X-ALD Annotated Bibliography


Aubourg, P., Blanche, S., Jambaqué, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., Rolland, M.-O., Debré, M., Chaussain, J.-L., Griscelli, C., Fischer, A., Bougnères, P.-F., 1990. Reversal of Early Neurologic and Neuroradiologic Manifestations of X-Linked Adrenoleukodystrophy by Bone Marrow Transplantation. N. Engl. J. Med. 322, 1860–1866. doi:10.1056/NEJM199006283222607

  • This provided information about the first successful bone marrow transplantation.  Only one child was treated, but this spurred on further successful trials.

Baarine, M., Andréoletti, P., Athias, A., Nury, T., Zarrouk, A., Ragot, K., Vejux, A., Riedinger, J.-M., Kattan, Z., Bessede, G., Trompier, D., Savary, S., Cherkaoui-Malki, M., Lizard, G., 2012. Evidence of oxidative stress in very long chain fatty acid – Treated oligodendrocytes and potentialization of ROS production using RNA interference-directed knockdown of ABCD1 and ACOX1 peroxisomal proteins. Neuroscience 213, 1–18. doi:10.1016/j.neuroscience.2012.03.058

  • This article demonstrated that VLCFA induced oxidative stress, especially in oligodendrocytes.

Bayeva, M., Khechaduri, A., Wu, R., Burke, M.A., Wasserstrom, J.A., Singh, N., Liesa, M., Shirihai, O.S., Langer, N.B., Paw, B.H., Ardehali, H., 2013. ATP-Binding Cassette B10 Regulates Early Steps of Heme Synthesis. Circ. Res. 113, 279–287. doi:10.1161/CIRCRESAHA.113.301552

  • This gives information about ABCB10, which is a homologue of ABCD1 that I studied.

Berger, J., Molzer, B., Fae, I., 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. Biochem. Biophys. Res. Commun. 205, 1638–1643. doi:10.1006/bbrc.1994.2855

  • This gave information about how there is no genotype-phenotype relationship in X-ALD because the same point mutation gave rise to 5 different phenotypes in 6 people of the same family.

Bezman, L., Moser, A.B., Raymond, G.V., Rinaldo, P., Watkins, P.A., Smith, K.D., Kass, N.E., Moser, H.W., 2001. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann. Neurol. 49, 512–517. doi:10.1002/ana.101

  • This gives information about the rates of X-ALD in the population and the rates of spontaneous mutations of the ABCD1 gene.

Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C.C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., 2009. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823. doi:10.1126/science.1171242

  • This article demonstrates that ALD can be treated by modifying hematopoietic stem cells with lentivirus vectors.  This is significant because the only curative treatment before this was bone marrow transplant.

Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C.C., Bougnères, P., Schmidt, M., Von Kalle,

C., Fischer, A., Cavazzana-Calvo, M., Aubourg, P., n.d. Chapter ten – Lentiviral Hematopoietic Cell Gene Therapy for X-Linked Adrenoleukodystrophy, in: Methods in Enzymology, Gene Transfer Vectors for Clinical Application. Academic Press, pp. 187–198.

  • This provided follow-up information about the outcomes of the two patients treated with gene therapy correction of their HSCs.

Eichler, F.S., Ren, J.-Q., Cossoy, M., Rietsch, A.M., Nagpal, S., Moser, A.B., Frosch, M.P., Ransohoff, R.M., 2008. Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy? Ann. Neurol. 63, 729–742. doi:10.1002/ana.21391

  • This provided insight into the effect of VLCFA-induced microglial apoptosis.

Fourcade, S., López-Erauskin, J., Galino, J., Duval, C., Naudi, A., Jove, M., Kemp, S., Villarroya, F., Ferrer, I., Pamplona, R., Portero-Otin, M., Pujol, A., 2008. Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. Hum. Mol. Genet. 17, 1762–1773. doi:10.1093/hmg/ddn085

  • This article presents information as to how VLCFA induce oxidative stress in neurons of X-ALD patients at an early stage of the disease progression, making it a causative agent of this disease.  It induces ROS generation and depletes GSH concentrations.  They even demonstrate that a drug, Trolox, can reverse damage done by oxidative stress.

Fourcade, S., Ruiz, M., Guilera, C., Hahnen, E., Brichta, L., Naudi, A., Portero-Otín, M., Dacremont, G., Cartier, N., Wanders, R., Kemp, S., Mandel, J.L., Wirth, B., Pamplona, R., Aubourg, P., Pujol, A., 2010. Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum. Mol. Genet. 19, 2005–2014. doi:10.1093/hmg/ddq082

  • This provides a treatment for X-ALD that induces ABCD2 expression by the HDAC inhibitor, valproic acid.  This reduces oxidative stress caused by VLCFA accumulation.

Glezer, I., Lapointe, A., Rivest, S., 2006. Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries. FASEB J. doi:10.1096/fj.05-5234fje

  • This showed that microglia stimulated oligodendrocytes to perform remyelination.

Hein, S., Schönfeld, P., Kahlert, S., 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. Hum. Mol. Genet. 17, 1750–1761. doi:10.1093/hmg/ddn066

  • This article identified that oligodendrocytes were the most affected by VLCFA accumulation, and that VLCFA accumulation decreases mitochondrial membrane potential.

Ho, J.K., Moser, H., Kishimoto, Y., Hamilton, J.A., 1995. Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy. J. Clin. Invest. 96, 1455–1463. doi:10.1172/JCI118182

  • This article gives insight into the mechanism by which myelin membranes are destabilized.  It has implications for triggering the inflammatory response.

Höftberger, R., Kunze, M., Weinhofer, I., Aboul-Enein, F., Voigtländer, T., Oezen, I., Amann, G., Bernheimer, H., Budka, H., Berger, J., 2007. Distribution and cellular localization of adrenoleukodystrophy protein in human tissues: implications for X-linked adrenoleukodystrophy. Neurobiol. Dis. 28, 165–174. doi:10.1016/j.nbd.2007.07.007

  • ABCD1 is expressed in higher quantities in cells that produce steroid hormones, such as the adrenal cortex.  This gives the link between X-ALD and hormone deficiency.

Hubbard, W.C., Moser, A.B., Liu, A.C., Jones, R.O., Steinberg, S.J., Lorey, F., Panny, S.R., Vogt, R.F., Jr, Macaya, D., Turgeon, C.T., Tortorelli, S., Raymond, G.V., 2009. Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol. Genet. Metab. 97, 212–220. doi:10.1016/j.ymgme.2009.03.010

  • Using LC-MS/MS, the authors developed a highly selective way of testing for X-ALD and other peroxisomal disorders in newborns because there was no way of testing before.  This will help detect X-ALD early, which will lead to longer life spans of X-ALD patients.

Igarashi, M., Schaumburg, H.H., Powers, J., Kishmoto, Y., Kolodny, E., Suzuki, K., 1976. Fatty acid abnormality in adrenoleukodystrophy. J. Neurochem. 26, 851–860. doi:10.1111/j.1471-4159.1976.tb04461.x-i1

  • This was the first study that demonstrated elevated VLCFA elevation in cholesterol esters in the brain and adrenal cortex and suggested that this could be the marker for X-ALD.

Jang, J., Kang, H.-C., Kim, H.-S., Kim, J.Y., Huh, Y.J., Kim, D.-S., Yoo, J.-E., Lee, J.-A., Lim, B., Lee, J., Yoon, T.-M., Park, I.-H., Hwang, D.-Y., Daley, G.Q., Kim, D.-W., 2011. Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Ann. Neurol. 70, 402–409. doi:10.1002/ana.22486

  • This patient used induced pluripotent stem cells to study X-ALD.  It demonstrated that oligodendrocyte dysfunction is much greater in those taken from CALD patients than AMN, which suggests an underlying genetic difference.


 Kihara, A., 2012. Very long-chain fatty acids: elongation, physiology and related disorders. J. Biochem. (Tokyo) 152, 387–395. doi:10.1093/jb/mvs105

  • Myelin membranes contain a higher percentage of VLCFA than other cells.

Kemp, S., Valianpour, F., Denis, S., Ofman, R., Sanders, R.-J., Mooyer, P., Barth, P.G., Wanders, R.J.A., 2005. Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy. Mol. Genet. Metab. 84, 144–151. doi:10.1016/j.ymgme.2004.09.015

  • Shows that VLCFA accumulation may occur because shorter VLCFA, such as C22:0 are being elongated by ELOVL to longer forms.  It also questions the toxicity of mono- and poly-unsaturated VLCFA.

 Launay, N., Ruiz, M., Fourcade, S., Schlüter, A., Guilera, C., Ferrer, I., Knecht, E., Pujol, A., 2013. Oxidative stress regulates the ubiquitin–proteasome system and immunoproteasome functioning in a mouse model of X-adrenoleukodystrophy. Brain 136, 891–904. doi:10.1093/brain/aws370

  • This established that oxidative stress has been shown to stimulate the ubiquitin-proteasome pathway in X-ALD.  This has implications for epigenetic factors that may cause the phenotypic variability.

López-Erauskin, J., Galino, J., Ruiz, M., Cuezva, J.M., Fabregat, I., Cacabelos, D., Boada, J., Martínez, J., Ferrer, I., Pamplona, R., Villarroya, F., Portero-Otín, M., Fourcade, S., Pujol, A., 2013. Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum. Mol. Genet. 22, 3296–3305. doi:10.1093/hmg/ddt186

  • This showed that VLCFA accumulation caused a reduction in oxidative phosphorylation, which caused the generation of ROS.

McGuinness, M.C., Powers, J.M., Bias, W.B., Schmeckpeper, B.J., Segal, A.H., Gowda, V.C., Wesselingh, S.L., Berger, J., Griffin, D.E., Smith, K.D., 1997. Human leukocyte antigens and cytokine expression in cerebral inflammatory demyelinative lesions of X-linked adrenoleukodystrophy and multiple sclerosis. J. Neuroimmunol. 75, 174–182. doi:10.1016/S0165-5728(97)00020-9

  • This was an early attempt at mapping inflammatory response profile.  Problems in their procedure were corrected in later work.

McGuinness, M.C., Lu, J.-F., Zhang, H.-P., Dong, G.-X., Heinzer, A.K., Watkins, P.A., Powers, J., Smith, K.D., 2003. Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy. Mol. Cell. Biol. 23, 744–753. doi:10.1128/MCB.23.2.744-753.2003

  • This article provides a link between the loss of ABCD1 and structure/function alterations of the mitochondria.

Migeon, B.R., Moser, H.W., Moser, A.B., Axelman, J., Sillence, D., Norum, R.A., 1981. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc. Natl. Acad. Sci. 78, 5066–5070. doi:10.1073/pnas.78.8.5066

  • This established the X-linkage of the gene responsible for causing X-ALD.

Moser, H.W., Moser, A.B., Frayer, K.K., Chen, W., Schulman, J.D., O’Neill, B.P., Kishimoto, Y., 1981. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology 31, 1241–1249.

  • This established the plasma assay for diagnosing X-ALD.

Moser HW, Raymond GV, Lu S, et al, 2005. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with lorenzo’s oil. Arch. Neurol. 62, 1073–1080. doi:10.1001/archneur.62.7.1073

  • This showed that Lorenzo’s Oil was only effective in patients who were asymptomatic or showed very few symptoms.

Moser, H.W., Moser, A.E., Singh, I., O’Neill, P., 1984. Adrenoleukodystrophy: survey of 303 cases: biochemistry, diagnosis, and therapy. Ann. Neurol. 16, 628–641. doi:10.1002/ana.410160603

  • This provides an early account of the characteristics of the varied phenotypic expressions of X-ALD.  It was a landmark summary of what the different forms are, how they can be detected, and possible therapies for this disease, including a bone marrow transplant.

Moser HW, Smith KD, Watkins PA, Powers J, Moser AB. X-linked adrenoleukodystrophy. In:Scriver CR, Beaudet AL, Valle D, Sly WS, eds. The Metabolic & Molecular Basis of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:3257-302.

  • This gave general background knowledge about the different forms of X-ALD.

Mosser, J., Douar, A.-M., Sarde, C.-O., Kioschis, P., Feil, R., Moser, H., Poustka, A.-M., Mandel, J.-L., Aubourg, P., 1993. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361, 726–730. doi:10.1038/361726a0

  • Establishes that ABCD1 mutations are the cause of X-ALD, which ended the controversy of what step of VLCFA degradation is not working.

Paintlia, A.S., Gilg, A.G., Khan, M., Singh, A.K., Barbosa, E., Singh, I., 2003. Correlation of very long chain fatty acid accumulation and inflammatory disease progression in childhood X-ALD: implications for potential therapies. Neurobiol. Dis. 14, 425–439. doi:10.1016/j.nbd.2003.08.013

  • This article provides the inflammatory response factors that cause demyleination.

Raymond, G.V., Seidman, R., Monteith, T.S., Kolodny, E., Sathe, S., Mahmood, A., Powers, J.M., 2010. Head trauma can initiate the onset of adreno-leukodystrophy. J. Neurol. Sci. 290, 70–74. doi:10.1016/j.jns.2009.11.005

  • This showed that the CALD phenotype can be triggered by head trauma, suggesting that the blood brain barrier structural integrity was compromised.  This could lead to infiltration by lymphocytes.

Rizzo, W.B., Leshner, R.T., Odone, A., Dammann, A.L., Craft, D.A., Jensen, M.E., Jennings, S.S., Davis, S., Jaitly, R., Sgro, J.A., 1989. Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 39, 1415–1422.

  • This article showed that erucic acid, which is used in Lorenzo’s Oil, was able to normalize VLCFA levels.

Sack, G.H., Raven, M.B., Moser, H.W., 1989. Color vision defects in adrenomyeloneuropathy. Am. J. Hum. Genet. 44, 794–798.

  • This helped map ABCD1 to the Xq28 locus.  It was used by Mosser et al. (1993) to identify ABCD1.

Salsano, E., Gambini, O., Giovagnoli, A.R., Farina, L., Uziel, G., Pareyson, D., 2012. Effectiveness of valproate for the treatment of manic-like behavior in X-linked adrenoleukodystrophy. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 33, 1197–1199. doi:10.1007/s10072-011-0863-2

  • This is a single case study where valproic acid was sufficient to stabilize a manic episode in an X-ALD patient.

Sassa, T., Wakashima, T., Ohno, Y., Kihara, A., 2014. Lorenzo’s oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid. J. Lipid Res. 55, 524–530. doi:10.1194/jlr.M044586

  • This article shows that Lorenzo’s Oil works by a mixed inhibition of ELOVL1 by the monounsaturated fatty acids found in it.

Shapiro, E., Krivit, W., Lockman, L., Jambaqué, I., Peters, C., Cowan, M., Harris, R., Blanche, S., Bordigoni, P., Loes, D., Ziegler, R., Crittenden, M., Ris, D., Berg, B., Cox, C., Moser, H., Fischer, A., Aubourg, P., 2000. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. The Lancet 356, 713–718. doi:10.1016/S0140-6736(00)02629-5

  • This was a follow-up to 12 successful bone marrow transplant surgeries.  It detailed the different functional recoveries that the different patients achieved.

Singh, H., Derwas, N., Poulos, A., 1987. β-oxidation of very-long-chain fatty acids and their coenzyme A derivatives by human skin fibroblasts. Arch. Biochem. Biophys. 254, 526–533. doi:10.1016/0003-9861(87)90133-0

  • This showed that the CoA ester forms of VLCFA were shown to be unaffected in X-ALD, which suggested that the defect was in the ACSVL enzyme.  This was shown to be false.

Singh, J., Giri, S., 2014. Loss of AMP-activated protein kinase in X-linked adrenoleukodystrophy patient-derived fibroblasts and lymphocytes. Biochem. Biophys. Res. Commun. 445, 126–131. doi:10.1016/j.bbrc.2014.01.126

  • In childhood cerebral ALD, AMPKα1 is inactivated, which worsens ALD because AMPKα1 promotes fatty acid oxidation and suppresses inflammatory genes.

Smith, K.D., Kemp, S., Braiterman, L.T., Lu, J.F., Wei, H.M., Geraghty, M., Stetten, G., Bergin, J.S., Pevsner, J., Watkins, P.A., 1999. X-linked adrenoleukodystrophy: genes, mutations, and phenotypes. Neurochem. Res. 24, 521–535.

  • This talked about the common mutations in X-ALD and that different phenotypes are observed from the same genetic mutations.

Van Roermund, C.W.T., Visser, W.F., Ijlst, L., van Cruchten, A., Boek, M., Kulik, W., Waterham, H.R., Wanders, R.J.A., 2008. The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 22, 4201–4208. doi:10.1096/fj.08-110866

  • ABCD1 functions as a homodimer, and it accepts a wide range of acyl-CoA esters

Weber, F.D., Wiesinger, C., Forss-Petter, S., Regelsberger, G., Einwich, A., Weber, W.H.A., Köhler, W., Stockinger, H., Berger, J., 2014. X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes. Hum. Mol. Genet. doi:10.1093/hmg/ddt645

  • This study provides insight into how VLCFA accumulation causes inflammatory demyleination.  It also gives an explanation as to why HSCT is effective by profiling the expression of ABCD1, ABCD2, and ABCD3 in different cells of the immune system.

Weinhofer, I., Forss-Petter, S., Zigman, M., Berger, J., 2002. Cholesterol regulates ABCD2 expression: implications for the therapy of X-linked adrenoleukodystrophy. Hum. Mol. Genet. 11, 2701–2708. doi:10.1093/hmg/11.22.2701

  • This focuses on ABCD2 as a method for treating X-ALD.  ABCD2 expression is stimulated under cholesterol depletion.

Wiesinger, C., Kunze, M., Regelsberger, G., Forss-Petter, S., 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. J. Biol. Chem. 288, 19269–19279. doi:10.1074/jbc.M112.445445

  • This article demonstrates for the first time that the degradation of the acyl-CoA esters of the VLCFA is impaired in X-ALD, which was debated before because conflicting results were shown.  C22:0 does not accumulate in X-ALD patients, but beta-oxidation of this is impaired in X-ALD fibroblasts, which suggests that these could be undergoing elongation to the C26:0 form.  This article also proposes that ABCD3 is responsible for residual beta-oxidation of VLCFA, not ABCD2 as many people have speculated.

Wong, C.M., McFall, E.R., Burns, J.K., Parks, R.J., 2013. The Role of Chromatin in Adenoviral Vector Function. Viruses 5, 1500–1515. doi:10.3390/v5061500

  • This showed the effectiveness of adenoviral vectors in gene therapy.