Summary
X-linked adrenoleukodystrophy (ALD) is a relatively common disorder that shows a great deal of phenotypic variability. Approximately half of the patients have the rapidly progressive childhood cerebral form that is associated with an inflammatory response in brain and leads to total disability or death during the first decade. Twenty five per cent or more of the patients have adrenomyeloneuropathy (AMN), a form that progresses slowly, involves the spinal cord mainly, shows little or no inflammatory response, manifests in adulthood, and is compatible with a near-normal life span. The two forms of the disease occur frequently within the same kindreds and nuclear families. Segregation analysis based on 3862 individuals in 89 kindreds points to the existence of an autosomal modifier locus with a likelihood ratio of 20:1. In addition, we present preliminary results of three types of therapy. Two hundred and four patients have received a dietary regimen that combines the administration of oils containing mono-unsaturated fatty acids (oleic and erucic) with the restricted intake of very long-chain fatty acids. This regimen normalizes the levels of satured very long-chain fatty acids in plasma within 4 weeks. It appears to improve peripheral nerve function in patients with AMN, and a large-scale trial is in progress to determine whether it can prevent the onset of neurological involvement in patients who have the biochemical abnormality of ALD but are neurologically intact. We report early results of bone marrow transplantation in 14 patients. There is encouraging but still preliminary evidence that transplantation can arrest the progression of the disease in patients with mild neurological involvement. There is urgent need to develop methods to combat the rapid progression of the cerebral forms of the disease, which so far has resisted therapeutic intervention, including immunosuppression or the administration of immunoglobulin.
Similar content being viewed by others
References
Antoku Y, Koike F, Othsuka Y et al (1991) Adrenoleukodystrophy: A correlation between saturated very long chain fatty acids in mononuclear cells and phenotype.Ann Neurol 30: 101–103.
Aubourg P, Sack GH, Meyers DA, Lease JJ, Moser HW (1987) Linkage of adrenoleukodystrophy to a polymorphic DNA probe.Ann Neurol 21: 240–249.
Aubourg P, Sack GH, Moser HW (1988) Frequent alteration of visual pigment genes in adrenoleukodystrophy.Am J Hum Genet 42: 408–413.
Aubourg P, Sellier N, Chaussain JL, Kalifa G (1989) MRI detects cerebral involvement in neurologically asymptomatic patients with adrenoleukodystrophy.Neurology 39: 1619–1621.
Aubourg P, Blanche S, Jambaque I et al (1990a) Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation.N Engl J Med 322: 1860–1866.
Aubourg PB, Feil R, Guidoux S et al (1990b) The red-green visual pigment gene region in adrenoleukodystrophy.Am J Hum Genet 46: 459–469.
Bebin EM, Gomez MR, Forbes GS, Moser HW (1990) Cerebral lesions of adrenoleukodystrophy remain static and patients asymptomatic during dietary therapy.Ann Neurol 28: 436a.
Bernheimer H, Budka H, Muller P (1983) Brain tissue immunoglobulins in adrenoleukodystrophy: A comparison with multiple sclerosis and systemic lupus erythematosus.Acta Neuropathol (Berlin) 59: 95–102.
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.
Borel J, Cohen J (1990)ALD/AMN Diet Cookbook. Baltimore: United Leukodystrophy Foundation and The Kennedy Institute.
Brown FR III, Van Duyn MA, Moser AB 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 Med J 151: 164–172.
Cavanagh JB (1964) The significance of the ‘dying-back’ process in human and experimental neurological diseases.Int Rev Exp Pathol 3: 219–267.
Edwards AWF (1972)Likelihood. New York: Cambridge University Press.
Edwin C, Speedie L, Naidie S, Moser HW (1990) Cognitive impairment in adult-onset adrenoleukodystrophy.Mol Chem Neuropath 12: 167–176.
Friedman Z, Lamberth EL, Stahlman MT, Oates JA (1977) Platelet dysfunction in the neonate with essential fatty acid deficiency.J Pediatr 90: 439–443.
Goodin DS (1991) The use of immunosuppressive agents in the treatment of multiple sclerosis: A critical review.Neurology 41: 980–985.
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.
Griffin JW, Goren E, Schaumburg H, Engel WK, Loriaux L (1977) Adrenomyeloneuropathy: A probable variant of adrenoleukodystrophy.Neurology 27: 1107–1113.
Holman RT (1960) The ratio of trienoic-tetranoic acids in tissue lipids as a measure of essential fatty acid requirement.J Nutr 70: 405.
Kishimoto Y, Moser HW, Kawamura N, Platt M, Pallante B, Fenselau C (1980) Evidence that abnormal very long chain fatty acids of brain cholesterol esters are of exogenous origin.Biochem Biophys Res Commun 96: 69–76.
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.
Kurtzke JF (1986) Neuroepidemiology. Part II: Assessment of therapeutic trials.Ann Neurol 19: 311–319.
Lazo O, Contreras M, Hashmi M, Stanley W, Irazu C, Singh I (1988) Peroxisomal lignoceroyl-CoA ligas deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy.Proc Natl Acad Sci USA 85: 7647–7651.
McKhann GM (1989) The trials of clinical trials.Arch Neurol 46: 611–614.
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.
Miike T, Taku K, Tamura T et al (1989) Clinical improvement of adrenoleukodystrophy following intravenous gammaglobulin therapy.Brain Dev 11: 134–137.
Moser HW, Moser AB (1989) X-linked adrenoleukodystrophy. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds.The Metabolic Basis of Inherited Disease. New York: McGraw Hill, 1511–1532.
Moser HW, Moser AB (1990) measurements of saturated very long chain fatty acids in plasma. In Hommes F, ed.Techniques in Diagnostic Human Biochemical Genetics. New York: Wiley-Liss, 117–191.
Moser HW, Moser AB, Frayer KK et al (1981) Adrenoleukodystrophy: Increased plasma content of saturated very long chain fatty acids.Neurology 31: 1241–1249.
Moser HW, Tutschka PJ, Brown FR III et al (1984) Bone marrow transplant in adrenoleukodystrophy.Neurology 34: 1410–1417.
Moser AB, Borel J, Odone A et al (1987) A new dietary therapy for adrenoleukodystrophy: Biochemical and preliminary clinical results in 36 patients.Ann Neurol 21: 240–249.
Moser AB, Moser HW, Della Cioppa G, Dorsey FC (1988) Ganglioside administration reduces plasma C26:0 levels in adrenoleukodystrophy and adrenomyeloneuropathy. Results of clinical trials.Ann Neurol 24: 148A.
Moser HW, Aubourg P, Cornblath D et al (1991a). The therapy of X-linked adrenoleukodystrophy. In Desnick RJ, ed.Treatment of Genetic Diseases. New York: Churchill Livingstone, 111–129.
Moser HW, Bergin A, Naidu S, Ladenson PW (1991b) Adrenoleukodystrophy: new aspects of adrenal cortical disease. In Nelson DH, ed.Endocrinology and Metabolism Clinics of North America: New Aspects of Adrenal Cortical Disease. Philadelphia: W.B. Saunders, 297–318.
Moser HW, Moser AB, Naidu S, Bergin A (1991c) Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy.Dev Neurosci 13: 254–261.
Murphy JV, Marquardt KM, Moser HW, Van Duyn MA (1982) Treatment of adrenoleukodystrophy by diet and plasmapheresis.Ann Neurol 12: 220.
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.
Powers JM (1985) Adrenoleukodystrophy (adreno-testiculo-leuko-myelo-neuropathic-complex).Clin Neuropathol 4: 181–199.
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.
Rizzo WB, Watkins PA, Phillips MW, Cranin D, Campbell B, Avigan J (1986) Adrenoleukodystrophy: Oleic acid lowers fibroblast saturated C22–C26 fatty acids.Neurology 36: 357–361.
Rizzo WB, Phillips MW, Dammann AL, Leshner RY, Jennings SVK (1987) Adrenoleukodystrophy: Dietary oleic acid lowers hexacosanoate levels.Ann Neurol 21: 232–239.
Rizzo WB, Leshner RT, Odone A et al (1989) Dietary erucic acid therapy for X-linked adrenoleukodystrophy.Neurology 39: 1415–1422.
Sack GH, Raven MB, Moser HW (1989) Color vision defects in adrenoleukodystrophy.Am J Hum Genet 44: 794–798.
Sadeghi-Nejad A, Senior B (1990) Adrenomyeloneuropathy presenting as Addison's disease in childhood.N Engl J Med 322: 13–16.
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.
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.
Steinberg D (1989). Refsum disease. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds.The Metabolic Basis of Inherited Disease. New York: McGraw Hill, 1533–1550.
Stumpf DA, Hayward A, Haas R, Schaumburg HH (1981) Adrenoleukodystrophy. Failure of immunosuppression to prevent neurological progression.Arch Neurol 38: 48–49.
Tiffany CW, Hoefler S, Moser HW, Burch RM (1991) Arachidonic acid metabolism in fibroblasts from patients with peroxisomal diseases.Biochim Biophys Acta 1096: 41–46.
Uziel G, Bertini E, Rimoldi M, Gambetti M (1990) Italian multicentric dietary therapeutical trial in adrenoleukodystrophy. InAdrenoleukodystrophy and Other Peroxisomal Disorders: Clinical, Biochemical, Genetic and Therapeutic Aspects. Excerpta Medica, Amsterdam, 163–180.
Van Duyn MA, Moser AB, Brown FR III, Sacktor N, Liu A, Moser HW (1984) The design of a diet restricted in saturated very long chain fatty acids: Therapeutic application in adrenoleukodystrophy.Am J Clin Nutr 40: 277–284.
Wanders RJA, van Roermund CWT, van Wijland MJA et al (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.
Weinberg K, Moser A, Watkins P et al (1988) Bone marrow transplantation (BMT) for adrenoleukodystrophy (ALD).Pediatr Res 23: 334A.
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Moser, H.W., Moser, A.B., Smith, K.D. et al. Adrenoleukodystrophy: Phenotypic variability and implications for therapy. J Inherit Metab Dis 15, 645–664 (1992). https://doi.org/10.1007/BF01799621
Issue Date:
DOI: https://doi.org/10.1007/BF01799621