X-Linked Adrenoleukodystrophy: A Heterogeneous Peroxisomal Disorder you Should Not Miss
DOI:
https://doi.org/10.46531/sinapse/CC/220057/2022Keywords:
Adrenoleukodystrophy/ diagnosis, Adrenoleukodystrophy/ genetics, Adrenoleukodystrophy/ therapyAbstract
X-linked adrenoleukodystrophy (X-ALD) is a rare peroxisomal disease caused by a mutation in gene ABCD1, impairing peroxisomal b-oxidation of very long-chain fatty acids. It has a heterogeneous clinical presentation that may difficult the diagnosis, with three main phenotypes: an Addison syndrome-like phenotype with adrenal insufficiency; a myeloneuropathic form, which progresses as a spastic paraparesis; a cerebral form with potentially extensive brain demyelination. Females can present with a phenotype resembling the myeloneuropathic form, but with a slow progression. Prompt recognition and diagnosis are essential, as allogenic hematopoietic stem cell transplantation can be offered for the cerebral form of the disease, the phenotype with the worst prognosis. We present four clinical cases of patients followed in our neurometabolic reference centre with X-ALD, highlighting different clinical presentations, diagnostic workup, management and possible clues for the diagnosis.Downloads
References
Aubourg P, Wanders R. Peroxisomal disorders. Handb Clin Neurol. 2013;113:1593-609. doi: 10.1016/B978-0-444-59565-2.00028-9.
Berger J, Forss-Petter S, Eichler FS. Pathophysiology of X-linked adrenoleukodystrophy. Biochimie. 2014;98:135-42. doi: 10.1016/j.biochi.2013.11.023.
Huffnagel IC, Laheji FK, Aziz-Bose R, Tritos NA, Marino R, Linthorst GE, et al. The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration. J Clin Endocrinol Metab. 2019;104:118-26. doi: 10.1210/jc.2018-01307.
Engelen M, Kemp S, Poll-The BT. X-linked adrenoleukodystrophy: pathogenesis and treatment. Curr Neurol Neurosci Rep. 2014;14:486. doi: 10.1007/s11910-014-0486-0.
Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. doi: 10.1186/1750-1172-7-51.
Turk BR, Theda C, Fatemi A, Moser AB. X-linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies. Int J Dev Neurosci. 2020;80:52-72. doi: 10.1002/jdn.10003.
Mallack EJ, Turk B, Yan H, Eichler FS. The Landscape of Hematopoietic Stem Cell Transplant and Gene Therapy for X-Linked Adrenoleukodystrophy. Curr Treat Options Neurol. 2019;21:61. doi: 10.1007/s11940-019-0605-y.
Fadiga L, Melo M, Saraiva J, Paiva I. The clinical spectrum of X-linked adrenoleukodystrophy: from Addison’s-only in men to middle-age neurologic manifestations in women. Hormones. 2022;21:33-40. doi: 10.1007/s42000-021-00325-y.
Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014;275:104-15. doi: 10.1111/ joim.12162.
Liberato AP, Mallack EJ, Aziz-Bose R, Hayden D, Lauer A, Caruso PA, Musolino PL, Eichler FS. MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy. Neurology. 2019;92:e1698-708. doi: 10.1212/ WNL.0000000000007294.
M Mallack EJ, Turk BR, Yan H, Price C, Demetres M, Moser AB, et al. MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. J Inherit Metab Dis. 2021;44:728-39. doi: 10.1002/jimd.12356.
Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 2007;6:687-92. doi: 10.1016/ S1474-4422(07)70177-1.
Lee AG, Olson RJ, Bonthius DJ, Phillips PH. Increasing exotropia and decreasing vision in a school-aged boy. Surv Ophthalmol. 2007;52:672-9. doi: 10.1016/j.survophthal.2007.08.020.
Gupta AO, Nascene DR, Shanley R, Kenney-Jung DL, Eisengart JB, Lund TC, et al. Differential outcomes for frontal versus posterior demyelination in childhood cerebral adrenoleukodystrophy. J Inherit Metab Dis. 2021;44:1434-40. doi: 10.1002/jimd.12435.
Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118:1971-8. doi: 10.1182/blood-2011-01-329235.
Moser AB, Seeger E, Raymond GV. Newborn Screening for X-Linked Adrenoleukodystrophy: Past, Present, and Future. Int J Neonatal Screen. 2022;8:16. doi: 10.3390/ijns8010016.
Bessey A, Chilcott JB, Leaviss J, Sutton A. Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme. Orphanet J Rare Dis. 2018;13:179. doi: 10.1186/s13023-018-0921-4.
Loes DJ, Fatemi A, Melhem ER, Gupte N, Bezman L, Moser HW, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology. 2003;61:369-74. doi: 10.1212/01. wnl.0000079050.91337.83.
Weinhofer I, Rommer P, Zierfuss B, Altmann P, Foiani M, Heslegrave A, et al. Neurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy. Nat Commun. 2021;12:1816. doi: 10.1038/s41467-021-22114-2.
Waldhüter N, Köhler W, Hemmati PG, Jehn C, Peceny R, Vuong GL, et al. Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy. J Inherit Metab Dis. 2019;42:313-24. doi: 10.1002/jimd.12044.
Palakuzhiyil SV, Christopher R, Chandra SR. Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy. World J Biol Chem. 2020;11:99-111. doi: 10.4331/wjbc.v11.i3.99.
Huffnagel IC, Dijkgraaf MG, Janssens GE, van Weeghel M, van Geel BM, Poll-The BT, et al. Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis. 2019;14:30. doi: 10.1186/s13023-019-1008-6.
Engelen M, Barbier M, Dijkstra IM, Schür R, de Bie RM, Verhamme C, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014;137:693-706. doi: 10.1093/brain/awt361.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Pedro Lopes das Neves, João Durães, Isabel Monteiro, Luísa Diogo, Maria do Carmo Macário
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
