X-linked Adrenoleukodystrophy (X-ALD) is a rare hereditary disease characterized by axon loss in the central nervous system. Axons are nerve fibers that carry nerve impulses between cells and are covered by a protective layer known as the myelin sheath. X-ALD leads to loss of myelin, a process known as demyelination, which hinders the transmission of nerve signals leading to neurological disorders (GARD, 2018; NORD, 2019). X-ALD is an X-linked genetic disorder that appears due to loss-of-function mutations in the ABCD1 gene. The X-linked nature of the disease means X-ALD disproportionately affects males, while females are carriers who might experience mild symptoms or be completely asymptomatic, meaning they do not experience any symptoms (GARD, 2018; NINDS, 2019). X-ALD is estimated to affect approximately 18,000 people in the US every year (Moser et al., 2007; NIH, 2020).

The ABCD1 gene is responsible for creating the adrenoleukodystrophy protein (ALDP), a transporter protein involved in carrying very long-chain fatty acids (VLCFAs) into peroxisomes. Peroxisomes are cell structures that break down VLCFAs. In X-ALD patients the ABCD1 gene is altered or lost, thus the breakdown of VLCFAs is disrupted, leading to their accumulation in the body. Such accumulation contributes to the destabilization of the myelin sheath, impairment of axonal function, and other X-ALD manifestations such as adrenal insufficiency (lack of certain hormones in the body), testicular dysfunction, and peripheral neuropathy (damage to the nerves located outside the brain and spinal cord) (Morita et al., 2012; NORD, 2019; Orphanet, 2013).

X-ALD is classified into three distinct groups differing in severity, symptoms, age of onset, and rate of progression: cerebral X-ALD (CALD), adrenomyeloneuropathy (AMN), and adrenal insufficiency also known as Addison’s disease (Palakuzhiyil et al., 2020). The most common type of CALD appears in children 2-3 years old, who exhibit attention deficit and hyperactivity disorder (ADHD), learning disabilities, mental impairment, hearing loss, reduced clarity of vision, and even convulsions and seizures, all of which lead to untimely deaths within 2-3 years of symptom onset. However, CALD can also develop in adults, who show a similar cognitive decline to that experienced by children, leading to a vegetative state or death. AMN appears in adults in their 20s to middle age and is characterized by stiffness and weakness in the legs, numbness and pain due to nerve peripheral neuropathy, bowel and bladder control problems, urinary dysfunction, and hair loss. Addison’s disease is characterized by adrenal insufficiency and patients present fatigue, weight loss, weakness, nausea, vomiting, low blood pressure, and low blood sugar levels (Engelen et al., 2014; NORD, 2019; Paláu-Hernández et al., 2019; Turk et al., 2020; Wiens et al., 2019).

There are no specific treatments for X-ALD patients but currently accepted treatments include corticosteroids replacement therapy for patients with adrenal insufficiency and hematopoietic stem cell transplantation (HSCT) for patients with childhood-onset CALD (NORD, 2019). Corticosteroid therapy consist of daily treatment to control the lack of hormones, but it does not influence the development of neurological symptoms (Berger et al., 2010; NORD, 2019; Raymond et al., 2018). HSCT involves the transplantation of stem cells from healthy individuals and is the only therapy known to stop the progression of the disease. However, HSCT is only effective in early stages of the disease and is associated with serious complications including death (Berger et al., 2010; Kemp et al., 2016; NINDS, 2019; NORD, 2019). Unfortunately, there is no treatment for the AMN type of X-ALD beyond rehabilitation and the use of mobility devices such as canes, walkers, and wheelchairs (Berger et al., 2010; Kemp et al., 2016). Therefore, there is substantial need for a novel therapy that can exert disease -modifying effects, providing a cure, and thus addressing the significant unmet medical need for X-ALD patients.

References

• Berger, J., Pujol, A., Aubourg, P., & Forss-Petter, S. (2010). Current and future pharmacological treatment strategies in X-linked adrenoleukodystrophy. Brain Pathol, 20(4), 845-856. doi:10.1111/j.1750-3639.2010.00393.x
• Engelen, Kemp, S., & Poll-The, B. T. (2014). X-linked adrenoleukodystrophy: pathogenesis and treatment. Curr Neurol Neurosci Rep, 14(10), 486. doi:10.1007/s11910-014-0486-0
• GARD. (2018). X- linked adrenoleukodystrophy. NIH National Center for Advancing Translational Sciences. Retrieved from https://rarediseases.info.nih.gov/diseases/5758/adrenoleukodystrophy
• Kemp, S., Huffnagel, I. C., Linthorst, G. E., Wanders, R. J., & Engelen, M. (2016). Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol, 12(10), 606-615. doi:10.1038/nrendo.2016.90
• Morita, M., & Imanaka, T. (2012). Peroxisomal ABC transporters: Structure, function and role in disease. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(9), 1387-1396. doi:https://doi.org/10.1016/j.bbadis.2012.02.009
• Moser, H. W., Mahmood, A., & Raymond, G. V. (2007). X-linked adrenoleukodystrophy. Nature Clinical Practice Neurology, 3(3), 140-151. doi:10.1038/ncpneuro0421
• NIH. (2020). X-linked adrenoluekodystrophy. NIH U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/genetics/condition/x-linked-adrenoleukodystrophy/
• NINDS. (2019). Adrenoleukodystrophy Information Page. National Institute of Neurological Disorders and Stroke Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Adrenoleukodystrophy-Information-Page
• NORD. (2019). X-Linked Adrenoleukodystrophy. Retrieved from https://rarediseases.org/rare-diseases/adrenoleukodystrophy/
• Orphanet. (2013). X-linked adrenoleukodystrophy. Retrieved from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=43
• Palakuzhiyil, S. V., Christopher, R., & Chandra, S. R. (2020). Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy. World J Biol Chem, 11(3), 99-111. doi:10.4331/wjbc.v11.i3.99
• Paláu-Hernández, S., Rodriguez-Leyva, I., & Shiguetomi-Medina, J. M. (2019). Late onset adrenoleukodystrophy: A review related clinical case report. eNeurologicalSci, 14, 62-67. doi:10.1016/j.ensci.2019.01.007
• Raymond, G., Moser AB, & A, F. (2018). X-Linked Adrenoleukodystrophy. GeneReviews.
• Turk, B. R., Theda, C., Fatemi, A., & Moser, A. B. (2020). X-linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies. Int J Dev Neurosci, 80(1), 52-72. doi:10.1002/jdn.10003
• Wiens, K., Berry, S. A., Choi, H., Gaviglio, A., Gupta, A., Hietala, A., . . . Orchard, P. J. (2019). A report on state-wide implementation of newborn screening for X-linked Adrenoleukodystrophy. Am J Med Genet A, 179(7), 1205-1213. doi:10.1002/ajmg.a.61171

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