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“Lorenzo’s Oil” Therapy for X-linked Adrenoleukodystrophy: Rationale and Current Assessment of Efficacy

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder that damages the nervous system and is associated with the accumulation of saturated very long chain fatty acids (SVLCFA). Oral administration of “Lorenzo’s oil” (LO), a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, normalizes the SVLCFA levels in plasma, but its clinical efficacy and the clinical indications for its use have been controversial for more than 15 years. We review the biochemical effects of LO administration and the rationale for its use and present a current appraisal of its capacity to reduce the risk for the childhood cerebral phenotype when administered to asymptomatic boys and to slow progression of adrenomyeloneuropathy in patients without cerebral involvement. We also present current efforts to provide definitive evaluation of its clinical efficacy and discuss its possible role in the new therapeutic opportunities that will arise if newborn screening for X-ALD is validated and implemented.

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References

  • Abdellatif, A. M. (1972). Cardiopathogenic effects of dietary rapeseed oil. Nutrition Reviews, 30, 2–6.

    PubMed  CAS  Article  Google Scholar 

  • Asheuer, M., Bieche, I., Laurendeau, I., Moser, A., Hainque, B., Vidaud, M., et al. (2005). Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy. Human Molecular Genetics, 14, 1293–1303.

    PubMed  Article  CAS  Google Scholar 

  • Assies, J., van Geel, B., Weverling, G. J., Haverkort, E. B., & Barth, P. G. (1994). Endocrine evaluation during dietary therapy for adrenomyeloneuropathy. In H. R. Bhatt, G. H. T. James, G. M. Besser, G. F. Bottazzo, & H. E. Keen (Eds.), Advances in Thomas Addison’s diseases (pp. 191–198). Bristol: Journal of Endocrinology.

    Google Scholar 

  • Aubourg, P., Adamsbaum, C., Lavallard-Rousseau, M. C., Rocchiccioli, F., Cartier, N., Jambaque, I., et al. (1993). A two-year trial of oleic and erucic acids (“Lorenzo’s oil”) as treatment for adrenomyeloneuropathy. New England Journal of Medicine, 329, 745–752.

    PubMed  Article  CAS  Google Scholar 

  • Aubourg, P., Blanche, S., Jambaque, I., Rocchiccioli, F., Kalifa, G., Naud-Saudreau, C., et al. (1990). Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. New England Journal of Medicine, 322, 1860–1866.

    PubMed  CAS  Article  Google Scholar 

  • Bezman, L., & Moser, H. W. (1998). Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes. American Journal of Medical Genetics, 76, 415–419.

    PubMed  Article  CAS  Google Scholar 

  • Bezman, L., Moser, A. B., Raymond, G. V., Rinaldo, P., Watkins, P. A., Smith, K. D., et al. (2001). Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening. Annals of Neurology, 49, 512–517.

    PubMed  Article  CAS  Google Scholar 

  • Bizzozero, O. A., Zuniga, G., & Lees, M. B. (1991). Fatty acid composition of human myelin proteolipid protein in peroxisomal disorders. Journal of Neurochemistry, 56, 872–878.

    PubMed  Article  CAS  Google Scholar 

  • Boehm, C. D., Cutting, G. R., Lachtermacher, M. B., Moser, H. W., & Chong, S. S. (1999). Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy. Molecular Genetics and Metabolism, 66, 128–136.

    PubMed  Article  CAS  Google Scholar 

  • Bourre, J. M., Daudu, O., & Baumann, N. (1976). Nervonic acid biosynthesis by erucyl-CoA elongation in normal and quaking mouse brain microsomes. Elongation of other unsaturated fatty acyl-CoAs (mono and poly-unsaturated). Biochimica Et Biophysica Acta, 424, 1–7.

    PubMed  CAS  Google Scholar 

  • Brown, F. R. 3rd, Van Duyn, M. A., Moser, A. B., Schulman, J. D., Rizzo, W. B., Snyder R. D., et al. (1982). Adrenoleukodystrophy: Effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids. Johns Hopkins Medical Journal, 151, 164–172.

    PubMed  Google Scholar 

  • Choi, J. K., Ho J., Curry, S., Qin, D., Bittman, R., & Hamilton, J. A. (2002). Interactions of very long-chain saturated fatty acids with serum albumin. Journal of Lipid Research, 43, 1000–1010.

    PubMed  Article  CAS  Google Scholar 

  • Cox, C., Dubey P., Raymond, G. V., Mahmood, A., Moser, A. B., & Moser, H. W. (2006). Cognitive evaluation of neurologically asymptomatic boys with X-linked adrenoleukodystrophy. Archives of Neurology, 63, 69–73.

    PubMed  Article  Google Scholar 

  • Dean, M., Hamon, Y., & Chimini, G. (2001). The human ATP-binding cassette (ABC) transporter superfamily. Journal of Lipid Research, 42, 1007–1017.

    PubMed  CAS  Google Scholar 

  • Di Biase, A., Di Benedetto, R., Fiorentini, C., Travaglione, S., Salvati, S., Attorri, L., et al. (2004). Free radical release in C6 glial cells enriched in hexacosanoic acid: Implication for X-linked adrenoleukodystrophy pathogenesis. Neurochemistry International, 44, 215–221.

    PubMed  Article  CAS  Google Scholar 

  • Dubey, P., Raymond, G., Moser, A. B., Kharkar, S., Bezman, L., & Moser, H. W. (2005). Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long chain fatty acid screening. Journal de Pediatria, 146, 528–532.

    Article  Google Scholar 

  • Dubois-Dalcq, M., Feigenbaum, V., & Aubourg, P. (1999). The neurobiology of X-linked adrenoleukodystrophy, a demyelinating peroxisomal disorder. Trends in Neurosciences, 22, 4–12.

    PubMed  Article  CAS  Google Scholar 

  • Fatemi, A., Smith, S. A., Dubey, P., Zackowski, K. M., Bastian, A. J., van Zijl, P. C., et al. (2005). Magnetization transfer MRI demonstrates spinal cord pathology in adrenomyeloneuropathy. Neurology, 64, 1739–1745.

    PubMed  Article  CAS  Google Scholar 

  • Feigenbaum, V., Gelot, A., Casanova, P., Daumas-Duport, C., Aubourg, P., & Dubois-Dalcq, M. (2000). Apoptosis in the central nervous system of cerebral adrenoleukodystrophy patients. Neurobiology of Disease, 7, 600–612.

    PubMed  Article  CAS  Google Scholar 

  • Gilg, A. G., Singh, A. K., & Singh, I. (2000). Inducible nitric oxide synthase in the central nervous system of patients with X-adrenoleukodystrophy. Journal of Neuropathology and Experimental Neurology, 59, 1063–1069.

    PubMed  CAS  Google Scholar 

  • Golovko, M. Y., & Murphy, E. J. (2006). Uptake and metabolism of plasma derived erucic acid by rat brain. Journal of Lipid Research, 47, 1289–1297.

    PubMed  Article  CAS  Google Scholar 

  • Hamilton, J. A., Era, S., Bhamidipati, S. P., & Reed, R. G. (1991). Locations of the three primary binding sites for long-chain fatty acids on bovine serum albumin. Proceedings of the National Academy of Sciences of the United States of America, 88, 2051–2054.

    PubMed  Article  CAS  Google Scholar 

  • 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. Journal of Clinical Investigation, 96, 1455–1463.

    PubMed  CAS  Google Scholar 

  • Hubbard, W. C., Moser, A. B., Tortorelli, S., Liu, A., Jones, D., & Moser, H. W. (2006). Combined liquid chromatography-Tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: Preliminary findings. Molecular Genetics and Metabolism, 89, 185-187.

    PubMed  Article  CAS  Google Scholar 

  • Igarashi, M., Belchis, D., & Suzuki, K. (1976a). Brain gangliosides in adrenoleukodystrophy. Journal of Neurochemistry, 27, 327–328.

    Article  CAS  Google Scholar 

  • Igarashi, M., Schaumburg, H. H., Powers, J., Kishmoto, Y., Kolodny, E., & Suzuki, K. (1976b). Fatty acid abnormality in adrenoleukodystrophy. Journal of Neurochemistry, 26, 851–860.

    PubMed  Article  CAS  Google Scholar 

  • Ito, M., Blumberg, B. M., Mock, D. J., Goodman, A. D., Moser, A. B., Moser, H. W., 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. Journal of Neuropathology and Experimental Neurology, 60, 1004–1019.

    PubMed  CAS  Google Scholar 

  • Kemp, S., Valianpour, F., Denis, S., Ofman, R., Sanders, R. J., Mooyer, P., et al. (2005). Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy. Molecular Genetics and Metabolism, 84, 144–151.

    PubMed  Article  CAS  Google Scholar 

  • Kickler, T. S., Zinkham, W. H., Moser, A., Shankroff, J., Borel, J., & Moser, H. (1996). Effect of erucic acid on platelets in patients with adrenoleukodystrophy. Biochemical and Molecular Medicine, 57, 125–133.

    PubMed  Article  CAS  Google Scholar 

  • Knazek, R. A., Rizzo, W. B., Schulman, J. D., & Dave, J. R. (1983). Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy. Journal of Clinical Investigation, 72, 245–248.

    PubMed  CAS  Google Scholar 

  • Koehler, W., & Sokolowski, P. (1999). A new disease-specific scoring system for adult phenotypes of X-linked adrenoleukodystrophy. Journal of Molecular Neuroscience, 13, 247–252.

    Article  Google Scholar 

  • Koehler, W., & Sokolowski, P. (2005). Clinical phenotypes, diagnosis and treatment of adulthood X-linked adrenoleukodystrophy. In J. Berger, S. Stoeckler & W. Koehler (Eds.), Understanding and treating adrenoleukodystrophy: Present state and future perspectives (pp. 28–60). SPS Verlagsgeseltschaft: Verlag Heilbronn.

    Google Scholar 

  • Kurtzke, J. F. (1983). Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology, 33, 1444–1452.

    PubMed  CAS  Google Scholar 

  • Moser, H. W., Aubourg P., Cornblath, D., Borel, J., Wu, Y.-W., Bergin, A., et al. (1991). Therapy for X-linked adrenoleukodystrophy. In R. J. Desnick (Ed.), Treatment of genetic disease (pp. 111–129). New York: Churchill Livingstone.

    Google Scholar 

  • Moser, H. W., & Brereton, N. H. (2005) Adrenoleukodystrophy and other peroxisomal disorders. In S. W. Ekvall & V. K. Ekvall (Eds.), Pediatric nutrition in chronic diseases and developmental disorders: Prevention, assessment and treatment (pp. 312–317). New York: Oxford Univ. Press.

    Google Scholar 

  • Moser, A. B., Jones, D. S., Raymond, G. V., & Moser, H. W. (1999a). Plasma and red blood cell fatty acids in peroxisomal disorders. Neurochemical Research, 24, 187–197.

    PubMed  Article  CAS  Google Scholar 

  • Moser, A. B., Kreiter, N., Bezman, L., Lu, S., Raymond, G. V., Naidu, S., et al. (1999b). Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Annals of Neurology, 45, 100–110.

    PubMed  Article  CAS  Google Scholar 

  • Moser, A. B., & Moser, H. W. (1999). The prenatal diagnosis of X-linked adrenoleukodystrophy. Prenatal Diagnosis, 19, 46–48.

    PubMed  Article  CAS  Google Scholar 

  • Moser, H. W., Moser, A. B., Kawamura, N., Murphy, J., Suzuki, K., Schaumburg, H., et al. (1980). Adrenoleukodystrophy: Elevated C26 fatty acid in cultured skin fibroblasts. Annals of Neurology, 7, 542–549.

    PubMed  Article  CAS  Google Scholar 

  • Moser, H. W., Raymond, G. V., & Dubey, P. (2005). Adrenoleukodystrophy: New approaches to a neurodegenerative disease. JAMA, 294, 3131–3134.

    PubMed  Article  CAS  Google Scholar 

  • Moser, H. W., Raymond, G. V., Koehler, W., Sokolowski, P., Hanefeld, F., Korenke, G. C., et al. (2003). Evaluation of the preventive effect of glyceryl trioleate–trierucate (“Lorenzo’s oil”) therapy in X-linked adrenoleukodystrophy: Results of two concurrent trials. Advances in Experimental Medicine and Biology, 544, 369–387.

    PubMed  CAS  Google Scholar 

  • Moser, H. W., Raymond, G. V., Lu, S. E., Muenz, L. R., Moser, A. B., Xu, J., et al. (2005). Follow-up of 89 Lorenzo’s oil treated asymptomatic adrenoleukodystrophy patients. Archives of Neurology, 62, 1073–1080.

    PubMed  Article  Google Scholar 

  • Mosser, J., Douar, A. M., Sarde, C. O., Kioschis, P., Feil, R., Moser, H., et al. (1993). Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature, 361, 726–730.

    PubMed  Article  CAS  Google Scholar 

  • Odone, A., & Odone, M. (1989) Lorenzo’s oil: A new treatment for adrenoleukodystrophy. Journal of Pediatric Neuroscience, 5, 55–61.

    Google Scholar 

  • Oya, Y., Nakayasu, H., Fujita, N., Suzuki, K., & Suzuki, K. (1998). Pathological study of mice with total deficiency of sphingolipid activator proteins (SAP knockout mice). Acta Neuropathologica (Berl.), 96, 29–40.

    Article  CAS  Google Scholar 

  • Oz, G., Tkac, I., Charnas, L. R., Choi, I. Y., Bjoraker, K. J., Shapiro, E. G., et al. (2005). Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients. Neurology, 64, 434–441.

    PubMed  CAS  Google Scholar 

  • Paintlia, A. S., Gilg, A. G., Khan, M., Singh, A. K., Barbosa, E., & Singh I. (2003) Correlation of very long chain fatty acids accumulation and inflammatory disease progression in childhood ALD: Implications for potential therapies. Neurobiology of Disease, 14, 425–439.

    PubMed  Article  CAS  Google Scholar 

  • Peters, C., Charnas, L. R., Tan, Y., Ziegler, R. S., Shapiro, E. G., DeFor, T., et al. (2004). Cerebral X-linked adrenoleukodystrophy: The international hematopoietic cell transplantation experience from 1982 to 1999. Blood, 104, 881–888.

    PubMed  Article  CAS  Google Scholar 

  • Poulos, A., Gibson, R., Sharp, P., Beckman, K., & Grattan-Smith, P. (1994). Very long chain fatty acids in X-linked adrenoleukodystrophy brain after treatment with Lorenzo’s oil. Annals of Neurology, 36, 741–746.

    PubMed  Article  CAS  Google Scholar 

  • Powers, J. M., DeCiero, D. P., Cox, C., Richfield, E. K., Ito, M., Moser, A. B., et al. (2001). The dorsal root ganglia in adrenomyeloneuropathy: Neuronal atrophy and abnormal mitochondria. Journal of Neuropathology and Experimental Neurology, 60, 493–501.

    PubMed  CAS  Google Scholar 

  • Powers, J. M., DeCiero, D. P., Ito, M., Moser, A. B., & Moser, H. W. (2000). Adrenomyeloneuropathy: A neuropathologic review featuring its noninflammatory myelopathy. Journal of Neuropathology and Experimental Neurology, 59, 89–102.

    PubMed  CAS  Google Scholar 

  • Powers, J. M., Liu, Y., Moser, A. B., & Moser, H. W. (1992). The inflammatory myelinopathy of adreno-leukodystrophy: Cells, effector molecules, and pathogenetic implications. Journal of Neuropathology and Experimental Neurology 51, 630–643.

    PubMed  CAS  Google Scholar 

  • Powers, J. M., Pei, Z., Heinzer, A. K., Deering, R., Moser, A. B., Moser, H. W., et al. (2005). Adrenoleukodystrophy: Oxidative stress of mice and men. Journal of Neuropathology and Experimental Neurology 64, 1067–1079.

    PubMed  CAS  Google Scholar 

  • Powers, J. M., Schaumburg, H. H., Johnson, A. B., & Raine, C. S. (1980). A correlative study of the adrenal cortex in adreno-leukodystrophy—evidence for a fatal intoxication with very long chain saturated fatty acids. Investigative & Cell Pathology, 3, 353–376.

    CAS  Google Scholar 

  • Rasmussen, M., Moser, A. B., Borel, J., Khangoora, S., & Moser, H. W. (1994). Brain, liver, and adipose tissue erucic and very long chain fatty acid levels in adrenoleukodystrophy patients treated with glyceryl trierucate and trioleate oils (Lorenzo’s oil). Neurochemical Research, 19, 1073–1082.

    PubMed  Article  CAS  Google Scholar 

  • Rizzo, W. B., Leshner, R. T., Odone, A., Craft, D. A., Jennings, S. S., & Jaitly, R. (1990). X-linked adrenoleukodystrophy: Biochemical and clinical efficacy of dietary erucic acid therapy. In G. Uziel, R. J. A. Wanders, & M. E. Cappa (Eds.), Adrenoleukodystrophy and other peroxisomal disorders (pp. 149–162). Amsterdam: Excerpta Medica.

    Google Scholar 

  • Rizzo, W. B., Leshner, R. T., Odone, A., Dammann, A. L., Craft, D. A., Jensen, M. E., et al. (1989). Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology, 39, 1415–1422.

    PubMed  CAS  Google Scholar 

  • Rizzo, W. B., Phillips, M. W., Dammann, A. L., Leshner, R. T., Jennings, S. S., Avigan J., et al. (1987). Adrenoleukodystrophy: Dietary oleic acid lowers hexacosanoate levels. Annals of Neurology, 21, 232–239.

    PubMed  Article  CAS  Google Scholar 

  • Rizzo, W. B., Watkins, P. A., Phillips, M. W., Cranin, D., Campbell, B., & Avigan, J. (1986). Adrenoleukodystrophy: Oleic acid lowers fibroblast saturated C22-26 fatty acids. Neurology, 36, 357–361.

    PubMed  CAS  Google Scholar 

  • Sauer, F. D., & Kramer, J. K. G. (1983). The Problems Associated with the Feeding of High Erucic Acid Rapeseed Oils and Some Fish Oils to Experimental Animals. In J. K. G. Kramer, F. D. Sauer, & W. J. Pigden (Eds.), High and low erucic acid rapeseed oils (pp. 253–292). Toronto: Academic Press.

    Google Scholar 

  • Schaumburg, H. H., Powers, J. M., Raine, C. S., Suzuki, K., & Richardson, E. P. Jr. (1975). Adrenoleukodystrophy. A clinical and pathological study of 17 cases. Archives of Neurology, 32, 577–591.

    PubMed  CAS  Google Scholar 

  • Shapiro, E., Krivit, W., Lockman, L., Jambaque, I., Peters, C., Cowan, M., et al. (2000). Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet, 356, 713–718.

    PubMed  Article  CAS  Google Scholar 

  • Tagawa, Y., Laroy, W., Nimrichter, L., Fromholt, S. E., Moser, A. B., Moser, H. W., et al. (2002). Anti-ganglioside antibodies bind with enhanced affinity to gangliosides containing very long chain fatty acids. Neurochemical Research, 27, 847–855.

    PubMed  Article  CAS  Google Scholar 

  • Tsuji, S., Suzuki, M., Ariga, T., Sekine, M., Kuriyama, M., & Miyatake, T. (1981). Abnormality of long-chain fatty acids in erythrocyte membrane sphingomyelin from patients with adrenoleukodystrophy. Journal of Neurochemistry, 36, 1046–1049.

    PubMed  Article  CAS  Google Scholar 

  • Uziel, G., Bertini, E., Bardelli, P., Rimoldi, M., & Gambetti, M. (1991). Experience on therapy of adrenoleukodystrophy and adrenomyeloneuropathy. Developmental Neuroscience, 13, 274–279.

    PubMed  CAS  Google Scholar 

  • Valianpour, F., Selhorst, J. J. M., van Lint, L. E. M., van Gennip, A. H., Wanders, R. J. A., & Kemp, S. (2003). Analysis of very long chain fatty acids using electrospray ionization mass spectrometry. Molecular Genetics and Metabolism, 79, 189–196.

    PubMed  Article  CAS  Google Scholar 

  • van Geel, B. M., Assies, J., Haverkort, E. B., Koelman, J. H., Verbeeten, B. Jr., Wanders R. J., 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.

    Article  Google Scholar 

  • Vargas, C. R., Wajner, M., Sirtori, L. R., Goulart, L., Chiochetta, M., Coelho, D., et al. (2004). Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy. Biochimica et Biophysica Acta, 1688, 26–32.

    PubMed  CAS  Google Scholar 

  • Whitcomb, R. W., Linehan, W. M., & Knazek, R. A. (1988). Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. Journal of Clinical Investigation, 81, 185–188.

    PubMed  CAS  Article  Google Scholar 

  • Zackowski, K., Dubey, P., Raymond, G. V., Mahmood, A., Moser, A. B., & Moser, H. W. (2006). Relating sensorimotor function and axonal integrity in adrenomyeloneuropathy. Archives of Neurology, 63, 74–80.

    PubMed  Article  Google Scholar 

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Correspondence to Ann B. Moser.

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Dr. Hugo W. Moser is deceased.

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Moser, H.W., Moser, A.B., Hollandsworth, K. et al. “Lorenzo’s Oil” Therapy for X-linked Adrenoleukodystrophy: Rationale and Current Assessment of Efficacy. J Mol Neurosci 33, 105–113 (2007). https://doi.org/10.1007/s12031-007-0041-4

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Keywords

  • Adrenoleukodystrophy
  • Therapy
  • Lorenzo’s oil
  • Glyceryl trioleate
  • Glyceryl trierucate
  • Fatty acids
  • Erucic acid
  • Very long chain fatty acids
  • Clinical trials
  • Newborn screening