Therapeutic Strategies for X-Linked Adrenoleukodystrophy, a Representative Peroxisomal Disorder

  • Masashi MoritaEmail author


X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder, and is caused by dysfunction of the peroxisomal ABC protein ABCD1. X-ALD patients with the most severe phenotype display cerebral inflammatory demyelination. In X-ALD, VLCFA accumulation, a characteristic feature of all patients, is thought to be the main culprit underlying the pathogenesis. However, the mechanisms by which the VLCFA accumulated in the brain causes demyelinating neurodegeneration have not yet been elucidated. At present, hematopoietic stem cell transplantation (HSCT) at an early symptomatic state is effective in halting disease progression, thus allowing long-term survival. Therefore, early diagnosis and conduct timely transplantation are particularly important to improve the outcome of HSCT. However, HSCT is always associated with significant mortality risk and the difficulty of finding a matching donor. Recently, genetically modified hematopoietic stem cells for ex vivo gene therapy have been tested as an alternative option and are expected to eventually become standard treatment for X-ALD. In parallel, the development of therapeutic drugs that can attenuate the symptoms or maintain the asymptomatic stage for patients diagnosed with X-ALD is in progress. To date, many candidate compounds have been reported. In this chapter, we focus on the current state of HSCT and pharmacological treatments, and describe the necessity for newborn screening and the identification of predictive biological markers in X-ALD.


ATP-binding cassette protein subfamily D1 (ABCD1) Ex vivo gene therapy X-Linked adrenoleukodystrophy (X-ALD) Newborn screening Hematopoietic stem cell transplantation (HSCT) Very long chain fatty acid (VLCFA) 



ATP-binding cassette protein subfamily D


Adult cerebral form


Alzheimer’s disease


Adolescent cerebral form




Blood-brain barrier


Bone marrow-derived macrophages


Cord blood transplantation


Childhood cerebral form


Central nervous system


Elongation of very long chain fatty acid


Hematopoietic stem cell transplantation


Multiple sclerosis


Magnetic resonance imaging


Peroxisome biogenesis disorder


Parkinson’s disease


Reactive oxygen species


Very long chain fatty acid


X-Linked adrenoleukodystrophy



The authors thank Professor Tsuneo Imanaka for his comments and suggestions. This work was supported in part by Grants-in-Aid for Scientific Research (C) (16K09961) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Pacific Edit reviewed the manuscript prior to submission.


  1. Asheuer M et al (2004) Human CD34+ cells differentiate into microglia and express recombinant therapeutic protein. Proc Natl Acad Sci U S A 101(10):3557–3562. Scholar
  2. Aubourg P et al (1990) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 322(26):1860–1866. Scholar
  3. Baarine M et al (2015a) ABCD1 deletion-induced mitochondrial dysfunction is corrected by SAHA: implication for adrenoleukodystrophy. J Neurochem 133(3):380–396. Scholar
  4. Baarine M et al (2015b) Functional characterization of IPSC-derived brain cells as a model for X-linked adrenoleukodystrophy. PLoS One 10(11):e0143238. Scholar
  5. Beckers L et al (2017) Specific suppression of microgliosis cannot circumvent the severe neuropathology in peroxisomal beta-oxidation-deficient mice. Mol Cell Neurosci 80:123–133. Scholar
  6. Beckers L et al (2018) Neuronal dysfunction and behavioral abnormalities are evoked by neural cells and aggravated by inflammatory microglia in peroxisomal beta-oxidation deficiency. Front Cell Neurosci 12:136. Scholar
  7. Benhamida S et al (2003) Transduced CD34+ cells from adrenoleukodystrophy patients with HIV-derived vector mediate long-term engraftment of NOD/SCID mice. Mol Ther 7(3):317–324PubMedCrossRefGoogle Scholar
  8. Berger J et al (2014) Pathophysiology of X-linked adrenoleukodystrophy. Biochimie 98:135–142. Scholar
  9. Bladowska J et al (2015) The role of MR imaging in the assessment of clinical outcomes in children with X-linked adrenoleukodystrophy after allogeneic haematopoietic stem cell transplantation. Pol J Radiol 80:181–190. Scholar
  10. Blaw M (1970) Melanodermic type leukodystrophy (adrenoleukodystrophy). In:Vinken PJ, Bruyn GW (eds) Neurodystrophies and neurolipidoses. North Holland Publishing Co., Amsterdam, pp. 128–133Google Scholar
  11. Budhram A, Pandey S (2017) Activation of cerebral X-linked adrenoleukodystrophy after head trauma. Can J Neurol Sci 44(5):597–598PubMedCrossRefGoogle Scholar
  12. Cappa M et al (1994) High dose immunoglobulin IV treatment in adrenoleukodystrophy. J Neurol Neurosurg Psychiatry 57(Suppl):69–70; discussion 71PubMedPubMedCentralCrossRefGoogle Scholar
  13. Cartier N, Aubourg P (2010) Hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy in X-linked adrenoleukodystrophy. Brain Pathol 20(4):857–862. Scholar
  14. Cartier N et al (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326(5954):818–823. Scholar
  15. Cartier N et al (2012) Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy. Methods Enzymol 507:187–198PubMedCrossRefPubMedCentralGoogle Scholar
  16. Cartier N et al (2014) The role of microglia in human disease: therapeutic tool or target? Acta Neuropathol 128(3):363–380PubMedPubMedCentralCrossRefGoogle Scholar
  17. Deon M et al (2016) Oxidative stress in patients with X-linked adrenoleukodystrophy. Cell Mol Neurobiol 36(4):497–512. Scholar
  18. Derecki NC et al (2013) The role of microglia in brain maintenance: implications for Rett syndrome. Trends Immunol 34(3):144–150. Scholar
  19. Eichler F et al (2017) Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 377(17):1630–1638PubMedPubMedCentralCrossRefGoogle Scholar
  20. Engelen M et al (2010) Lovastatin in X-linked adrenoleukodystrophy. N Engl J Med 362(3):276–277PubMedCrossRefPubMedCentralGoogle Scholar
  21. Engelen M et al (2012a) X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis 7:51. Scholar
  22. Engelen M et al (2012b) Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation. J Inherit Metab Dis 35(6):1137–1145PubMedPubMedCentralCrossRefGoogle Scholar
  23. Engelen M et al (2014) X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain 137(Pt 3):693–706. Scholar
  24. Fanconi A et al. (1963) [Addison’s disease with cerebral sclerosis in childhood. A hereditary syndrome transmitted through chromosome X?]. Helv Paediatr Acta 18:480–501Google Scholar
  25. Ferrara S et al (2017) Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorg Med Chem 25(10):2743–2753PubMedPubMedCentralCrossRefGoogle Scholar
  26. Ferrer I et al (2005) Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage. Hum Mol Genet 14(23):3565–3577. Scholar
  27. Fourcade S et al (2003) Thyroid hormone induction of the adrenoleukodystrophy-related gene (ABCD2). Mol Pharmacol 63(6):1296–1303. Scholar
  28. Fourcade S et al (2010) Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum Mol Genet 19(10):2005–2014. Scholar
  29. Fourcade S et al (2014) Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal degeneration in X-linked adrenoleukodystrophy. Biochimie 98:143–149. Scholar
  30. Galino J et al (2011) Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-adrenoleukodystrophy. Antioxid Redox Signal 15(8):2095–2107. Scholar
  31. Geric I et al (2018) Lipid homeostasis and inflammatory activation are disturbed in classically activated macrophages with peroxisomal beta-oxidation deficiency. Immunology 153(3):342–356. Scholar
  32. Gilg AG et al (2000) Inducible nitric oxide synthase in the central nervous system of patients with X-adrenoleukodystrophy. J Neuropathol Exp Neurol 59(12):1063–1069PubMedCrossRefGoogle Scholar
  33. Gong Y et al (2019) Intrathecal adeno-associated virus vector-mediated gene delivery for adrenomyeloneuropathy. Hum Gene Ther 30(5):544–555PubMedCrossRefGoogle Scholar
  34. Görtz AL et al (2018) Heat shock protein expression in cerebral X-linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss. Neuropathol Appl Neurobiol 44(4):363–376PubMedCrossRefGoogle Scholar
  35. Gronemeyer T et al (2013) The proteome of human liver peroxisomes: identification of five new peroxisomal constituents by a label-free quantitative proteomics survey. PLoS One 8(2):e57395. Scholar
  36. Gueugnon F et al (2003) Dehydroepiandrosterone induction of the Abcd2 and Abcd3 genes encoding peroxisomal ABC transporters: implications for X-linked adrenoleukodystrophy. Adv Exp Med Biol 544:245PubMedCrossRefGoogle Scholar
  37. Hartley M et al (2017) A thyroid hormone-based strategy for correcting the biochemical abnormality in X-linked adrenoleukodystrophy. Endocrinology 158(5):1328–1338PubMedPubMedCentralCrossRefGoogle Scholar
  38. Heinzer AK et al (2003) Mouse models and genetic modifiers in X-linked adrenoleukodystrophy. Adv Exp Med Biol 544:75–93PubMedCrossRefGoogle Scholar
  39. Horvath G et al (2012) Failure of repeated cyclophosphamide pulse therapy in childhood cerebral X-linked adrenoleukodystrophy. Neuropediatrics 43(1):48–52PubMedCrossRefGoogle Scholar
  40. Huffnagel IC et al (2019) Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis 14(1):30. Scholar
  41. Igarashi M et al (1976) Fatty acid abnormality in adrenoleukodystrophy. J Neurochem 26(4):851–860CrossRefGoogle Scholar
  42. Ito M et al (2001) Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation. J Neuropathol Exp Neurol 60(10):1004–1019PubMedCrossRefGoogle Scholar
  43. Jang J et al (2011) Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Ann Neurol 70(3):402–409PubMedCrossRefGoogle Scholar
  44. Jang J et al (2016) 25-Hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nat Commun 7:13129–13129PubMedPubMedCentralCrossRefGoogle Scholar
  45. Jiang H et al (2015) Combination of a haploidentical stem cell transplant with umbilical cord blood for cerebral X-linked adrenoleukodystrophy. Pediatr Neurol 53(2):163–165.e161PubMedCrossRefGoogle Scholar
  46. Kartha R et al (2015) Mechanisms of antioxidant induction with high-dose N-acetylcysteine in childhood cerebral adrenoleukodystrophy. CNS Drugs 29(12):1041–1047PubMedCrossRefGoogle Scholar
  47. Kato K et al (2019) Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy. Mol Genet Metab Rep 18:1–6. Scholar
  48. Kemp S, Wanders R (2010) Biochemical aspects of X-linked adrenoleukodystrophy. Brain Pathol 20(4):831–837. Scholar
  49. Kemp S et al (1998) Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy. Nat Med 4(11):1261–1268. Scholar
  50. Kemp S et al (2012) X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta 1822(9):1465–1474. Scholar
  51. Kemp S et al (2016) Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol 12(10):606–615CrossRefGoogle Scholar
  52. Kemper A et al (2017) Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genet Med 19(1):121–126PubMedCrossRefGoogle Scholar
  53. Koç ON et al (1999) Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol 27(11):1675–1681PubMedCrossRefGoogle Scholar
  54. Kohler W (2010) Leukodystrophies with late disease onset: an update. Curr Opin Neurol 23(3):234–241. Scholar
  55. Korenke GC et al (1997) Progression of X-linked adrenoleukodystrophy under interferon-beta therapy. J Inherit Metab Dis 20(1):59–66PubMedCrossRefGoogle Scholar
  56. Kuhl JS et al (2018) Potential risks to stable long-term outcome of allogeneic hematopoietic stem cell transplantation for children with cerebral X-linked adrenoleukodystrophy. JAMA Netw Open 1(3):e180769. Scholar
  57. Lauer A et al (2017) ABCD1 dysfunction alters white matter microvascular perfusion. Brain 140(12):3139–3152PubMedPubMedCentralCrossRefGoogle Scholar
  58. Launay N et al (2015) Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy. Acta Neuropathol 129(3):399–415PubMedCrossRefGoogle Scholar
  59. Launay N et al (2017) Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy. Acta Neuropathol 133(2):283–301PubMedCrossRefGoogle Scholar
  60. Lee CAA et al (2018) Modeling and rescue of defective blood-brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients. Fluids Barriers CNS 15(1):9PubMedPubMedCentralCrossRefGoogle Scholar
  61. Lopez-Erauskin J et al (2011) Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. Ann Neurol 70(1):84–92. Scholar
  62. Lopez-Erauskin J et al (2012) Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy. Brain 135(Pt 12):3584–3598. Scholar
  63. Lu J-F et al (2007) The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage. Lab Invest 87(3):261–272PubMedCrossRefGoogle Scholar
  64. Mahmood A et al (2007) Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol 6(8):687–692. Scholar
  65. Marchetti D et al (2015) Protective effect of antioxidants on DNA damage in leukocytes from X-linked adrenoleukodystrophy patients. Int J Dev Neurosci 43:8–15PubMedCrossRefGoogle Scholar
  66. Marchetti D et al (2018) Oxidative imbalance, nitrative stress, and inflammation in C6 glial cells exposed to hexacosanoic acid: protective effect of N-acetyl-L-cysteine, trolox, and rosuvastatin. Cell Mol Neurobiol 38(8):1505–1516PubMedCrossRefGoogle Scholar
  67. McGuinness MC et al (2001) Evaluation of pharmacological induction of fatty acid beta-oxidation in X-linked adrenoleukodystrophy. Mol Genet Metab 74(1–2):256–263PubMedCrossRefGoogle Scholar
  68. Melhem ER et al (2000) X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. AJNR Am J Neuroradiol 21(5):839–844PubMedGoogle Scholar
  69. Miller WP et al (2011) Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood 118(7):1971–1978. Scholar
  70. Miller WP et al (2016) Intensity of MRI gadolinium enhancement in cerebral adrenoleukodystrophy: a biomarker for inflammation and predictor of outcome following transplantation in higher risk patients. AJNR Am J Neuroradiol 37(2):367–372PubMedCrossRefGoogle Scholar
  71. Mills EL, O’Neill LA (2016) Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur J Immunol 46(1):13–21. Scholar
  72. Morato L et al (2013) Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Brain 136(Pt 8):2432–2443. Scholar
  73. Morató L et al (2015) Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy. Cell Death Differ 22(11):1742–1753PubMedPubMedCentralCrossRefGoogle Scholar
  74. Morita M (2007) [Adrenoleukodystrophy: molecular pathogenesis and development of therapeutic agents]. Yakugaku Zasshi 127(7):1059–1064PubMedCrossRefGoogle Scholar
  75. Morita M et al (2005) Baicalein 5,6,7-trimethyl ether, a flavonoid derivative, stimulates fatty acid beta-oxidation in skin fibroblasts of X-linked adrenoleukodystrophy. FEBS Lett 579(2):409–414. Scholar
  76. Morita M et al (2008) Baicalein 5,6,7-trimethyl ether activates peroxisomal but not mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 31(3):442–449. Scholar
  77. Morita M et al (2011) ABC subfamily D proteins and very long chain fatty acid metabolism as novel targets in adrenoleukodystrophy. Curr Drug Targets 12(5):694–706PubMedCrossRefGoogle Scholar
  78. Morita M et al (2015) Brain microsomal fatty acid elongation is increased in abcd1-deficient mouse during active myelination phase. Metab Brain Dis 30(6):1359–1367. Scholar
  79. Morita M et al (2018) Stability of the ABCD1 protein with a missense mutation: a novel approach to finding therapeutic compounds for X-linked adrenoleukodystrophy. JIMD Rep. Scholar
  80. Moser HW (1995) Adrenoleukodystrophy. Curr Opin Neurol 8(3):221–226PubMedCrossRefGoogle Scholar
  81. Moser A, Fatemi A (2018) Newborn screening and emerging therapies for X-linked adrenoleukodystrophy. JAMA Neurol 75(10):1175–1176PubMedCrossRefPubMedCentralGoogle Scholar
  82. Moser HW et al (2005) Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol 62(7):1073–1080. Scholar
  83. Moser HW et al (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3(3):140–151. Scholar
  84. Mosser J et al (1993) Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361(6414):726–730. Scholar
  85. Musolino P et al (2015) Brain endothelial dysfunction in cerebral adrenoleukodystrophy. Brain 138(11):3206–3220PubMedPubMedCentralCrossRefGoogle Scholar
  86. Naidu S et al (1988) Childhood adrenoleukodystrophy. Failure of intensive immunosuppression to arrest neurologic progression. Arch Neurol 45(8):846–848PubMedCrossRefPubMedCentralGoogle Scholar
  87. Netik A et al (1999) Adrenoleukodystrophy-related protein can compensate functionally for adrenoleukodystrophy protein deficiency (X-ALD): implications for therapy. Hum Mol Genet 8(5):907–913PubMedCrossRefPubMedCentralGoogle Scholar
  88. Nury T et al (2017) 7-Ketocholesterol is increased in the plasma of X-ALD patients and induces peroxisomal modifications in microglial cells: potential roles of 7-ketocholesterol in the pathophysiology of X-ALD. J Steroid Biochem Mol Biol 169:123–136CrossRefGoogle Scholar
  89. Ogino T, Suzuki K (1981) Specificities of human and rat brain enzymes of cholesterol ester metabolism toward very long chain fatty acids: implication for biochemical pathogenesis of adrenoleukodystrophy. J Neurochem 36(2):776–779PubMedCrossRefPubMedCentralGoogle Scholar
  90. Oishi Y et al (2017) SREBP1 contributes to resolution of pro-inflammatory TLR4 signaling by reprogramming fatty acid metabolism. Cell Metab 25(2):412–427. Scholar
  91. Orchard PJ et al (2019) Successful donor engraftment and repair of the blood brain barrier in cerebral adrenoleukodystrophy. Blood. Scholar
  92. Paintlia AS et al (2003) Correlation of very long chain fatty acid accumulation and inflammatory disease progression in childhood X-ALD: implications for potential therapies. Neurobiol Dis 14(3):425–439PubMedCrossRefPubMedCentralGoogle Scholar
  93. Pierpont E et al (2017) Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy. JAMA Neurol 74(6):710–717PubMedPubMedCentralCrossRefGoogle Scholar
  94. Powers JM et al (1992) The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 51(6):630–643PubMedCrossRefPubMedCentralGoogle Scholar
  95. Powers J et al (2005) Adreno-leukodystrophy: oxidative stress of mice and men. J Neuropathol Exp Neurol 64(12):1067–1079PubMedCrossRefPubMedCentralGoogle Scholar
  96. Pujol A (2016) Novel therapeutic targets and drug candidates for modifying disease progression in adrenoleukodystrophy. Endocr Dev 30:147–160. Scholar
  97. Pujol A et al (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum Mol Genet 11(5):499–505PubMedPubMedCentralCrossRefGoogle Scholar
  98. Pujol A et al (2004) Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy. Hum Mol Genet 13(23):2997–3006. Scholar
  99. Raas Q et al (2019) CRISPR/Cas9-mediated knockout of Abcd1 and Abcd2 genes in BV-2 cells: novel microglial models for X-linked adrenoleukodystrophy. Biochim Biophys Acta Mol Cell Biol Lipids. Scholar
  100. Ranea Robles P et al (2018) Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy. EMBO Mol Med 10(8):e8604PubMedPubMedCentralCrossRefGoogle Scholar
  101. Raymond GV et al (2010) Head trauma can initiate the onset of adreno-leukodystrophy. J Neurol Sci 290(1–2):70–74. Scholar
  102. Rizzo WB et al (1989) Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 39(11):1415–1422PubMedCrossRefPubMedCentralGoogle Scholar
  103. Sassa T et al (2014) Lorenzo’s oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid. J Lipid Res 55(3):524–530PubMedPubMedCentralCrossRefGoogle Scholar
  104. Schlüter A et al (2018) Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation. Brain Pathol 28(6):902–919PubMedPubMedCentralCrossRefGoogle Scholar
  105. Semmler A et al (2008) Therapy of X-linked adrenoleukodystrophy. Expert Rev Neurother 8(9):1367–1379. Scholar
  106. 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(1):126–131. Scholar
  107. Singh I et al (1998a) Lovastatin for X-linked adrenoleukodystrophy. N Engl J Med 339(10):702–703. Scholar
  108. Singh I et al (1998b) Lovastatin and sodium phenylacetate normalize the levels of very long chain fatty acids in skin fibroblasts of X-adrenoleukodystrophy. FEBS Lett 426(3):342–346PubMedCrossRefPubMedCentralGoogle Scholar
  109. Strachan L et al (2017) A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination. Hum Mol Genet 26(18):3600–3614PubMedPubMedCentralCrossRefGoogle Scholar
  110. Tagawa Y et al (2002) Anti-ganglioside antibodies bind with enhanced affinity to gangliosides containing very long chain fatty acids. Neurochem Res 27(7–8):847–855PubMedCrossRefPubMedCentralGoogle Scholar
  111. Takahashi N et al (2007) Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein (ALDP/ABCD1) with naturally occurring missense mutations. J Neurochem 101(6):1632–1643. Scholar
  112. Takemoto Y et al (2002) Epidemiology of X-linked adrenoleukodystrophy in Japan. J Hum Genet 47(11):590–593. Scholar
  113. Taylor JL, Lee S (2019) Lessons learned from newborn screening in pilot studies. N C Med J 80(1):54–58. Scholar
  114. Thibert KA et al (2012) Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction. PLoS One 7(11):e50430. Scholar
  115. Tran C et al (2017) Long-term outcome of patients with X-linked adrenoleukodystrophy: a retrospective cohort study. Eur J Paediatr Neurol 21(4):600–609PubMedCrossRefGoogle Scholar
  116. Troffer Charlier N et al (1998) Mirror expression of adrenoleukodystrophy and adrenoleukodystrophy related genes in mouse tissues and human cell lines. Eur J Cell Biol 75(3):254–264PubMedCrossRefGoogle Scholar
  117. Tsuji S et al (1984) Fatty acid elongation activity in fibroblasts from patients with adrenoleukodystrophy (ALD). J Biochem 96(4):1241–1247PubMedCrossRefGoogle Scholar
  118. Turk B et al (2017a) Antioxidant capacity and superoxide dismutase activity in adrenoleukodystrophy. JAMA Neurol 74(5):519–524PubMedPubMedCentralCrossRefGoogle Scholar
  119. Turk BR et al (2017b) Therapeutic strategies in adrenoleukodystrophy. Wien Med Wochenschr 167(9–10):219–226. Scholar
  120. Turk B et al (2018) Dendrimer-N-acetyl-L-cysteine modulates monophagocytic response in adrenoleukodystrophy. Ann Neurol 84(3):452–462PubMedPubMedCentralCrossRefGoogle Scholar
  121. van den Broek BTA et al (2018) Early and late outcomes after cord blood transplantation for pediatric patients with inherited leukodystrophies. Blood Adv 2(1):49–60PubMedPubMedCentralCrossRefGoogle Scholar
  122. van der Voorn JP et al (2011) Correlating quantitative MR imaging with histopathology in X-linked adrenoleukodystrophy. AJNR Am J Neuroradiol 32(3):481–489. Scholar
  123. van Engen CE et al (2016) CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids. Biochim Biophys Acta 1862(10):1861–1870. Scholar
  124. van Geel BM et al (2001) Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 49(2):186–194PubMedCrossRefPubMedCentralGoogle Scholar
  125. van Geel BM et al (2015) Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy: a retrospective study. J Inherit Metab Dis 38(2):359–361. Scholar
  126. van Roermund CW et al (2008) The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters. FASEB J 22(12):4201–4208. Scholar
  127. van Roermund CW et al (2011) Differential substrate specificities of human ABCD1 and ABCD2 in peroxisomal fatty acid beta-oxidation. Biochim Biophys Acta 1811(3):148–152. Scholar
  128. Vogel BH et al (2015) Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab 114(4):599–603CrossRefGoogle Scholar
  129. Weber F et al (2014) X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes. Hum Mol Genet 23(10):2542–2550PubMedCrossRefPubMedCentralGoogle Scholar
  130. Weinhofer I et al (2005) Liver X receptor alpha interferes with SREBP1c-mediated Abcd2 expression. Novel cross-talk in gene regulation. J Biol Chem 280(50):41243–41251. Scholar
  131. Weinhofer I et al (2018) Impaired plasticity of macrophages in X-linked adrenoleukodystrophy. Brain 141(8):2329–2342PubMedPubMedCentralCrossRefGoogle Scholar
  132. Wiesinger C et al (2013) Impaired very long-chain acyl-CoA beta-oxidation in human X-linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction. J Biol Chem 288(26):19269–19279. Scholar
  133. Wiesinger C et al (2015) The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet 8:109–121. Scholar
  134. Yamada T et al (2004) Therapeutic effects of normal cells on ABCD1 deficient cells in vitro and hematopoietic cell transplantation in the X-ALD mouse model. J Neurol Sci 218(1–2):91–97. Scholar
  135. Zhang X et al (2011) Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression. Biochem J 436(3):547–557. Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan

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