X-linked Adrenoleukodystrophy

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X-linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy, simply called ALD, is rare X-linked neuro-metabolic disorder1. The first X-linked adrenoleukodystrophy case – a 6-year-old male X-ALD patient- was detected by Mosser in 19931*. Mutations in the ABCD1 (ATP-binding cassette transporter subfamily D member 1), ALDP, peroxisomal half-transporter gene, which is included in the ABC transporter superfamily, gives rise to ALD, so it is also known as single gene disorder2 3. The mutation leads to the accumulation of high levels of very-long-chain fatty acids ≥ C22:0 (VLCFAs) in plasma, and especially accumulation in the white matter of the brain, spinal cord, and adrenal cortex4 2 3. Both men and women are affected by ALD. Progressive spinal cord disease and adrenomyeloneuropathy that is characterised by weakness, bladder and bowel dysfunction, impaired movement are mostly encountered in men and most women with ALD5. Primary adrenal insufficiency and cerebral inflammatory disease occur in men. On the other hand, the frequency of emergence of primary adrenal insufficiency and cerebral disease is less than 1% in women6 7 8 9.

Accumulation of lipids containing VLCFA happens in all kinds of tissues. Especially, the brain, spinal cord, adrenal cortex, and the Leydig cells of the testis, which are necessary for the development of secondary sexual characteristics, have the highest level of VLCFA accumulation2*. Esterification of VLCFA takes place with cholesterol and glycerophospholipids11. Esterification of VCLFA to cholesterol occurs in the adrenal cortex, testis, and demyelinating brain whose myelin sheath is damaged so that the work of neurons is affected 4. Because lipoprotein-bound cholesterol is not able to cross the blood-brain barrier, the greater portion of the cholesterol synthesis occurs in the brain with high storage in myelin as a form of free cholesterol, and the rest of it is stored in neurons and glial cells12. Extra cholesterol in cells including neurons is deposited in ester form10. Cytoplasmic cholesterol esters in lipid droplets comprise 1% of brain cholesterol in a healthy person.

Surplus of the cholesterol in the brain can be transported from the brain by converting it to different forms of cholesterol such as 27-hydroxy cholesterol or 24-hydroxy cholesterol10. 27- hydroxy cholesterol and 24-hydroxy cholesterol can cross the blood-brain barrier. Blood-brain barrier impairment results from raised permeability of it to sterols14. Cholesterol plays an essential role in the synthesis of steroid hormones, regulation of oxysterols and it is an element of several cellular membranes. Thus, the impairment of transportation of cholesterol has a negative impact on cholesterol homeostasis15.

A small amount of VLCFA is of dietary origin. Most of it is produced by chain elongation that is happened by ‘’VLCFA-specific elongase’’ ELOVL1 (ELOVL fatty acid elongase 1). Normally, ABCD1 protein participates in the transportation of saturated straight-chain VLCFA in form of CoA esters to the peroxisome where their degradation is carried out via β-oxidation10. Degradation of excess VLCFA in macrophages and microglia can not occur due to deficiency of ABCD110. Gene expression of Acyl-CoA cholesterol acyltransferase 1 (ACAT1), which catalyses the generation of cholesteryl esters from long-chain fatty Acetyl-CoA and cholesterol, rises when ER has surplus cholesterol10 22. Enhanced ACAT1 activity occurs as a result of neurotoxic agents, oxidative stress, or inflammation and results in increased cholesterol esters with VLCFA 4. Generally, cholesterol ester hydrolases provide to remain the cholesterol esters concentration low in the brain but the enzyme does not show greater activity on cholesterol esters with VLCFA13. So, an excess amount of saturated straight-chain VLCFA exists in blood samples of patients with ALD.

Figure1: Synthesis of VLCFA through elongation of long-chain fatty acids in the cell with defective ABCD1.

Figure1: Synthesis of VLCFA through elongation of long-chain fatty acids in the cell with defective ABCD1.

Patients with ALD have normal brain function when they were born10. However, the sudden development of the demyelinating disease is encountered in nearly 60% of male patients with ALD. About half of the cases are detected in 3-10 years old, 5% of it occurs in adolescence or adulthood10. Especially, males with ALD, in their 20s or 30s, show progressive myeloneuropathy. nearly 60% of females with ALD in their 60s exhibit development symptoms of spinal cord disease. Loss of sensation in the legs, spastic gait, and bladder and bowel incontinence are the early symptoms of progressive spinal cord disease10. Unlikely, some females with ALD may develop symptoms of the disease by the age of 208. Dysesthesia which means the painful, abnormal sensation such as burning or itchy-prickly3* is typically encountered in females with ALD16.

Figure 2

Graphical Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is applied to treat ALD. Early diagnosis by newborn screening increases the chance of success of therapy. Newborn screening for ALD provides monitoring and timely therapeutic intervention, thus preventing life- threatening damages 21. It is better to administer therapy before symptoms of ALD appear. As mentioned before, most of the men suffer from adrenal insufficiency and the men succumb to adrenal crisis. Therefore, in particular for men, early diagnosis of adrenal disease decreases the death ratio 6. Measurement of the level of VCLFA (for elevated VLCFA levels or abnormal ratios of VLCFA) in the blood is also diagnostic 17. Besides, the verification of diagnosis of ALD can be done by genetic testing 3. Amniocentesis might be also applied for prenatal genetic diagnosis of ALD for at-risk fetuses. This process may lead to miscarry 18 19. In some studies, not-FDA-approved Lorenzo’s oil therapy was applied. The results of the researches reveal the fact that Lorenzo’s oil hinders ELOVL1 20. Overall, different therapies have been developed and tried to treat individuals with X-linked adrenoleukodystrophy. The most important point of the treatment of ALD is to diagnose it before symptoms occur as in most such cases. Awareness of the disease can save the lives of people.

References: 

  1. Zhu J, Eichler F, Biffi A, Duncan CN, Williams DA, Majzoub JA. The Changing Face of Adrenoleukodystrophy. Endocr Rev. Published online 2020. doi:10.1210/endrev/bnaa013
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  3. Mosser J, Douar AM, Sarde CO, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. Published online 1993. doi:10.1038/361726a0
  4. Igarashi M, Schaumburg HH, Powers J, Kishimoto Y, Koilodny E, Suzuki K. FATTY ACID ABNORMALITY IN J Neurochem. Published online 1976. doi:10.1111/j.1471-4159.1976.tb04462.x
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  7. Engelen M, Kemp S, De Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): Clinical presentation and guidelines for diagnosis, follow-up and Orphanet J Rare Dis. Published online 2012. doi:10.1186/1750-1172-7-51
  8. Engelen M, Barbier M, Dijkstra IME, et al. X-linked adrenoleukodystrophy in women: A cross-sectional cohort study. Brain. Published online 2014. doi:10.1093/brain/awt361
  9. Habekost CT, Schestatsky P, Torres VF, et al. Neurological impairment among heterozygote women for X-linked Adrenoleukodystrophy: A case control study on a clinical, neurophysiological and biochemical characteristics. Orphanet J Rare Dis. Published online 2014. doi:10.1186/1750-1172-9-6
  10. Turk BR, Theda C, Fatemi A, Moser AB. X-linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies. Int J Dev Neurosci. Published online 2020. doi:10.1002/jdn.10003
  11. Johnson AB, Schaumburg HH, Powers JM. Histochemical characteristics of the striated inclusions of adrenoleukodystrophy. J Histochem Cytochem. Published online 1976. doi:10.1177/24.6.59773
  12. Dietschy JM. Central nervous system: Cholesterol turnover, brain development and neurodegeneration. Biol Chem. Published online 2009. doi:10.1515/BC.2009.035
  13. Ogino T, Suzuki Specificities of Human and Rat Brain Enzymes of Cholesterol Ester Metabolism Toward Very Long Chain Fatty Acids: Implication for Biochemical Pathogenesis of Adrenoleukodystrophy. J Neurochem. Published online 1981. doi:10.1111/j.1471-4159.1981.tb01657.x
  14. Saeed AA, Genové G, Li T, et Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain. J Biol Chem. Published online 2014. doi:10.1074/jbc.M114.556159
  15. Diotel N, Charlier TD, Lefebvre d’Hellencourt C, et Steroid transport, local synthesis, and signaling within the brain: Roles in neurogenesis, neuroprotection, and sexual behaviors. Front Neurosci. Published online 2018. doi:10.3389/fnins.2018.00084
  16. Van Geel BM, Koelman JHTM, Barth PG, Ongerboer De Visser BW. Peripheral nerve abnormalities in adrenomyeloneuropathy: A clinical and electrodiagnostic study. Neurology. Published online 1996. doi:10.1212/WNL.46.1.112
  17. Moser AB, Kreiter N, Bezman L, et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 Annals of Neurology. 1999;45(1):100- 10. 34.
  18. Maier EM, Roscher AA, Kammerer S, et al. Prenatal diagnosis of X-linked adrenoleukodystrophy combining biochemical, immunocytochemical and DNA analyses. Prenat Diagn. 1999;19(4):364-8.
  19. Lan F, Wang Z, Ke L, et al. A rapid and sensitive protocol for prenatal molecular diagnosis of X-linked adrenoleukodystrophy, 2010;411(23-24):1992-7
  20. Sassa, T., Wakashima, T., Ohno, Y., & Kihara, A., Lorenzo’s oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty Journal of Lipid Research, 55, 524–530. https://doi.org/10.1194/jlr.M044586, 2014
  21. Rinse W. Barendsen, Inge M. E. Dijkstra et al. Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor
  22. Bo-Liang L., Xia-Lu L., et al. Human Acyl-CoA:Cholesterol Acyltransferase-1 (ACAT-

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