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World J Biol Chem. Nov 27, 2020; 11(3): 99-111
Published online Nov 27, 2020. doi: 10.4331/wjbc.v11.i3.99
Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy
Shruti V Palakuzhiyil, Rita Christopher, Sadanandavalli Retnaswami Chandra
Shruti V Palakuzhiyil, Rita Christopher, Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru 560029, India
Sadanandavalli Retnaswami Chandra, Department of Neurology, Sri Ramakrishna Ashram Charitable Hospital, Trivandrum 695010, India
Author contributions: All the authors have contributed equally to the preparation of the manuscript.
Supported by Department of Biotechnology, New Delhi, India. No. BT/PR26150/MED/12/768/2017.
Conflict-of-interest statement: The authors declare no conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Rita Christopher, MD, Professor, Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru 560029, India. rita.nimhans@yahoo.com
Received: June 4, 2020
Peer-review started: June 4, 2020
First decision: July 4, 2020
Revised: July 10, 2020
Accepted: September 18, 2020
Article in press: September 18, 2020
Published online: November 27, 2020
Processing time: 160 Days and 2.3 Hours
Abstract

X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation, is caused by defects in the ATP Binding Cassette Subfamily D Member 1 (ABCD1) gene. X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild, severe cerebral adrenoleuko-dystrophy to mild adrenomyeloneuropathy (AMN). Although most female heterozygotes present with AMN-like symptoms after 60 years of age, occasional cases of females with the cerebral form have been reported. Phenotypic variability has been described within the same kindreds and even among monozygotic twins. There is no association between the nature of ABCD1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.

Keywords: X-adrenoleukodystrophy; Cerebral adrenoleukodystrophy; Adrenomyelo-neuropathy; Phenotypic variation; Modifiers

Core Tip: The monogenic peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), presents with different clinical phenotypes. The molecular basis for the phenotypic variation has yet to be resolved and is considered to be influenced by genetic, epigenetic, cellular, or environmental factors. We herein discuss the various modifying factors, which can potentially alter the phenotypic presentation of X-ALD.