Molecular Genetics of X‐linked Adrenoleukodystrophy


X‐linked adrenoleukodystrophy (X‐ALD), which affects 1 in 17 000 newborns, is one of the most puzzling inborn errors of metabolism of the central nervous system. All X‐ALD patients have mutations in the ABCD1 gene, which affect the function of the encoded protein ALDP, an adenosine triphosphate (ATP)‐binding cassette transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta‐oxidation of very long‐chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in the accumulation of VLCFA in the plasma and tissues. The clinical spectrum ranges from progressive myelopathy in adults to fatal cerebral demyelinating disease in boys and adult males (cerebral ALD). In the absence of a genotype–phenotype correlation, the disease course remains completely unpredictable, even within families, and is therefore defined by modifier genes, epigenetics and the environment. For the majority of patients there is no curative therapy.

Key Concepts:

  • The clinical spectrum of X‐ALD ranges from a progressive myelopathy (adrenomyeloneuropathy) in adult males and females to a fatal cerebral demyelinating disease in boys and adult males (cerebral ALD).

  • X‐ALD has been diagnosed in all geographic regions and ethnic groups, and there is no evidence that the prevalence varies with ethnic background.

  • Mutations in the ABCD1 gene have no predictive value with respect to the clinical outcome of a patient.

  • Approximately 65% of heterozygous females develop AMN by the age of 60 years.

  • VLCFA accumulating in X‐ALD mostly result from endogenous synthesis through elongation of LCFA by ELOVL1, the VLCFA‐specific elongase.

  • Newborn screening allows prospective monitoring and early intervention.

Keywords: adrenoleukodystrophy; peroxisome; fatty acids; myelin; ABCD1; ELOVL1; adrenomyeloneuropathy

Figure 1.

A T2‐weighted image shows a typical pattern of white matter lesions in cerebral ALD with a hyperintense (white) signal in the splenium of the corpus callosum and parietooccipital white matter (left). T1‐weighted images show a hypointense signal (dark) in the same regions (centre), with prominent rim enhancement after administration of gadolinium which reflects disruption of the blood–brain barrier as a sign of inflammation (right).

Figure 2.

The ABCD1 gene contains 10 exons and codes for ALDP. Hypothesised structure of ALDP containing six transmembrane segments and a nucleotide‐binding domain (NBD). The hydrolysis of ATP generates the energy to drive the transport of VLCFA‐CoA across the peroxisomal membrane.

Figure 3.

Hypothetical model of phenotype development in X‐ALD. Virtually all X‐ALD patients that reach adulthood develop AMN. The onset of cerebral ALD, either in childhood or secondary to AMN, is defined by the concerted action of variations in modifier genes, epigenetics and the environment.

Figure 4.

Plasma VLCFA analysis in controls, male and female X‐ALD patients. In males, unambiguous diagnosis of X‐ALD can be achieved by demonstration of elevated levels of C26:0 fatty acids in the plasma. However, for females a normal plasma VLCFA level does not exclude heterozygosity for X‐ALD.

Figure 5.

VLCFA are synthesised through elongation of long‐chain fatty acids. VLCFA synthesis requires ELOVL1, the VLCFA‐specific elongase. ALDP transports VLCFA‐CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal VLCFA beta‐oxidation but also raises cytosolic levels of VLCFA‐CoA, which are substrates for further elongation by ELOVL1.



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Further Reading

Eichler F and Aubourg P (2008) Therapeutics of X‐linked adrenoleukodystrophy. Drug Discovery Today: Therapeutic Strategies 5: 237–242.

Kemp S and Wanders R (2010) Biochemical aspects of X‐linked adrenoleukodystrophy. Brain Pathology 20: 831–837.

Moser HW (1993) Lorenzo's oil. Lancet 341: 544.

Moser HW, Mahmood A and Raymond GV (2007) X‐linked adrenoleukodystrophy. Nature Clinical Practice Neurology 3: 140–151.

Web Link

The X‐linked adrenoleukodystrophy database. http://www.x‐

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Kemp, Stephan(May 2014) Molecular Genetics of X‐linked Adrenoleukodystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024277]