van de Beek Malu-Clair, Dijkstra Inge M E, van Lenthe Henk, Ofman Rob, Goldhaber-Pasillas Dalia, Schauer Nicolas, Schackmann Martin, Engelen-Lee Joo-Yeon, Vaz Frédéric M, Kulik Wim, Wanders Ronald J A, Engelen Marc, Kemp Stephan
Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Metabolomic Discoveries GmbH, Potsdam-Golm, Germany.
PLoS One. 2016 Apr 28;11(4):e0154597. doi: 10.1371/journal.pone.0154597. eCollection 2016.
X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. Virtually all males develop progressive myelopathy (AMN). A subset of patients, however, develops a fatal cerebral demyelinating disease (cerebral ALD). Hematopoietic stem cell transplantation is curative for cerebral ALD provided the procedure is performed in an early stage of the disease. Unfortunately, this narrow therapeutic window is often missed. Therefore, an increasing number of newborn screening programs are including ALD. To identify new biomarkers for ALD, we developed an Abcd1 knockout mouse with enhanced VLCFA synthesis either ubiquitous or restricted to oligodendrocytes. Biochemical analysis revealed VLCFA accumulation in different lipid classes and acylcarnitines. Both C26:0-lysoPC and C26:0-carnitine were highly elevated in brain, spinal cord, but also in bloodspots. We extended the analysis to patients and confirmed that C26:0-carnitine is also elevated in bloodspots from ALD patients. We anticipate that validation of C26:0-carnitine for the diagnosis of ALD in newborn bloodspots may lead to a faster inclusion of ALD in newborn screening programs in countries that already screen for other inborn errors of metabolism.
X连锁肾上腺脑白质营养不良（ALD）是一种进行性神经退行性疾病，由ABCD1基因突变引起，其特征是极长链脂肪酸（VLCFA）积累。几乎所有男性都会发展为进行性脊髓病（AMN）。然而，一部分患者会发展为致命的脑脱髓鞘疾病（脑型ALD）。造血干细胞移植对脑型ALD具有治愈作用，前提是该手术在疾病的早期阶段进行。不幸的是，这个狭窄的治疗窗口常常被错过。因此，越来越多的新生儿筛查项目将ALD纳入其中。为了确定ALD的新生物标志物，我们开发了一种Abcd1基因敲除小鼠，其VLCFA合成增强，可在全身或仅限于少突胶质细胞中发生。生化分析揭示了不同脂质类别和酰基肉碱中VLCFA的积累。C26:0-溶血磷脂酰胆碱（lysoPC）和C26:0-肉碱在脑、脊髓以及血斑中均显著升高。我们将分析扩展到患者，并证实C26:0-肉碱在ALD患者的血斑中也升高。我们预计，验证C26:0-肉碱用于诊断新生儿血斑中的ALD，可能会使已经筛查其他先天性代谢缺陷的国家更快地将ALD纳入新生儿筛查项目。
