Full Access
Adrenoleukodystrophy: Molecular Genetics, Pathology, and Lorenzo's oil
Hugo W. Moser,
James M. Powers,
Kirby D. Smith,
Corresponding Author
Hugo W. Moser
Kennedy Krieger Institute and the Departments of Neurology and Pediatrics at Johns Hopkins University, 707 North Broadway, Baltimore, MD 21205, USA.
Corresponding author: Dr. Hugo W. Moser, Kennedy Krieger Institute and the Departments of Neurology and Pediatrics at Johns Hopkins University, 707 North Broadway, Baltimore, MD 21205, USA. Phone: +1 (4101)–550–9405; Fax: +1 (410)–550–9839Search for more papers by this authorJames M. Powers
University of Rochester Medical Center, Department of Pathology, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Search for more papers by this authorKirby D. Smith
Kennedy Krieger Institute and the Department of Pediatrics at the Johns Hopkins University, 707 North Broadway, Baltimore, MD 21205, USA.
Search for more papers by this authorHugo W. Moser,
James M. Powers,
Kirby D. Smith,
Corresponding Author
Hugo W. Moser
Kennedy Krieger Institute and the Departments of Neurology and Pediatrics at Johns Hopkins University, 707 North Broadway, Baltimore, MD 21205, USA.
Corresponding author: Dr. Hugo W. Moser, Kennedy Krieger Institute and the Departments of Neurology and Pediatrics at Johns Hopkins University, 707 North Broadway, Baltimore, MD 21205, USA. Phone: +1 (4101)–550–9405; Fax: +1 (410)–550–9839Search for more papers by this authorJames M. Powers
University of Rochester Medical Center, Department of Pathology, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Search for more papers by this authorKirby D. Smith
Kennedy Krieger Institute and the Department of Pediatrics at the Johns Hopkins University, 707 North Broadway, Baltimore, MD 21205, USA.
Search for more papers by this authorAbstract
Knowledge about adrenoleukodystrophy (ALD), a disorder which was described first in 1923, has increased greatly during recent years. The principal biochemical abnormality, the presumed enzyme defect, and the gene defect, have been defined. A dietary therapy has been proposed and attracted world-wide attention through a motion picture. Nevertheless, many questions remain and cannot be answered without a more fundamental understanding of pathology and pathogenesis. This article will provide a review of the history, clinical features, pathology, biochemistry, and the gene defect, and then appraise current efforts to clarify pathogenesis and develop therapeutic approaches.
References
- 1 Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, Rocchiccioli F, Cartier N, Jambaque I, Jakobezak C, Lemaitre A, Boureau F, Wolf C, Bougneres PF (1993) A two-year trial of oleic and erucic acids (‘Lorenzo's oil’) as treatment for adrenomyeloneuropathy. N Engl J Med 329: 745–752.
- 2 Aubourg P, Blanche S, Jambaque I, Rocchiccioli F, Kalifa G, Naud-Saudreau C, Rolland MO, Debre M, Chaussain JL, Griscelli C, Fischer A, Bougneres PF (1990) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 322: 1860–1866.
- 3 Barcelo A, Giros M, Sarde CO, Martinez-Bermejo X, Mandel JL, Pampols T, Estivill X (1994) Identification of a new framshift mutation (1801 delAG) in the ALD gene. Hum Mol Genet 3: 1889–1890.
- 4 Berger J, Molzer B, Fae I, Bernheimer H (1995) 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 : in press.
- 5 Bizzozero OA, Zuniga G, Lees MB (1991) Fatty acid composition of human myelin proteolipid protein in peroxisomal disorders. J Neurochem 56: 872–878.
- 6 Blaw, M. E. Melanodermic type leucodystrophy (adreno-leukodystrophy). P. J. Vinken, G. W. Bruyn Amsterdam : North Holland Publishing Company; 1970) 10: 128–133.
- 7 Boles DJ, Craft DA, Padgett DA, Loria RM, Rizzo WB (1991) Clinical variation in X-linked adrenoleukodystrophy - Fatty acid and lipid metabolism in cultured fibroblasts. Biochem Med Metab Biol 45: 74–91.
- 8 Brown III FR, Chen WW, Kirschner DA, Frayer KL, Powers JM, Moser AB, Moser HW (1983) Myelin membrane from adrenoleukodystrophy brain white matter - Isolation and physical/chemical properties. J Neurochem 41: 341–348.
- 9 Budka H, Molzer B, Bernheimer H, Lassmann H, Pilz P, Toifi K (1983) Clinical, morphological and neurochemical findings in adrenoleukodystrophy and its variants. Neuropathology (Tokyo) 1: 209–224.
- 10 Budka H, Sluga E, Heiss WD (1976) Spastic paraplegia associated with Addison's disease: Adult variant of adrenoleukodystrophy. J Neurol 213: 237–250.
- 11 Cartier N, Lopez J, Moullier P, Rocchiccioli F, Rolland MO, Jorge P, Mosser J, Mandel JM, Bougneres PF, Danos O, Aubourg P (1995) Retroviral-mediated gene transfer corrects very-long-chain fatty acid metabolism in adrenoleukodystrophy fibroblasts. Proc Natl Acad Aci USA 92: 1674–1678.
- 12 Cartier N, Sarde CO, Douar AM, Mosser J, Mandel JL, Aubourg P (1993) Abnormal messenger RNA expression and a missense mutation in patients with X-linked adrenoleukodystrophy. Hum Mol Genet 2: 1949–1951.
- 13 Fanconi VA, Prader A, Isler W, Luthy F, Siebenmann R (1963) Morbus Addison mit hirnsklerose im kindesalter -Ein hereditares syndrom mit X-chromosomaler vererbung Helv Paed Acta 18: 480–501.
- 14 Fanen P, Guidoux S, Sarde CO, Mandel JL, Goossens M, Aubourg P (1994) Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene. J Clin Invest 94: 516–520.
- 15 Fuchs S, Sarde CO, Wedemann H, Schwinger E, Mandel JL, Gal A (1994) Missense mutations are frequent in the gene for X-chromosomal adrenoleukodystrophy (ALD). Hum Mol Genet 3: 1903–1905.
- 16 Gartner J, Moser H, Valle D (1992) Mutations in the 70K peroxisomal membrane protein gene in Zellweger syndrome. Nature Genet 1: 16–23.
- 17 Griffin DE, Moser HW, Mendoza Q, Moench T, O'Toole S, Moser AB (1985) Identification of the inflammatory cells in the nervous system of patients with adrenoleukodystrophy. Ann Neurol 18: 660–664.
- 18 Griffin JW, Goren E, Schaumburg H, Engel WK, Loriaux L (1977) Adrenomyeloneuropathy: A probable variant of adrenoleukodystrophy. Neurology 27: 1107–1113.
- 19 Higgins CF (1992) ABC transporters: From microorganisms to man. Annu Rev Cell Biol 8: 67–113.
- 20 Ho JK, Moser H, Kishimoto Y, Hamilton JA (1995) Interaction of very long chain fatty acid with model membranes and serum albumin: Implications for the pathogenesis of adrenoleukodystrophy. J Clin Invest 96: in press.
- 21 Igarashi M, Schaumburg HH, Powers J, Kishimoto Y, Kolodny E, Suzuki K (1976) Fatty acid abnormality in adrenoleukodystrophy. J Neurochem 26: 851–860.
- 22 Johnson AB, Schaumburg HH, Powers JM (1976) Histochemical characteristics of the striated inclusions of adrenoleukodystrophy. J Histochem Cytochem 24: 725–730.
- 23 Kamijo K, Taketani S, Yokota S, Osumi T, Hashimoto T (1990) The 70-kDa peroxisomal membrane protein is a member of the Mdr (P-glycoprotein)-related ATP-binding protein superfamily. J Biol Chem 265: 4534–4540.
- 24 Kemp S, Ligtenberg JL, van Geel BM, Barth PG, Wolterman RA, Schoute F, Sarde CO, Mandel JL, van Oost BA, Bolhuis PA (1994) Identification of a two base pair deletion in five unrelated families with adrenoleukodystrophy: A possible hot spot for mutations. Biochem Biophys Res Commun 202: 647–653.
- 25 Kishimoto, Y., Moser, H. W., Suzuki, K. Neurochemistry of adrenoleukodystrophy. A. Lajtha The Handbook of Neurochemistry. New York : Plenum Press; 1984; 10: 125–151.
- 26 Knazek RA, Rizzo WB, Schulman JD, Dave JR (1983) Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy. J Clin Invest 72: 245–248.
- 27 Kok F, Neumann S, Sarde CO, Zheng S, Wu KH, Wei HM, Bergin J, Watkins PA, Gould S, Sack G, Moser H, Mandel JL, Smith KD (1994) Mutational analysis of patients with X-linked adrenoleukodystrophy. Hum Mutat: in press.
- 28 Krivit, W., Shapiro, E., Lockman, L., Torres, F, Stillman, A., Moser, A., Moser, H. Recommendations for Treatment of Childhood Cerebral Form of Adrenoleukodystrophy. J. R. Hobbs, P. G. Riches Correction of Certain Genetic Diseases by Transplantation. London : COGENT Trust; 1992; 38–49.
- 29 Lazo O, Contreras M, Bhushan A, Stanley W, Singh I (1989) Adrenoleukodystrophy: Impaired oxidation of fatty acids due to peroxisomal lignoceroyl-CoA ligase deficiency. Arch Biochem Biophys 270: 722–728.
- 30 Lazo O, Contreras M, Hashmi M, Stanley W, Irazu C, Singh I (1988) Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy. Proc Natl Acad Sci USA 85: 7647–7651.
- 31 Ligtenberg MJL, Kemp S, Sarde CO, van Geel B, Kleijer WJ, Barth PJ, Mandel JL, van Oost A, Bolhuis PA (1995) Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. Am J Hum Genet 56: 44–50.
- 32 Matsumoto T, Kondoh T, Masuzaki H, Harada N, Matsusaka T, Kinochita E, Takeo G, Tsujihata M, Suzuki Y, Tsuji Y (1994) A point mutation at the ATP-binding region of the ALD gene in a family with X-linked adrenoleukodystrophy. Jpn J Hum Genet 39: 345–351.
- 33 McGuinness MC, Griffin DE, Raymond GV, Washington CA, Moser HW, Smith KD (1995) Tumor necrosis factor-alpha and X-linked adrenoleukodystrophy. J Neumimmunol: in press.
- 34 Migeon BR, Moser HW, Moser AB, Axelman J, Sillence D, Norum RA (1981) Adrenoleukodystrophy: Evidence for X-linkage, inactivation and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci USA 78: 5066–5070.
- 35 Moser HW (1993) Lorenzo's oil. Film Review. Lancet 341: 544.
- 36 Moser HW, Borel J (1995) Dietary therapy for adrenoleukodystrophy. Annu Rev Nutr 15: 379–397.
- 37 Moser HW, Kok F, Neumann S, Borel J, Bergin A, Darwish Mostafa S, Panoscha R, Davoli CT, Shankroff J, Smith KD (1994) Adrenoleukodystrophy update: Genetics and effect of Lorenzo's oil therapy in asymptomatic patients. Int Pediatr 9: 196–204.
- 38 Moser HW, Moser AB, Frayer KK, Chen WW, Schulman JD, O'Neill BP, Kishimoto Y (1981) Adrenoleukodystrophy: Increased plasma content of saturated very long chain fatty acids. Neurology 31: 1241–1249.
- 39 Moser HW, Moser AB, Naidu S, Bergin A (1991) Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy. Dev Neurosci 13: 254–261.
- 40 Moser HW, Moser AB, Smith KD, Bergin A, Borel J, Shankroff J, Stine OC, Merette C, Ott J, Krivit W, Shapiro E (1992) Adrenoleukodystrophy: Phenotypic variability: Implications for therapy. J Inner Metab Dis 15: 645–664.
- 41 Moser, H. W., Bergin, A., Naidu, S., Ladenson, P. W. Adrenoleukodystrophy: New Aspects of Adrenal Cortical Disease. D. H. Nelson Endocrinology and Metabolism Clinics of North America: New Aspects of Adrenal Cortical Disease. Philadelphia : W.B. Saunders Company; 1991; 20(2): 297–318.
- 42 Moser, H. W., Moser, A. B. Measurements of Saturated Very Long Chain Fatty Acids in Plasma. F. Hommes Techniques in Diagnostic Human Biochemical Genetics. New York : Wiley-Liss, Inc.; 1999; Chapter 12: 177–191.
- 43 Moser, H. W., Smith, K. D., Moser, A. B. X-linked Adrenoleukodystrophy. Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. The Metabolic and Molecular Basis of Inherited Disease. Seventh Edition ed. New York : McGraw Hill; 1994(Chapter 72): 2325–2349.
- 44 Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JM, Aubourg P (1993) Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361: 726–730.
- 45 Mosser J, Lutz Y, Stoeckel ME, Sarde CO, Kretz C, Douar AM, Lopez J, Aubourg P, Mandel JL (1994) The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. Hum Mol Genet 3: 265–271.
- 46 Naidu S, Bresnan MJ, Griffin D, O'Toole S, Moser HW (1988) Intensive immunosuppression fails to alter neurological progression in childhood adrenoleukodystrophy. Arch Neurol 45: 846–848.
- 47 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. Ann Neurol 36: 741–746.
- 48 Powers JM (1985) Adrenoleukodystrophy (Adreno-testiculo-leuko-myelo-neuropathic-complex). Clin Neuropathol 4: 181–199.
- 49 Powers JM, Liu Y, Moser A, Moser H (1992) The inflammatory myelinopathy of adreno-leukodystrophy: Cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 51: 630–643.
- 50 Powers JM, Moser HW, Moser AB, Schaumburg HH (1982) Fetal adrenoleukodystrophy: The significance of pathologic lesions in adrenal gland and testis. Hum Pathol 13: 1013–1019.
- 51 Powers JM, Schaumberg HH (1973) The adrenal cortex in adrenoleukodystrophy. Arch Pathol 96: 305–310.
- 52 Powers JM, Schaumburg HH (1974) Adreno-leukodystrophy: Similar ultrastructural changes in adrenal cortical and Schwann cells. Arch Neurol 30: 406–408.
- 53 Powers JM, Schaumburg HH (1981) The testis in adrenoleukodystrophy. Am J Pathol 102: 90–98.
- 54 Powers JM, Schaumburg HH, Johnson AB, Raine CS (1980) A correlative study of the adrenal cortex in adrenoleukodystrophy: Evidence for a fatal intoxication with very long chain fatty acids. Invest Cell Pathol 3: 353–376.
- 55 Rasmussen M, Moser AB, Borel J, Khangoora S, Moser HW (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). Neurochem Res 19: 1073–1082.
- 56 Rizzo WB, Leshner RT, Odone A, Dammann AL, Craft DA, Jensone ME, Jennings SS, Davis S, Jaitly R, Sgro JA (1989) Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 39: 1415–1422.
- 57 Sarde CO, Mosser J, Kioschis P, Kretz C, Vicaire S, Aubourg P, Poustka A, Mandel JL (1994) Genomic organization of the adrenoleukodystrophy gene. Genomics 22: 13–20.
- 58 Schaumburg H, Powers JM, Raine CS, Spencer PS, Griffin JW, Prineas JW, Boehme DM (1977) Adrenomyeloneuropathy: A probable variant of adrenoleukodystrophy. II. General pathologic, neuropathologic, and biochemical aspects. Neurology 27: 1114–1119.
- 59 Schaumburg H, Richardson EP, Johnson PC, Cohen RB, Powers JM, Raine CS (1972) Schilder's disease: Sex-linked recessive transmission with specific adrenal changes. Arch Neurol 27: 458–460.
- 60
Schaumburg HH,
Powers JM,
Raine CS,
Suzuki K,
Richardson EP (1975) Adrenoleukodystrophy: A clinical and pathological study of 17 cases.
Arch Neurol
33: 577–591.
10.1001/archneur.1975.00490510033001 Google Scholar
- 61 Schilder P (1912) Zur kenntnis der Sogenannten Diffusen Sklerose. Zfdg Neur u Pscyh O 10: 1–60.
- 62
Siemerling E,
Creutzfeldt HG (1923) Bronzekrankheit und sklerosierende encephalomyelitis.
Arch Psychiatr Nervenkr
68: 217–244.
10.1007/BF01835678 Google Scholar
- 63 Singh I, Moser AB, Goldfischer S, Moser HW (1984) Lignoceric acid is oxidized in the peroxisomes: Implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci USA 81: 4203–4207.
- 64 Singh I, Moser AB, Moser HW, Kishimoto Y (1984) Adrenoleukodystrophy: Impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts and amniocytes. Pediatr Res 18: 286–290.
- 65 Theda C, Moser A, Moser H, Debuch H (1987) Temporal evolution of brain biochemical changes in adrenoleukodystrophy. J Neurochem 48: s35. old ref no.: 60.
- 66 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. J Neurochem 36: 1046–1049.
- 67 Uchiyama A, Suzuki Y, Song XQ, Fukao T, Imamura A, Tomatsu S, Shimozawa N, et al. (1994) Identification of a nonsense mutation in ALD protein cDNA from a patient with adrenoleukodystrophy. Biochem Biophys Res Commun 198: 632–636.
- 68 Valle D, Gartner J (1993) Penetrating the peroxisome. Nature 361: 682–683.
- 69 Vorgerd M, Fuchs S, Tegenthoff M, Malin JP (1995) A missense point mutation (Ser515Phe) in the adrenoleukodystrophy gene in a family with adrenomyeloneuropathy: A clinical, biochemical, and genetic study. J Neurol Neurosurg Psychiatry 58: 229–231.
- 70 Wanders RJA, van Roermund CWT, van Wijland MJA, Schutgens RBH, van deb Bosch H, Schram AW, Tager JM (1988) Direct evidence that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids. Biochem Biophys Res Commun 153: 618–624.
- 71 Watkins PA, Gould SJ, Smith MA, Braiterman LT, Wei HM, Kok F, Moser AB, Moser HW, Smith KD (1995) Altered expression of ALDP in X-linked adrenoleukodystrophy. Am J Hum Genet 57: 292–301.
- 72 Whitcomb RW, Linehan WR, Knazek RA (1988) Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. J Clin Invest 81: 185–188.
Citing Literature
