RSS-Feed abonnieren
DOI: 10.1055/s-2000-9236
Georg Thieme Verlag Stuttgart · New York
X-Linked Adrenoleukodystrophy: Overview and Prognosis as a Function of Age and Brain Magnetic Resonance Imaging Abnormality. A Study Involving 372 Patients
Publikationsverlauf
Publikationsdatum:
31. Dezember 2000 (online)
![](https://www.thieme-connect.de/media/neuropediatrics/200005/lookinside/thumbnails/10.1055-s-2000-9236-1.jpg)
The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy (AMN) in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. This study reports on 372 patients ranging in age from less than 3 years to adulthood, who have been followed at the Kennedy Krieger Institute. With the aim of determining whether a method could be developed to predict clinical course by analysis of data available at time of first contact, the patients were subdivided into 18 subgroups on the basis of age and the extent of brain magnetic resonance (MRI) abnormality utilizing the MRI scoring system devised by Loes et al. Scores to grade degree of neurologic and neuropsychologic impairment were also developed. There was strong correlation between MRI and the neurology and neuropsychology scores at baseline. Information based exclusively on age and MRI score at time of first contact was highly predictive of future clinical course and should aid the evaluation of the effects of bone marrow transplantation and the selection of patients for this procedure, as well as the evaluation of other therapies that may be developed in the future.
Key words
Adrenoleukodystrophy - Therapy - Bone marrow transplant - Magnetic resonance imaging - Magnetic resonance spectroscopy - Prognosis - Phenotypes - Natural history
References
- 1 Aubourg P. X-Linked Adrenoleukodystrophy. Handbook of Clinical Neurology. Amsterdam; Elsevier 1996
- 2 Aubourg P, Adamsbaum C, Lavallard-Rousseau M C, Rocchiccioli F, Cartier N, Jambaque I. et al . A two-year trial of oleic and erucic acids (“Lorenzo's oil”) as treatment for adrenomyeloneuropathy. N Engl J Med. 1993; 329 745-752
- 3 Aubourg P, Blanche S, Jambaque I, Rocchiccioli F, Kalifa G, Naud-Saudreau C. et al . Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med. 1990; 322 1860-1866
- 4 Benton A L, Hamsher K, Varney N, Spreen O. Judgement of Line Orientation. Contributions to Neuropsychological Assessment. New York; Oxford University Press 1983
- 5 Benton A L, Hamsher K, Varney N, Spreen O. Contributions to Neuropsychological Assessment. New York; Oxford University Press 1983
- 6 Bezman L, Moser H W. Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes. Am J Med Genet. 1998; 76 415-419
- 7 Boehm C D, Cutting G R, Lachtermacher M B, Moser H W, Chong S S. Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy. Mol Genet Metab. 1999; 66 128-136
- 8 Boles D J, Craft D A, Padgett D A, Loria R M, Rizzo W B. Clinical variation in X-linked adrenoleukodystrophy: fatty acid and lipid metabolism in cultured fibroblasts. Biochem Med Metab Biol. 1991; 45 74-91
- 9 Braiterman L T, Watkins P A, Moser A B, Smith K D. Peroxisomal very long chain fatty acid beta-oxidation activity is determined by the level of adrenoleukodystrophy protein (ALDP) expression. Mol Genet Metab. 1999; 66 91-99
- 10 Braiterman L T, Zheng S, Watkins P A, Geraghty M T, Johnson G, McGuinness M C. et al . Suppression of peroxisomal membrane protein defects by peroxisomal ATP binding cassette (ABC) proteins. Hum Mol Genet. 1998; 7 239-247
- 11 Bushke H. Selective reminding for analysis of memory and learning. Journal of Verbal Learning and Behavior. 1973; 12 543-550
- 12 Cartier N, Lopez J, Moullier P, Rocchiccioli F, Rolland M O, Jorge P. et al . Retroviral-mediated gene transfer corrects very-long-chain fatty acid metabolism in adrenoleukodystrophy fibroblasts. Proc Natl Acad Sci USA. 1995; 92 1674-1678
- 13 Confort-Gouny S, Vion-Dury J, Chabrol B, Nicoli F, Cozzone P J. Localised proton magnetic resonance spectroscopy in X-linked adrenoleukodystrophy. Neuroradiology. 1995; 37 568-575
- 14 Costakos D, Abramson R K, Edwards J G, Rizzo W B, Best R G. Attitudes toward presymptomatic testing and prenatal diagnosis for adrenoleukodystrophy among affected families. Am J Med Genet. 1991; 1 295-300
- 15 Delis D C, Kramer J H, Kaplan E, Ober B A. California Verbal Learning Test: Child Version. San Antonio, TX; The Psychological Corporation 1987
- 16 Dodd A, Rowland S A, Hawkes S L, Kennedy M A, Love D R. Mutations in the adrenoleukodystrophy gene. Hum Mutat. 1997; 9 500-511
- 17 Dubois-Dalcq M, Feigenbaum V, Aubourg P. The neurobiology of X-linked adrenoleukodystrophy, a demyelinating peroxisomal disorder. Trends Neurosci. 1999; 22 4-12
- 18 Dunn L M, Dunn L M. Peabody Picture Vocabulary Test - Revised. Circle Pines, MN; American Guidance Service 1981
- 19 Forss-Petter S, Werner H, Berger J, Lassmann H, Molzer B, Schwab M H. et al . Targeted inactivation of the X-linked adrenoleukodystrophy gene in mice. J Neurosci Res. 1997; 50 829-843
- 20 Gartner J, Braun A, Holzinger A, Roerig P, Lenard H G, Roscher A A. Clinical and genetic aspects of X-linked adrenoleukodystrophy. Neuropediatrics. 1998; 29 3-13
- 21 Higgins C F. ABC transporters: From microorganisms to man. Annu Rev Cell Biol. 1992; 8 67-113
- 22 Igarashi M, Schaumburg H H, Powers J, Kishmoto Y, Kolodny E, Suzuki K. Fatty acid abnormality in adrenoleukodystrophy. J Neurochem. 1976; 26 851-860
- 23 Kaplan P W, Tusa R J, Shankroff J, Heller J, Moser H W. Visual evoked potentials in adrenoleukodystrophy: a trial with glycerol trioleate and Lorenzo oil. Ann Neurol. 1993; 34 169-174
- 24 Kaufman A S, Kaufman N L. KABC Kaufman Assessment Battery for Children. Circle Pines, MN; American Guidance Service 1983
- 25 Kemp S, Wei H M, Lu J F, Braiterman L T, McGuinness M C, Moser A B. et al . Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy. Nat Med. 1998; 4 1261-1268
- 26 Kobayashi T, Shinnoh N, Kondo A, Yamada T. Adrenoleukodystrophy protein-deficient mice represent abnormality of very long chain fatty acid metabolism. Biochem Biophys Res Commun. 1997; 232 631-636
- 27 Kok F, Neumann S, Sarde C O, Zheng S, Wu K H, Wei H M. et al . Mutational analysis of patients with X-linked adrenoleukodystrophy. Hum Mutat. 1995; 6 104-115
- 28 Korenke G C, Christen H J, Kruse B, Hunneman D H, Hanefeld F. Progression of X-linked adrenoleukodystrophy under interferon-beta therapy. J Inherit Metab Dis. 1997; 20 59-66
- 29 Korenke G C, Pouwels P JW, Frahm J, Hunneman D H, Stoeckler S, Krasemann E. et al . Arrested cerebral adrenoleukodystrophy: A clinical and proton MRS study in 3 patients. Pediatr Neurol. 1996; 15 103-107
- 30 Krasemann E W, Meier V, Korenke G C, Hunneman D H, Hanefeld F. Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet. 1996; 97 194-197
- 31 Krivit W, Lockman L A, Watkins P A, Hirsch J, Shapiro E G. The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inherit Metab Dis. 1995; 18 398-412
- 32 Krivit W, Peters C, Shapiro E G. Bone marrow transplantation as effective treatment of central nervous system disease in globoid leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, manosidosis, fucosidosis, aspartylglutaminuria, Hurler Maroteaux-Lamy and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol. 1999; 12 167-176
-
33 Krivit W, Shapiro E, Lockman L, Torres F, Stillman A E, Moser A. et al .
Recommendations for treatment of childhood cerebral form of adrenoleukodystrophy. Hobbs JR, Riches PG Correction of Certain Genetic Diseases by Transplantation. London; COGENT Trust 1992: 38-49 - 34 Kruse B, Barker P B, van Zijl P C, Duyn J H, Moonen C T, Moser H W. Multislice proton magnetic resonance spectroscopic imaging in X-linked adrenoleukodystrophy. Ann Neurol. 1994; 36 595-608
- 35 Kumar A J, Rosenbaum A E, Naidu S, Wener L, Citrin C M, Lindenberg R. et al . Adrenoleukodystrophy: correlating MR imaging with CT. Radiology. 1987; 165 497-504
- 36 Ladenson P W. Adrenoleukodystrophy. JAMA. 1989; 262 1504-1506
- 37 Lazo O, Contreras M, Hashmi M, Stanley W, Irazu C, Singh I. Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy. Proc Natl Acad Sci USA. 1988; 85 7647-7651
- 38 Ligtenberg M J, Kemp S, Sarde C O, van Geel B M, Kleijer W J, Barth P G. et al . Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. Am J Hum Genet. 1995; 56 44-50
- 39 Loes D J, Hite S, Moser H, Stillman A E, Shapiro E, Lockman L. et al . Adrenoleukodystrophy: a scoring method for brain MR observations. Am J Neuroradiol. 1994; 15 1761-1766
- 40 Lombard-Platet G, Savary S, Sarde C O, Mandel J L, Chimini G. A close relative of the adrenoleukodystrophy (ALD) gene codes for a peroxisomal protein with a specific expression pattern. Proc Natl Acad Sci USA. 1996; 93 1265-1269
- 41 Lu J F, Lawler A M, Watkins P A, Powers J M, Moser A B, Moser H W. et al . A mouse model for X-linked adrenoleukodystrophy. Proc Natl Acad Sci USA. 1997; 94 9366-9371
- 42 Maestri N E, Beaty T H. Predictions of a 2-locus model for disease heterogeneity: application to adrenoleukodystrophy. Am J Med Genet. 1992; 44 576-582
- 43 Maier E M, Roscher A A, Kammerer S, Mehnert K, Conzelmann E, Holzinger A. Prenatal diagnosis of X-linked adrenoleukodystrophy combining biochemical, immunocytochemical and DNA analyses. Prenat Diagn. 1999; 19 364-368
- 44 Malm G, Ringden O, Anvret M, von Dobeln U, Hagenfeldt L, Isberg B. et al . Treatment of adrenoleukodystrophy with bone marrow transplantation. Acta Paediatr. 1997; 86 484-492
- 45 McCarthy D. McCarthy Scales of Children's Abilities. San Antonio; The Psychological Corporation 1972
- 46 Melhem E R, Breiter S N, Ulug A M, Raymond G V, Moser H W. Improved tissue characterization in adrenoleukodystrophy using magnetization transfer imaging. Am J Roentgenol. 1996; 166 689-695
- 47 Melhem E R, Loes D J, Georgiades C S, Raymond G V, Moser H W. X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. Am J Neuroradiol. 2000; 21 839-844
- 48 Migeon B R, Moser H W, Moser A B, Axelman J, Sillence D, Norum R A. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci USA. 1981; 78 5066-5070
- 49 Moser A B, Kreiter N, Bezman L, Lu S, Raymond G V, Naidu S. et al . Plasma very long chain fatty acids in 3000 peroxisome disease patients and 29, 000 controls. Ann Neurol. 1999; 45 100-110
- 50 Moser A B, Moser H W. The prenatal diagnosis of X-linked adrenoleukodystrophy. Prenat Diagn. 1999; 19 46-48
- 51 Moser H W. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain. 1997; 120 1485-1508
- 52 Moser H W, Bergin A, Naidu S, Ladenson P W. Adrenoleukodystrophy. Endocrinol Metab Clin North Am. 1991; 20 297-318
- 53 Moser H W, Borel J. Dietary management of X-linked adrenoleukodystrophy. Annu Rev Nutr. 1995; 15 379-397
- 54 Moser H W, Tutschka P J, Brown F R, Moser A E, Yeager A M, Singh I. et al . Bone marrow transplant in adrenoleukodystrophy. Neurology. 1984; 34 1410-1417
- 55 Mosser J, Douar A M, Sarde C O, Kioschis P, Feil R, Moser H. et al . Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993; 361 726-730
- 56 Mosser J, Lutz Y, Stoeckel M E, Sarde C O, Kretz C, Douar A M. et al . The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. Hum Mol Genet. 1994; 3 265-271
- 57 Naidu S, Bresnan M J, Griffin D, O'Toole S, Moser H W. Childhood adrenoleukodystrophy. Failure of intensive immunosuppression to arrest neurologic progression. Arch Neurol. 1988; 45 846-848
- 58 Pai G S, Khan M, Barbosa E, Key L, Craver J R, Cure J K. et al . Lovastatin therapy for X-linked adrenoleukodystrophy: Clinical and biochemical observations on twelve patients. Mol Genet Metab. 2000; 69 312-322
- 59 Poulos A, Gibson R, Sharp P, Beckman K, Grattan-Smith P. Very long chain fatty acids in X-linked adrenoleukodystrophy brain after treatment with Lorenzo's oil. Ann Neurol. 1994; 36 741-746
- 60 Pouwels P J, Kruse B, Korenke G C, Mao X, Hanefeld F A, Frahm J. Quantitative proton magnetic resonance spectroscopy of childhood adrenoleukodystrophy. Neuropediatrics. 1998; 29 254-264
- 61 Powers J M, DeCiero D P, Ito M, Moser A B, Moser H W. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol. 2000; 59 89-102
- 62 Powers J M, Liu Y, Moser A B, Moser H W. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol. 1992; 51 630-643
- 63 Rajanayagam V, Grad J, Krivit W, Loes D J, Lockman L, Shapiro E. et al . Proton MR spectroscopy of childhood adrenoleukodystrophy. Am J Neuroradiol. 1996; 17 1013-1024
- 64 Rasmussen M, Moser A B, Borel J, Khangoora S, Moser H W. 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. 1994; 19 1073-1082
- 65 Raven J. Raven Progressive Matrices - Research Supplement #3. San Antonio; The Psychological Corporation 1986
- 66 Rey A. L'examen psychologique dans les cas d'encéphalopatie traumatique. Archives De Psychologie. 1941; 28 268-345
- 67 Rizzo W B. Lorenzo's oil - hope and disappointment [editorial]. N Engl J Med. 1993; 329 801-802
- 68 Rizzo W B, Leshner R T, Odone A, Dammann A L, Craft D A, Jensen M E. et al . Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology. 1989; 39 1415-1422
- 69 Ruiz M, Coll M J, Pampols T, Giros M. ALDP expression in fetal cells and its application in prenatal diagnosis of X-linked adrenoleukodystrophy. Prenat Diagn. 1997; 17 651-656
- 70 Schaumburg H H, Powers J M, Raine C S, Suzuki K, Richardson E P. Adrenoleukodystrophy. A clinical and pathological study of 17 cases. Arch Neurol. 1975; 32 577-591
- 71 Shapiro E, Krivit W, Lockman L, Jambaque I, Peters C, Cowan M. et al . Long-term beneficial effect of bone marrow transplantation for childhood onset cerebral X-linked adrenoleukodystrophy. Lancet. 2000; 356 713-718
-
72 Shapiro E G, Klein K A.
Dementia in childhood: Issues in neuropsychological assessment with application to the natural history and treatment of degenerative storage diseases. Tramontana MG, Hooer SR Advances in Child Neuropsychology. New York; Springer-Verlag 1994: 119-171 - 73 Shapiro E G, Lockman L A, Balthazor M, Krivit W. Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis. 1995; 18 413-429
- 74 Singh I, Moser A E, Goldfischer S, Moser H W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci USA. 1984; 81 4203-4207
- 75 Singh I, Pahan K, Khan M. Lovastatin and sodium phenylacetate normalize the levels of very long chain fatty acids in skin fibroblasts of X-adrenoleukodystrophy. FEBS Lett. 1998; 426 342-346
- 76 Smith K D, Kemp S, Braiterman L T, Lu J F, Wei H M, Geraghty M. et al . X-linked adrenoleukodystrophy: genes, mutations, and phenotypes. Neurochem Res. 1999; 24 521-535
- 77 Smith K D, Sack G, Beaty T, Bergin A, Naidu S, Moser A. et al . A genetic basis for the multiple phenotypes of X-linked adrenoleukodystrophy. Am J Hum Genet. 1991; 49 864 a
- 78 Spreen O, Strauss E. A Compendium of Neuropsychological Tests. New York, NY; Oxford University Press 1991
- 79 Stanislaus R, Pahan K, Singh A K, Singh I. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci Lett. 1999; 269 71-74
- 80 Steinberg S J, Kemp S, Braiterman L T, Watkins P A. Role of very-long-chain acyl-coenzyme A synthetase in X-linked adrenoleukodystrophy. Ann Neurol. 1999; 46 409-412
- 81 Steinberg S J, Wang S J, McGuinness M C, Watkins P A. Human liver-specific very-long-chain acyl-coenzyme A synthetase: cDNA cloning and characterization of a second enzymatically active protein. Mol Genet Metab. 1999; 68 32-42
- 82 Takano H, Koike R, Onodera O, Sasaki R, Tsuji S. Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy. Arch Neurol. 1999; 56 295-300
- 83 Tourbah A, Stievenart J L, Iba-Zizen M T, Lubetzki C, Baumann N, Eymard B. et al . Localized proton magnetic resonance spectroscopy in patients with adult adrenoleukodystrophy. Increase of choline compounds in normal appearing white matter. Arch Neurol. 1997; 54 586-592
- 84 Tzika A A, Ball W S, Vigneron D B, Dunn R S, Kirks D R. Clinical proton MR spectroscopy of neurodegenerative disease in childhood. Am J Neuroradiol. 1993; 14 1267-1281
- 85 Uchiyama A, Aoyama T, Kamijo K, Uchida Y, Kondo N, Orii T. et al . Molecular cloning of cDNA encoding rat very long-chain acyl-CoA synthetase. J Biol Chem. 1996; 271 30 360-30 365
- 86 van Geel B M, Assies J, Haverkort E B, Koelman J H, Verbeeten B, Wanders R J. et al . Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with “Lorenzo's oil”. J Neurol Neurosurg Psychiatry. 1999; 67 290-299
- 87 van Geel B M, Assies J, Wanders R J, Barth P G. X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy. J Neurol Neurosurg Psychiatry. 1997; 63 4-14
- 88 Wechsler D. Wechsler Preschool and Primary Scale of Intelligence - Revised (WPPSI-R). San Antonio; The Psychological Corporation 1989
- 89 Wechsler D. Wechsler Intelligence Scale for Children Third Edition (WISC III). San Antonio; The Psychological Corporation 1991
- 90 Woodcock R W, Mather N. Woodcock Johnson Psychoeducational Battery Tests of Achievement - Revised. Allen, TX; DLM Teaching Resources 1972
- 91 Zinkham W H, Kickler T, Borel J, Moser H W. Lorenzo's oil and thrombocytopenia in patients with adrenoleukodystrophy [letter]. N Engl J Med. 1993; 328 1126-1127
M. D. Hugo W. Moser
Kennedy Krieger Institute
707 North Broadway
Baltimore, MD 21205
USA