- Ronald JA Wanders, PhD
Ronald JA Wanders, PhD
- Professor of Clinical Enzymology of Inborn Errors of Metabolism
- University of Amsterdam
- Florian S Eichler, MD
Florian S Eichler, MD
- Associate Professor of Neurology
- Harvard Medical School
- Section Editors
- Marc C Patterson, MD, FRACP
Marc C Patterson, MD, FRACP
- Section Editor — Pediatric Neurology
- Professor of Neurology, Pediatrics, and Medical Genetics
- Chair, Division of Child and Adolescent Neurology
- Mayo Clinic College of Medicine
- Sihoun Hahn, MD, PhD
Sihoun Hahn, MD, PhD
- Section Editor — Genetics
- Professor of Pediatrics
- University of Washington School of Medicine, Seattle Children's Hospital
Adrenoleukodystrophy (ALD; MIM #300100) is a peroxisomal disorder of beta-oxidation that results in accumulation of very long chain fatty acids in all tissues. ALD consists of a spectrum of phenotypes (including adrenomyeloneuropathy [AMN]) that vary in the age and severity of clinical presentation (table 1A-C) [1,2]. These conditions are known as the ALD/AMN complex.
The pathophysiology, clinical manifestations, and treatment of ALD will be reviewed here. Other peroxisomal disorders, including neonatal ALD, are discussed separately. (See "Peroxisomal disorders".)
ALD is the most common peroxisomal disorder . In a report that included data from the two laboratories that perform most of the assays for the disorder, the minimum frequency in the United States was estimated at 1 in 21,000 and 1 in 16,800 for hemizygotes and hemizygotes plus heterozygotes, respectively .
ALD is an X-linked disorder. It is caused by mutations in the adenosine triphosphate (ATP)-binding cassette (ABC), subfamily D, member 1 gene (ABCD1 gene), located at Xq28, that encodes an ABC transporter, similar to cystic fibrosis transmembrane conductance regulator (CFTR) [5-9]. The ABC transporter helps form the channel through which very long chain fatty acids move into the peroxisome, probably as coenzyme A (CoA)-esters . The phenotype does not correlate with the type of mutation.
ABCD1 mutations may prevent normal transport of very long chain fatty acids (VLCFAs) into peroxisomes, thereby preventing beta-oxidation and breakdown of VLCFAs. Accumulation of abnormal VLCFAs in affected organs (central nervous system [CNS], Leydig cells of the testes, and the adrenal cortex) is presumed to underlie the pathologic process of the adrenoleukodystrophies (ALD) . However, plasma VLCFA levels do not predict phenotype and cell-specific functions of ABCD1 may play a role in the pathogenesis independent of VLCFA .
- Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA 2005; 294:3131.
- Berger J, Gärtner J. X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. Biochim Biophys Acta 2006; 1763:1721.
- Moser HW, Moser AB. Peroxisomal disorders: overview. Ann N Y Acad Sci 1996; 804:427.
- Bezman L, Moser AB, Raymond GV, et al. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol 2001; 49:512.
- Mosser J, Douar AM, Sarde CO, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993; 361:726.
- Mosser J, Lutz Y, Stoeckel ME, et al. The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. Hum Mol Genet 1994; 3:265.
- Migeon BR, Moser HW, Moser AB, et al. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci U S A 1981; 78:5066.
- Holzinger A, Kammerer S, Berger J, Roscher AA. cDNA cloning and mRNA expression of the human adrenoleukodystrophy related protein (ALDRP), a peroxisomal ABC transporter. Biochem Biophys Res Commun 1997; 239:261.
- McGuinness MC, Lu JF, Zhang HP, et al. Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy. Mol Cell Biol 2003; 23:744.
- van Roermund CW, Visser WF, Ijlst L, et al. The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters. FASEB J 2008; 22:4201.
- Kemp S, Wanders R. Biochemical aspects of X-linked adrenoleukodystrophy. Brain Pathol 2010; 20:831.
- Musolino PL, Gong Y, Snyder JM, et al. Brain endothelial dysfunction in cerebral adrenoleukodystrophy. Brain 2015; 138:3206.
- Höftberger R, Kunze M, Weinhofer I, et al. Distribution and cellular localization of adrenoleukodystrophy protein in human tissues: implications for X-linked adrenoleukodystrophy. Neurobiol Dis 2007; 28:165.
- Hudspeth MP, Raymond GV. Immunopathogenesis of adrenoleukodystrophy: current understanding. J Neuroimmunol 2007; 182:5.
- Raymond GV, Seidman R, Monteith TS, et al. Head trauma can initiate the onset of adreno-leukodystrophy. J Neurol Sci 2010; 290:70.
- Eichler FS, Ren JQ, Cossoy M, et al. Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy? Ann Neurol 2008; 63:729.
- Powers JM, Pei Z, Heinzer AK, et al. Adreno-leukodystrophy: oxidative stress of mice and men. J Neuropathol Exp Neurol 2005; 64:1067.
- López-Erauskin J, Galino J, Bianchi P, et al. Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy. Brain 2012; 135:3584.
- Oezen I, Rossmanith W, Forss-Petter S, et al. Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency. Hum Mol Genet 2005; 14:1127.
- Hein S, Schönfeld P, Kahlert S, Reiser G. Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture. Hum Mol Genet 2008; 17:1750.
- Powers JM. Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex). Clin Neuropathol 1985; 4:181.
- Ferrer I, Aubourg P, Pujol A. General aspects and neuropathology of X-linked adrenoleukodystrophy. Brain Pathol 2010; 20:817.
- Powers JM, Liu Y, Moser AB, Moser HW. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 1992; 51:630.
- Ito M, Blumberg BM, Mock DJ, et al. 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. J Neuropathol Exp Neurol 2001; 60:1004.
- Singh J, Khan M, Singh I. Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy. J Lipid Res 2009; 50:135.
- Powers JM, DeCiero DP, Ito M, et al. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol 2000; 59:89.
- Powers JM, DeCiero DP, Cox C, et al. The dorsal root ganglia in adrenomyeloneuropathy: neuronal atrophy and abnormal mitochondria. J Neuropathol Exp Neurol 2001; 60:493.
- Moser HW, Loes DJ, Melhem ER, et al. X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics 2000; 31:227.
- Moser HW, Moser AB, Steinberg SJ. X-linked adrenoleukodystrophy. GeneReviews. www.genetests.org. (Accessed on February 06, 2015).
- Percy AK, Rutledge SL. Adrenoleukodystrophy and related disorders. Ment Retard Dev Disabil Res Rev 2001; 7:179.
- Sakai S, Hirayama K, Ogura K, et al. Visual function of a patient with advanced adrenoleukodystrophy: comparison of luminance and color contrast sensitivities. Brain Dev 2008; 30:68.
- Zackowski KM, Dubey P, Raymond GV, et al. Sensorimotor function and axonal integrity in adrenomyeloneuropathy. Arch Neurol 2006; 63:74.
- Pillion JP, Moser HW, Raymond GV. Auditory function in adrenomyeloneuropathy. J Neurol Sci 2008; 269:24.
- Pillion JP, Kharkar S, Mahmood A, et al. Auditory brainstem response findings and peripheral auditory sensitivity in adrenoleukodystrophy. J Neurol Sci 2006; 247:130.
- van Geel BM, Bezman L, Loes DJ, et al. Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 2001; 49:186.
- de Beer M, Engelen M, van Geel BM. Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. Neurology 2014; 83:2227.
- Moser HW, Moser AB, Smith KD, et al. Adrenoleukodystrophy: phenotypic variability and implications for therapy. J Inherit Metab Dis 1992; 15:645.
- Laureti S, Casucci G, Santeusanio F, et al. X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison's disease in young adult male patients. J Clin Endocrinol Metab 1996; 81:470.
- Dubey P, Raymond GV, Moser AB, et al. Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening. J Pediatr 2005; 146:528.
- Polgreen LE, Chahla S, Miller W, et al. Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison's disease improves survival and neurological outcomes. Eur J Pediatr 2011; 170:1049.
- Maier EM, Kammerer S, Muntau AC, et al. Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation. Ann Neurol 2002; 52:683.
- Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain 2014; 137:693.
- http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendations/secretary-final-response-x-ald.pdf (Accessed on July 13, 2016).
- Kemper AR, Brosco J, Comeau AM, et al. Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genet Med 2017; 19:121.
- Vogel BH, Bradley SE, Adams DJ, et al. Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab 2015; 114:599.
- Moser AB, Kreiter N, Bezman L, et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999; 45:100.
- Unterberger U, Regelsberger G, Sundt R, et al. Diagnosis of X-linked adrenoleukodystrophy in blood leukocytes. Clin Biochem 2007; 40:1037.
- Boehm CD, Cutting GR, Lachtermacher MB, et al. Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy. Mol Genet Metab 1999; 66:128.
- Schackmann MJ, Ofman R, van Geel BM, et al. Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics. Mol Genet Metab 2016; 118:123.
- Young RS, Ramer JC, Towfighi J, et al. Adrenoleukodystrophy: unusual computed tomographic appearance. Arch Neurol 1982; 39:782.
- Esiri MM, Hyman NM, Horton WL, Lindenbaum RH. Adrenoleukodystrophy: clinical, pathological and biochemical findings in two brothers with the onset of cerebral disease in adult life. Neuropathol Appl Neurobiol 1984; 10:429.
- MacDonald JT, Stauffer AE, Heitoff K. Adrenoleukodystrophy: early frontal lobe involvement on computed tomography. J Comput Assist Tomogr 1984; 8:128.
- Melhem ER, Loes DJ, Georgiades CS, et al. X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. AJNR Am J Neuroradiol 2000; 21:839.
- Eichler FS, Itoh R, Barker PB, et al. Proton MR spectroscopic and diffusion tensor brain MR imaging in X-linked adrenoleukodystrophy: initial experience. Radiology 2002; 225:245.
- Eichler FS, Barker PB, Cox C, et al. Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy. Neurology 2002; 58:901.
- Dubey P, Fatemi A, Barker PB, et al. Spectroscopic evidence of cerebral axonopathy in patients with "pure" adrenomyeloneuropathy. Neurology 2005; 64:304.
- Dubey P, Fatemi A, Huang H, et al. Diffusion tensor-based imaging reveals occult abnormalities in adrenomyeloneuropathy. Ann Neurol 2005; 58:758.
- Fatemi A, Smith SA, Dubey P, et al. Magnetization transfer MRI demonstrates spinal cord abnormalities in adrenomyeloneuropathy. Neurology 2005; 64:1739.
- Marino S, De Luca M, Dotti MT, et al. Prominent brain axonal damage and functional reorganization in "pure" adrenomyeloneuropathy. Neurology 2007; 69:1261.
- Ratai E, Kok T, Wiggins C, et al. Seven-Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy. Arch Neurol 2008; 65:1488.
- Castellano A, Papinutto N, Cadioli M, et al. Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy: in vivo assessment of structural changes. Brain 2016; 139:1735.
- Musolino PL, Rapalino O, Caruso P, et al. Hypoperfusion predicts lesion progression in cerebral X-linked adrenoleukodystrophy. Brain 2012; 135:2676.
- Miller WP, Mantovani LF, Muzic J, et al. Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of Outcome following Transplantation in Higher Risk Patients. AJNR Am J Neuroradiol 2016; 37:367.
- McKinney AM, Benson J, Nascene DR, et al. Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation. AJNR Am J Neuroradiol 2016; 37:1713.
- Furushima W, Inagaki M, Gunji A, et al. Early signs of visual perception and evoked potentials in radiologically asymptomatic boys with X-linked adrenoleukodystrophy. J Child Neurol 2009; 24:927.
- Berger J, Pujol A, Aubourg P, Forss-Petter S. Current and future pharmacological treatment strategies in X-linked adrenoleukodystrophy. Brain Pathol 2010; 20:845.
- Mahmood A, Dubey P, Moser HW, Moser A. X-linked adrenoleukodystrophy: therapeutic approaches to distinct phenotypes. Pediatr Transplant 2005; 9 Suppl 7:55.
- Aubourg P, Blanche S, Jambaqué I, et al. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 1990; 322:1860.
- Cartier N, Aubourg P. Hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy in X-linked adrenoleukodystrophy. Brain Pathol 2010; 20:857.
- Petryk A, Polgreen LE, Chahla S, et al. No evidence for the reversal of adrenal failure after hematopoietic cell transplantation in X-linked adrenoleukodystrophy. Bone Marrow Transplant 2012; 47:1377.
- Shapiro E, Krivit W, Lockman L, et al. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 2000; 356:713.
- Peters C, Charnas LR, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 2004; 104:881.
- Mahmood A, Raymond GV, Dubey P, et al. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol 2007; 6:687.
- Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood 2011; 118:1971.
- van Geel BM, Poll-The BT, Verrips A, et al. Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy: a retrospective study. J Inherit Metab Dis 2015; 38:359.
- Moser HW, Moser AB, Hollandsworth K, et al. "Lorenzo's oil" therapy for X-linked adrenoleukodystrophy: rationale and current assessment of efficacy. J Mol Neurosci 2007; 33:105.
- Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, 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.
- van Geel BM, Assies J, Haverkort EB, 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.
- Moser HW, Raymond GV, Lu SE, et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's oil. Arch Neurol 2005; 62:1073.
- Bezman L, Moser HW. Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes. Am J Med Genet 1998; 76:415.
- Deon M, Wajner M, Sirtori LR, et al. The effect of Lorenzo's oil on oxidative stress in X-linked adrenoleukodystrophy. J Neurol Sci 2006; 247:157.
- Expanded Access for Lorenzo's Oil (GTO/GTE) in Adrenoleukodystrophy. Study record detail available at: https://clinicaltrials.gov/ct2/show/NCT02233257 (Accessed on July 13, 2016).
- 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.
- Pai GS, Khan M, Barbosa E, et al. Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients. Mol Genet Metab 2000; 69:312.
- Engelen M, Ofman R, Dijkgraaf MG, et al. Lovastatin in X-linked adrenoleukodystrophy. N Engl J Med 2010; 362:276.
- Moser HW, Bezman L, Lu SE, Raymond GV. Therapy of X-linked adrenoleukodystrophy: prognosis based upon age and MRI abnormality and plans for placebo-controlled trials. J Inherit Metab Dis 2000; 23:273.
- Gondcaille C, Depreter M, Fourcade S, et al. Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator. J Cell Biol 2005; 169:93.
- Kemp S, Wanders RJ. X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism, ABC half-transporters and the complicated route to treatment. Mol Genet Metab 2007; 90:268.
- Sanders RJ, Ofman R, Duran M, et al. Omega-oxidation of very long-chain fatty acids in human liver microsomes. Implications for X-linked adrenoleukodystrophy. J Biol Chem 2006; 281:13180.
- Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009; 326:818.
- Gong Y, Mu D, Prabhakar S, et al. Adenoassociated virus serotype 9-mediated gene therapy for x-linked adrenoleukodystrophy. Mol Ther 2015; 23:824.
- CLINICAL FEATURES
- Childhood cerebral forms
- Addison disease only
- Other presentations
- Female carriers
- Newborn screening
- Laboratory testing
- Visual evoked responses
- Adrenal insufficiency
- Hematopoietic cell transplantation
- Dietary therapy
- Pharmacologic therapy
- Gene therapy
- SUMMARY AND RECOMMENDATIONS