Abstract
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.
Highlights
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disorder caused by mutations in the ABCD1 gene [1]
We anticipated that increased very long-chain fatty acids (VLCFA) levels in the central nervous system of Abcd1 knockout mice play a role in the clinical phenotype of the Abcd1 knockout mouse and may lead to the identification of new biomarkers
We developed an Abcd1 knockout mouse with a Cre-inducible ELOVL1 transgene
Summary
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disorder caused by mutations in the ABCD1 gene [1]. The disease is characterized by impaired degradation of very long-chain fatty acids (VLCFA; >C22) [2, 3], resulting in VLCFA accumulation in plasma and tissues [4]. ALD affects approximately 1 in 17.000 males [5] and has been diagnosed in all PLOS ONE | DOI:10.1371/journal.pone.0154597. C26:0-Carnitine Is a New Biomarker for ALD. Metabolomic Discoveries GmbH provided support in the form of salary for author NS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of the author is articulated in the ‘author contributions’ section.”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript The specific role of the author is articulated in the ‘author contributions’ section.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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