Review Article | Published:

Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history

Nature Reviews Endocrinology volume 12, pages 606615 (2016) | Download Citation

Abstract

X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. Virtually all men with ALD develop adrenal insufficiency and myelopathy. Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). However, one cannot identify these individuals until the early changes are seen using brain imaging. Women with ALD also develop myelopathy, but generally at a later age than men and adrenal insufficiency or cerebral ALD are very rare. Owing to the multisystem symptomatology of the disease, patients can be assessed by the paediatrician, general practitioner, endocrinologist or a neurologist. This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies. Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.

Key points

  • Adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder owing to mutations in ABCD1 with a highly complex clinical presentation

  • Presenting complaints are usually adrenal insufficiency (80% in childhood) or myelopathy (in adulthood)

  • Cerebral ALD can occur at any age and is most likely defined by the interplay between the primary ABCD1 mutation, a multitude of genetic variants and environmental factors

  • Haematopoietic stem cell transplantation (HSCT) remains the only therapeutic intervention for cerebral ALD, but the outcome of the procedure is poor unless performed at an early stage of cerebral disease

  • No treatment is currently available for the progressive myelopathy associated with ALD

  • Early diagnosis of boys with ALD by screening at birth allows the early detection of adrenal insufficiency to initiate timely adrenal steroid replacement therapy and the early detection of cerebral ALD to offer allogeneic HSCT

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Acknowledgements

The authors are grateful to R. Salzman (The Stop ALD Foundation) for critical review of the manuscript and helpful discussions. Work in the authors' laboratory was supported by a grant from the Netherlands Organization for Scientific Research (VENI-Grant: 016.156.033 awarded to M.E.).

Author information

Affiliations

  1. Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

    • Stephan Kemp
    • , Irene C. Huffnagel
    • , Ronald J. Wanders
    •  & Marc Engelen
  2. Pediatric Neurology, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

    • Irene C. Huffnagel
    •  & Marc Engelen
  3. Genetic Metabolic Diseases, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

    • Stephan Kemp
    •  & Ronald J. Wanders
  4. Endocrinology and Metabolism, Academisch Medisch Centrum, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

    • Gabor E. Linthorst

Authors

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Contributions

I.C.H. and M.E. researched data for the article. All authors made substantial contribution to discussion of the content, wrote, reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stephan Kemp.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrendo.2016.90

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