Skip to main content
SpringerLink
Log in

Therapeutic strategies in adrenoleukodystrophy

Therapeutische Strategien bei Adrenoleukodystrophie

  • main topic
  • Published:
Wiener Medizinische Wochenschrift Aims and scope Submit manuscript

Summary

Adrenoleukodystrophy (ALD) is an X‑linked hereditary disorder due to mutations of the ABCD1 gene, which encodes a peroxisomal transport protein necessary for very long-chain fatty acid degradation (VLCFA). Toxic accumulation thereof is associated with a proinflammatory state and eventual cell death in multiple tissues. ALD may manifest either as a fatal, rapidly progressive demyelinating disease in boys and adult men, or as a slowly progressive adult-onset long-tract myelopathy along with peripheral neuropathy. Our understanding of manifold mechanisms implicated in the disease pathology is currently incomplete, as neither genotype–phenotype correlation nor the trigger for cerebral disease has been described. Therapy objectives are therefore broadly aimed at correcting either the gene mutation or downstream molecular effects, such as oxidative stress. Advancements in disease detection, including the newly implemented newborn screening in the US and imaging modalities, allow for more timely intervention in the form of hematopoietic stem cell transplantation (HSCT), which may only be performed in early cerebral disease states.

Zusammenfassung

Adrenoleukodystrophie (ALD) ist eine X‑chromosomale Erbkrankheit, die auf Mutationen des ABCD1-Gens basiert. Dieses codiert für ein peroxisomales Transportprotein, welches zur metabolischen Degradation überlangkettiger Fettsäuren notwendig ist. Bei Dysfunktion können diese akkumulieren und führen zu einem proinflammatorischen Zustand sowie schließlich zum Zelltod in vielen Geweben. ALD kann sich bei männlichen Kindern und Erwachsenen als rasch fortschreitende, tödliche, demyelinisierende Erkrankung der weißen Substanz manifestieren oder als langsam fortschreitende Myelopathie der langen Bahnen des Rückenmarks mit peripherer Neuropathie und Beginn im Erwachsenenalter. Die molekularen Mechanismen der Krankheit sind nicht zur Gänze geklärt, da weder die Genotyp-Phänotyp-Korrelationen noch zerebrale Krankheitsauslöser bekannt sind. Therapieansätze konzentrieren sich daher darauf, die Genmutation oder die daraus abgeleiteten molekularen Effekte wie oxidativen Stress zu kompensieren. Neue Diagnosemethoden wie das in den USA neuimplementierte Neugeborenenscreening oder neuere bildgebende Verfahren erlauben einen frühzeitigeren Therapiebeginn durch hämatopoetische Stammzelltransplantation, die möglicherweise nur in den Anfangsstadien der Krankheit durchgeführt werden kann.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, Rocchiccioli F, Cartier N, Jambaqué I, et al. A two-year trial of oleic and erucic acids (“Lorenzo’s oil”) as treatment for adrenomyeloneuropathy. New Engl J Med. 1993;329(11):745–52. doi:10.1056/NEJM199309093291101.

    Article  CAS  PubMed  Google Scholar 

  2. Baumann M, Korenke GC, Weddige-Diedrichs A, Wilichowski E, Hunneman DH, Wilken B, et al. Haematopoietic stem cell transplantation in 12 patients with cerebral X‑linked adrenoleukodystrophy. Eur J Pediatr. 2003;162(1):6–14. doi:10.1007/s00431-002-1097-3.

    Article  PubMed  Google Scholar 

  3. Berger J, Forss-Petter S, Eichler FS. Pathophysiology of X‑linked adrenoleukodystrophy. Biochimie. 2014;98:135–42. doi:10.1016/j.biochi.2013.11.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, Smith KD, et al. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49(4):512–7.

    Article  CAS  PubMed  Google Scholar 

  5. Biffi A, Aubourg P, Cartier N. Gene therapy for leukodystrophies. Hum Mol Genet. 2011;20(R1):R42–R53. doi:10.1093/hmg/ddr142.

    Article  CAS  PubMed  Google Scholar 

  6. Birken DL, Oldendorf WH. N‑acetyl-L-aspartic acid: a literature review of a compound prominent in 1 H-NMR spectroscopic studies of brain. Neurosci Biobehav Rev. 1989;13(1):23–31.

    Article  CAS  PubMed  Google Scholar 

  7. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X‑linked adrenoleukodystrophy. Science. 2009;326(5954):818–23. doi:10.1126/science.1171242.

    Article  CAS  PubMed  Google Scholar 

  8. Cartier N, Aubourg P. Hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy in X‑linked adrenoleukodystrophy. Brain Pathol. 2010;20(4):857–62. doi:10.1111/j.1750-3639.2010.00394.x.

    Article  PubMed  Google Scholar 

  9. Dubey P, Fatemi A, Barker PB, Degaonkar M, Troeger M, Zackowski K, et al. Spectroscopic evidence of cerebral axonopathy in patients with “pure” adrenomyeloneuropathy. Neurology. 2005a;64(2):304–10. doi:10.1212/01.WNL.0000149514.13580.84.

    Article  CAS  PubMed  Google Scholar 

  10. Dubey P, Fatemi A, Huang H, Nagae-Poetscher L, Wakana S, Barker PB, et al. Diffusion tensor-based imaging reveals occult abnormalities in adrenomyeloneuropathy. Ann Neurol. 2005b;58(5):758–66. doi:10.1002/ana.20643.

    Article  PubMed  Google Scholar 

  11. Eichler FS, Itoh R, Barker PB, Mori S, Garrett ES, van Zijl PCM, et al. Proton MR spectroscopic and diffusion tensor brain MR imaging in X‑linked adrenoleukodystrophy: initial experience. Radiology. 2002;225(1):245–52. doi:10.1148/radiol.2251011040.

    Article  PubMed  Google Scholar 

  12. Eichler FS, Ren J‑Q, Cossoy M, Rietsch AM, Nagpal S, Moser AB, et al. Is microglial apoptosis an early pathogenic change in cerebral X‑linked adrenoleukodystrophy? Ann Neurol. 2008;63(6):729–42. doi:10.1002/ana.21391.

    Article  PubMed  Google Scholar 

  13. Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJA, Aubourg P, Poll-The BT. X‑linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7(1):51. doi:10.1186/1750-1172-7-51.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Engelen M, Kemp S, Poll-The BT. X‑linked adrenoleukodystrophy: pathogenesis and treatment. Curr Neurol Neurosci Rep. 2014;14(10):486–8. doi:10.1007/s11910-014-0486-0.

    Article  PubMed  Google Scholar 

  15. Fatemi A, Barker PB, Ulug AM, Nagae-Poetscher LM, Beauchamp NJ, Moser AB, et al. MRI and proton MRSI in women heterozygous for X‑linked adrenoleukodystrophy. Neurology. 2003;60(8):1301–7.

    Article  CAS  PubMed  Google Scholar 

  16. Fatemi A, Smith SA, Dubey P, Zackowski KM, Bastian AJ, van Zijl PC, et al. Magnetization transfer MRI demonstrates spinal cord abnormalities in adrenomyeloneuropathy. Neurology. 2005;64(10):1739–45. doi:10.1212/01.WNL.0000164458.02141.06.

    Article  CAS  PubMed  Google Scholar 

  17. Fourcade S, Lopez-Erauskin J, Galino J, Duval C, Naudi A, Jove M, et al. Early oxidative damage underlying neurodegeneration in X‑adrenoleukodystrophy. Hum Mol Genet. 2008;17(12):1762–73. doi:10.1093/hmg/ddn085.

    Article  CAS  PubMed  Google Scholar 

  18. Garside S, Rosebush PI, Levinson AJ, Mazurek MF. Late-onset adrenoleukodystrophy associated with long-standing psychiatric symptoms. J Clin Psychiatry. 1999;60(7):460–8.

    Article  CAS  PubMed  Google Scholar 

  19. Genin EC, Gondcaille C, Trompier D, Savary S. Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics. J Steroid Biochem Mol Biol. 2009;116(1–2):37–43. doi:10.1016/j.jsbmb.2009.04.006.

    Article  CAS  PubMed  Google Scholar 

  20. Gong Y, Mu D, Prabhakar S, Moser A, Musolino P, Ren J, et al. Adenoassociated virus serotype 9‑mediated gene therapy for x‑linked adrenoleukodystrophy. Mol Ther. 2015;23(5):824–34. doi:10.1038/mt.2015.6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hoefnagel D, Brun A, Ingbar SH, Goldman H. Addison’s disease and diffuse cerebral sclerosis. J Neurol Neurosurg Psychiatr. 1967;30(1):56–60.

    Article  PubMed Central  Google Scholar 

  22. Igarashi M, Schaumburg HH, Powers J, Kishmoto Y, Kolodny E, Suzuki K. Fatty acid abnormality in adrenoleukodystrophy. J Neurochem. 1976;26(4):851–60.

    Article  CAS  PubMed  Google Scholar 

  23. Jardim LB, da Silva ACF, Blank D, Villanueva MM, Renck L, Costa MLB, et al. X‑linked adrenoleukodystrophy: clinical course and minimal incidence in South Brazil. Brain Dev. 2010;32(3):180–90. doi:10.1016/j.braindev.2009.02.002.

    Article  PubMed  Google Scholar 

  24. Korenke GC, Fuchs S, Krasemann E, Doerr HG, Wilichowski E, Hunneman DH, Hanefeld F. Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype. Ann Neurol. 1996;40(2):254–7. doi:10.1002/ana.410400221.

    Article  CAS  PubMed  Google Scholar 

  25. Kumar AJ, Köhler W, Kruse B, Naidu S, Bergin A, Edwin D, Moser HW. MR findings in adult-onset adrenoleukodystrophy. Am J Neuroradiol. 1995;16(6):1227–37.

    CAS  PubMed  Google Scholar 

  26. Laureti S, Casucci G, Santeusanio F, Angeletti G, Aubourg P, Brunetti P. X‑linked adrenoleukodystrophy is a frequent cause of idiopathic Addison’s disease in young adult male patients. J Clin Endocrinol Metab. 1996;81(2):470–4. doi:10.1210/jcem.81.2.8636252.

    CAS  PubMed  Google Scholar 

  27. Loes DJ, Hite S, Moser H, Stillman AE, Shapiro E, Lockman L, et al. Adrenoleukodystrophy: a scoring method for brain MR observations. Am J Neuroradiol. 1994;15(9):1761–6.

    CAS  PubMed  Google Scholar 

  28. Loes DJ, Fatemi A, Melhem ER, Gupte N, Bezman L, Moser HW, Raymond GV. Analysis of MRI patterns aids prediction of progression in X‑linked adrenoleukodystrophy. Neurology. 2003;61(3):369–74.

    Article  CAS  PubMed  Google Scholar 

  29. Lopez-Erauskin J, Fourcade S, Galino J, Ruiz M, Schluter A, Naudi A, et al. Antioxidants halt axonal degeneration in a mouse model of X‑adrenoleukodystrophy. Ann Neurol. 2011;70(1):84–92. doi:10.1002/ana.22363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X‑linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 2007;6(8):687–92. doi:10.1016/S1474-4422(07)70177-1.

    Article  PubMed  Google Scholar 

  31. Melhem ER, Loes DJ, Georgiades CS, Raymond GV, Moser HW. X‑linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. Am J Neuroradiol. 2000;21(5):839–44.

    CAS  PubMed  Google Scholar 

  32. Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118(7):1971–8. doi:10.1182/blood-2011-01-329235.

    Article  CAS  PubMed  Google Scholar 

  33. Moser HW, Raymond GV, Lu S‑E, Muenz LR, Moser AB, Xu J, et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol. 2005;62(7):1073–80. doi:10.1001/archneur.62.7.1073.

    Article  PubMed  Google Scholar 

  34. Moser HW, Mahmood A, Raymond GV. X‑linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007;3(3):140–51. doi:10.1038/ncpneuro0421.

    Article  PubMed  Google Scholar 

  35. Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, et al. Putative X‑linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993;361(6414):726–30. doi:10.1038/361726a0.

    Article  CAS  PubMed  Google Scholar 

  36. Musolino PL, Rapalino O, Caruso P, Caviness VS, Eichler FS. Hypoperfusion predicts lesion progression in cerebral X‑linked adrenoleukodystrophy. Brain. 2012;135(Pt 9):2676–83. doi:10.1093/brain/aws206.

    Article  PubMed  PubMed Central  Google Scholar 

  37. O’Neill BP, Moser HW, Saxena KM, Marmion LC. Adrenoleukodystrophy: clinical and biochemical manifestations in carriers. Neurology. 1984;34(6):798–801.

    Article  PubMed  Google Scholar 

  38. O’Neill GN, Aoki M, Brown RH. ABCD1 translation-initiator mutation demonstrates genotype-phenotype correlation for AMN. Neurology. 2001;57(11):1956–62.

    Article  PubMed  Google Scholar 

  39. Ofman R, Dijkstra IME, van Roermund CWT, Burger N, Turkenburg M, van Cruchten A, et al. The role of ELOVL1 in very long-chain fatty acid homeostasis and X‑linked adrenoleukodystrophy. EMBO Mol Med. 2010;2(3):90–7. doi:10.1002/emmm.201000061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pai GS, Khan M, Barbosa E, Key LL, Craver JR, Cure JK, et al. Lovastatin therapy for X‑linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients. Mol Genet Metab. 2000;69(4):312–22.

    Article  CAS  PubMed  Google Scholar 

  41. Pillai BK, Jasuja R, Simard JR, Hamilton JA. Fast diffusion of very long chain saturated fatty acids across a bilayer membrane and their rapid extraction by cyclodextrins: implications for adrenoleukodystrophy. J Biol Chem. 2009;284(48):33296–304. doi:10.1074/jbc.M109.043737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Powers JM, Schaumburg HH. Adreno-leukodystrophy (sex-linked Schilder’s disease). A pathogenetic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerve and testis. Am J Pathol. 1974;76(3):481–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Powers JM, DeCiero DP, Ito M, Moser AB, Moser HW. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol. 2000;59(2):89–102.

    Article  CAS  PubMed  Google Scholar 

  44. Raymond GV, Jones RO, Moser AB. Newborn screening for adrenoleukodystrophy: implications for therapy. Mol Diagn Ther. 2007;11(6):381–4.

    Article  PubMed  Google Scholar 

  45. Restuccia D. Neurophysiological abnormalities in adrenoleukodystrophy carriers. Evidence of different degrees of central nervous system involvement. Brain. 1997;120(7):1139–48. doi:10.1093/brain/120.7.1139.

    Article  PubMed  Google Scholar 

  46. Schluter A, Espinosa L, Fourcade S, Galino J, Lopez E, Ilieva E, et al. Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy. Hum Mol Genet. 2012;21(5):1062–77. doi:10.1093/hmg/ddr536.

    Article  PubMed  Google Scholar 

  47. Shulman DI, Palmert MR, Kemp SF, Lawson Wilkins Drug and Therapeutics Committee. Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007;119(2):e484–e494. doi:10.1542/peds.2006-1612.

    Article  PubMed  Google Scholar 

  48. Smith KD, Kemp S, Braiterman LT, Lu JF, Wei HM, Geraghty M, et al. X‑linked adrenoleukodystrophy: genes, mutations, and phenotypes. Neurochem Res. 1999;24(4):521–35.

    Article  CAS  PubMed  Google Scholar 

  49. van Geel BM, Koelman JH, Barth PG, Ongerboer de Visser BW. Peripheral nerve abnormalities in adrenomyeloneuropathy: a clinical and electrodiagnostic study. Neurology. 1996;46(1):112–8.

    Article  PubMed  Google Scholar 

  50. van Geel BM, Bezman L, Loes DJ, Moser HW, Raymond GV. Evolution of phenotypes in adult male patients with X‑linked adrenoleukodystrophy. Ann Neurol. 2001;49(2):186–94.

    Article  PubMed  Google Scholar 

  51. van Geel BM, Poll-The BT, Verrips A, Boelens J‑J, Kemp S, Engelen M. Hematopoietic cell transplantation does not prevent myelopathy in X‑linked adrenoleukodystrophy: a retrospective study. J Inherit Metab Dis. 2015;38(2):359–61. doi:10.1007/s10545-014-9797-1.

    Article  PubMed  Google Scholar 

  52. Vogel BH, Bradley SE, Adams DJ, D’Aco K, Erbe RW, Fong C, et al. Newborn screening for X‑linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab. 2015;114(4):599–603. doi:10.1016/j.ymgme.2015.02.002.

    Article  CAS  PubMed  Google Scholar 

  53. Whitcomb RW, Linehan WM, Knazek RA. Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. J Clin Invest. 1988;81(1):185–8. doi:10.1172/JCI113292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wiesinger C, Eichler FS, Berger J. The genetic landscape of X‑linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet. 2015;8:109–21. doi:10.2147/TACG.S49590.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the Myelin Project, the Brian’s Hope Foundation, and the ALD families for their continuous support and commitment.

Author information

Authors and Affiliations

  1. Kennedy Krieger Institute, Johns Hopkins Medical Institutions, The Moser Center for Leukodystrophies, Baltimore, USA

    Bela R. Turk, Ann B. Moser & Ali Fatemi

Authors
  1. Bela R. Turk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann B. Moser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ali Fatemi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Fatemi.

Ethics declarations

Conflict of interest

B.R. Turk, A.B. Moser, and A. Fatemi declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Turk, B.R., Moser, A.B. & Fatemi, A. Therapeutic strategies in adrenoleukodystrophy. Wien Med Wochenschr 167, 219–226 (2017). https://doi.org/10.1007/s10354-016-0534-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10354-016-0534-2

Keywords

Schlüsselwörter

Search

Navigation