平没有变化。此外，小儿 SMA 患者的 CSF TSP4 水平在首次服用 Nusinersen 后升高：我们发现，TSP4水平在小儿SMA患者的脑脊液中完全降低，并在治疗后升高，因此我们假设TSP4可作为一种脑脊液生物标志物，用于监测小儿SMA患者的治疗反应。此外，TSP4 还能区分症状前患者和症状患者，这表明它有可能成为一种分层标记物。
Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy.
Background and purpose: Spinal muscular atrophy (SMA) as the second most common neurodegenerative disorder in childhood is characterized by the deficiency of survival of motor neuron (SMN) protein leading predominantly to degeneration of alpha motor neurons and consequently to progressive muscle weakness and atrophy. Besides some biomarkers like SMN2 copy number therapeutic biomarkers for SMA with known relevance for neuromuscular transmission are lacking. Here, we examined the potential of Thrombospondin-4 (TSP4) to serve as a cerebrospinal fluid (CSF) biomarker, which may also indicate treatment response.
Methods: We used untargeted proteomic analyses to determine biomarkers in CSF samples derived from pediatric pre-symptomatic (n = 6) and symptomatic (n = 4) SMA patients. The identified biomarker TSP4 was then validated in additional 68 CSF samples (9 adult and 24 pediatric SMA patients, 5 adult and 13 pediatric non-disease controls in addition to 17 pediatric disease controls) by enzyme-linked immunosorbent assay (ELISA) as an additional analytical approach.
Results: Untargeted proteomic analyses of CSF identified a dysregulation of TSP4 and revealed a difference between pre-symptomatic SMA patients and patients identified after the onset of first symptoms. Subsequent ELISA-analyses showed that TSP4 is decreased in pediatric but not adult SMA patients. CSF of pediatric patients with other neurological disorders demonstrated no alteration of TSP4 levels. Furthermore, CSF TSP4 levels of pediatric SMA patients increased after first dose of Nusinersen.
Conclusions: We found that TSP4 levels are exclusively reduced in CSF of pediatric SMA patients and increase after treatment, leading us to the hypothesis that TSP4 could serve as a CSF biomarker with the potential to monitor treatment response in pediatric SMA patients. Moreover, TSP4 enable to distinguish pre-symptomatic and symptomatic patients suggesting a potential to serve as a stratification marker.
期刊介绍：
The Journal of Neurology is an international peer-reviewed journal which provides a source for publishing original communications and reviews on clinical neurology covering the whole field.
In addition, Letters to the Editors serve as a forum for clinical cases and the exchange of ideas which highlight important new findings. A section on Neurological progress serves to summarise the major findings in certain fields of neurology. Commentaries on new developments in clinical neuroscience, which may be commissioned or submitted, are published as editorials.
Every neurologist interested in the current diagnosis and treatment of neurological disorders needs access to the information contained in this valuable journal.
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