C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man

PLoS One. 2016 Apr 28;11(4):e0154597. doi: 10.1371/journal.pone.0154597. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters / genetics*
  • Acetyltransferases / genetics*
  • Adrenoleukodystrophy / diagnosis*
  • Adrenoleukodystrophy / pathology*
  • Animals
  • Biomarkers / metabolism
  • Brain / metabolism
  • Carnitine / analogs & derivatives*
  • Carnitine / metabolism
  • Early Diagnosis
  • Fatty Acid Elongases
  • Fatty Acids / metabolism
  • Gene Knock-In Techniques
  • Humans
  • Lysophosphatidylcholines / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligodendroglia / metabolism
  • Spinal Cord / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters
  • Abcd1 protein, mouse
  • Biomarkers
  • Fatty Acids
  • Lysophosphatidylcholines
  • acylcarnitine
  • Acetyltransferases
  • Fatty Acid Elongases
  • Carnitine

Grants and funding

Funded by European Leukodystrophy Association (http://ela-asso.com) ELA:2006-031I4 (SK); ELA:2007-026I4 (SK); ELA:2011-024I1 (SK) and ELA:2014-014I1 (SK); European Union Framework Programme 7 (https://ec.europa.eu/research/fp7/) (LeukoTreat (241622) RW, SK); Marie Curie International Training Network (http://www.mediasres-itn.eu/) (PerFuMe (316723) DG, NS); and Netherlands Organization for Scientific Research (http://www.nwo.nl/) (VIDI-grant (91786328) SK). 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.