Molecular Genetics of X‐linked Adrenoleukodystrophy

Abstract

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.

close

References

Amorosi CA, Myskova H, Monti MR et al. (2012) X‐linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients. PLoS One 7: e52635.

Asheuer M, Bieche I, Laurendeau I et al. (2005) Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X‐linked adrenoleukodystrophy. Human Molecular Genetics 14: 1293–1303.

Berger J, Molzer B, Fae I and Bernheimer H (1994) X‐linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes. Biochemical Biophysical Research Communications 205: 1638–1643.

Boehm CD, Cutting GR, Lachtermacher MB, Moser HW and Chong SS (1999) Accurate DNA‐based diagnostic and carrier testing for X‐linked adrenoleukodystrophy. Molecular Genetics and Metabolism 66: 128–136.

Cartier N, Hacein‐Bey‐Abina S, Bartholomae CC et al. (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X‐linked adrenoleukodystrophy. Science 326: 818–823.

Di Rocco M, Doria‐Lamba L and Caruso U (2001) Monozygotic twins with X‐linked adrenoleukodystrophy and different phenotypes. Annals of Neurology 50: 424.

Dubey P, Raymond GV, Moser AB et al. (2005) Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long‐chain fatty acid screening. Journal of Pediatrics 146: 528–532.

Dvorakova L, Storkanova G, Unterrainer G et al. (2001) Eight novel ABCD1 gene mutations and three polymorphisms in patients with X‐linked adrenoleukodystrophy: the first polymorphism causing an amino acid exchange. Human Mutatation 18: 52–60.

Eichler FS, Ren JQ, Cossoy M et al. (2008) Is microglial apoptosis an early pathogenic change in cerebral X‐linked adrenoleukodystrophy? Annals of Neurology 63: 729–742.

Engelen M, Barbier M, Dijkstra IM et al. (2014) X‐linked adrenoleukodystrophy in women: a cross‐sectional cohort study. Brain 137: 693–706. doi: 10.1093/brain/awt361

Engelen M, Kemp S, de Visser M et al. (2012a) X‐linked adrenoleukodystrophy (X‐ALD): clinical presentation and guidelines for diagnosis, follow‐up and management. Orphanet Journal of Rare Diseases 7: 51.

Engelen M, Ofman R, Dijkgraaf MGW et al. (2010) Lovastatin in X‐linked adrenoleukodystrophy. New England Journal of Medicine 362: 276–277.

Engelen M, Schackmann MJ, Ofman R et al. (2012b) Bezafibrate lowers very long‐chain fatty acids in X‐linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation. Journal of Inherited Metabolic Diseases 35: 1137–1145.

Engelen M, Tran L, Ofman R et al. (2012c) Bezafibrate for X‐linked adrenoleukodystrophy. PLoS One 7: e41013.

Forss‐Petter S, Werner H, Berger J et al. (1997) Targeted inactivation of the X‐linked adrenoleukodystrophy gene in mice. Journal of Neuroscience Research 50: 829–843.

Fouquet F, Zhou JM, Ralston E et al. (1997) Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system. Neurobiology of Disease 3: 271–285.

Fourcade S, Lopez‐Erauskin J, Galino J et al. (2008) Early oxidative damage underlying neurodegeneration in X‐adrenoleukodystrophy. Human Molecular Genetics 17: 1762–1773.

van Geel BM, Assies J, Haverkort EB et al. (1999) Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X‐linked adrenoleukodystrophy despite treatment with ‘Lorenzo's oil’. Journal of Neurology, Neurosurgery and Psychiatry 67: 290–299.

van Geel BM, Assies J, Weverling GJ and Barth PG (1994) Predominance of the adrenomyeloneuropathy phenotype of X‐linked adrenoleukodystrophy in the Netherlands: a survey of 30 kindreds. Neurology 44: 2343–2346.

van Geel BM, Bezman L, Loes DJ, Moser HW and Raymond GV (2001) Evolution of phenotypes in adult male patients with X‐linked adrenoleukodystrophy. Annals of Neurology 49: 186–194.

Hein S, Schonfeld P, Kahlert S and Reiser G (2008) Toxic effects of X‐linked adrenoleukodystrophy‐associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture. Human Molecular Genetics 17: 1750–1761.

Ho JK, Moser H, Kishimoto Y and Hamilton JA (1995) Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy. Journal of Clinical Investigations 96: 1455–1463.

Igarashi M, Schaumburg HH, Powers J et al. (1976) Fatty acid abnormality in adrenoleukodystrophy. Journal of Neurochemistry 26: 851–860.

Kassmann CM, Lappe‐Siefke C, Baes M et al. (2007) Axonal loss and neuroinflammation caused by peroxisome‐deficient oligodendrocytes. Nature Genetics 39: 969–976.

Kemp S, Berger J and Aubourg P (2012) X‐linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochimica et Biophysica Acta – Molecular Basis of Disease 1822: 1465–1474.

Kemp S, Ligtenberg MJL, van Geel BM et al. (1994) Identification of A 2 base‐pair deletion in 5 unrelated families with adrenoleukodystrophy – A possible hot‐spot for mutations. Biochemical and Biophysical Research Communications 202: 647–653.

Kemp S, Pujol A, Waterham HR et al. (2001) ABCD1 mutations and the X‐linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Human Mutation 18: 499–515.

Kemp S, Theodoulou FL and Wanders RJ (2011) Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. British Journal of Pharmacology 164: 1753–1766.

Kemp S, Valianpour F, Denis S et al. (2005) Elongation of very long‐chain fatty acids is enhanced in X‐linked adrenoleukodystrophy. Molecular Genetics and Metabolism 84: 144–151.

Kishimoto Y, Moser HW, Kawamura N et al. (1980) Adrenoleukodystrophy: evidence that abnormal very long chain fatty acids of brain cholesterol esters are of exogenous origin. Biochemical and Biophysical Research Communications 96: 69–76.

Knazek RA, Rizzo WB, Schulman JD and Dave JR (1983) Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy. Journal of Clinical Investigations 72: 245–248.

Korenke GC, Fuchs S, Krasemann E et al. (1996) Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype. Annals of Neurology 40: 254–257.

Lu JF, Lawler AM, Watkins PA et al. (1997) A mouse model for X‐linked adrenoleukodystrophy. Proceedings of the National Academy of Sciences of the USA 94: 9366–9371.

Maestri NE and Beaty TH (1992) Predictions of a 2‐locus model for disease heterogeneity: application to adrenoleukodystrophy. American Journal of Medical Genetics 44: 576–582.

Miller WP, Rothman SM, Nascene D et al. (2011) Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single‐institution cohort report. Blood 118: 1971–1978.

Moser HW, Moser AB, Frayer KK et al. (1981) Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology 31: 1241–1249.

Moser HW, Smith KD, Watkins PA, Powers J and Moser AB (2001) X‐linked adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, pp. 3257–3301. New York: McGraw Hill.

Mosser J, Douar AM, Sarde CO et al. (1993) Putative X‐linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361: 726–730.

Odone A and Odone M (1989) Lorenzo's oil: a new treatment for adrenoleukodystrophy. Journal of Pediatric Neurosciences 5: 55–61.

Ofman R, Dijkstra IM, van Roermund CW et al. (2010) The role of ELOVL1 in very long‐chain fatty acid homeostasis and X‐linked adrenoleukodystrophy. EMBO Molecular Medicine 2: 90–97.

Powers JM and Schaumburg HH (1974) Adreno‐leukodystrophy (sex‐linked Schilder's disease). A pathogenetic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerve and testis. American Journal of Pathology 76: 481–491.

Pujol A, Hindelang C, Callizot N et al. (2002) Late onset neurological phenotype of the X‐ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Human Molecular Genetics 11: 499–505.

Raymond GV, Seidman R, Monteith TS et al. (2010) Head trauma can initiate the onset of adreno‐leukodystrophy. Journal of the Neurological Sciences 290: 70–74.

Rizzo WB, Phillips MW, Dammann AL et al. (1987) Adrenoleukodystrophy: dietary oleic acid lowers hexacosanoate levels. Annals of Neurology 21: 232–239.

van Roermund CWT, Visser WF, IJlst L et al. (2008) The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl‐CoA esters. FASEB Journal 22: 4201–4208.

Sanders RJ, Ofman R, Valianpour F, Kemp S and Wanders RJ (2005) Evidence for two enzymatic pathways for omega‐oxidation of docosanoic acid in rat liver microsomes. Journal of Lipid Research 46: 1001–1008.

Singh I, Khan M, Key L and Pai S (1998) Lovastatin for X‐linked adrenoleukodystrophy. New England Journal of Medicine 339: 702–703.

Singh I, Moser AE, Moser HW and Kishimoto Y (1984) Adrenoleukodystrophy: impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts, and amniocytes. Pediatric Research 18: 286–290.

Theda C, Gibbons K, Defor TE et al. (2014) Newborn screening for X‐linked adrenoleukodystrophy: further evidence high throughput screening is feasible. Molecular Genetics and Metabolism 111: 55–57.

Tsuji S, Sano T, Ariga T and Miyatake T (1981) Increased synthesis of hexacosanoic acid (C26:0) by cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). Journal of Biochemistry 90: 1233–1236.

Valianpour F, Selhorst JJ, van Lint LE et al. (2003) Analysis of very long‐chain fatty acids using electrospray ionization mass spectrometry. Molecular Genetics and Metabolism 79: 189–196.

Wiesinger C, Kunze M, Regelsberger G, Forss‐Petter S and Berger J (2013) Impaired very long‐chain acyl‐CoA β‐oxidation in human X‐linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction. Journal of Biological Chemistry 288: 19269–19279.

Zhang X, De Marcos LC, Schutte‐Lensink N et al. (2011) Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross‐kingdom expression. Biochemical Journal 436: 547–557.

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‐ald.nl/

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kemp, Stephan(May 2014) Molecular Genetics of X‐linked Adrenoleukodystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024277]