X-adrenoleukodystrophy

Česká verzia

Authors: M. Kolníková ¹; P. Sýkora ¹; R. Petrovič ²; M. Fischerová ²; J. Chandoga ²
Authors place of work: Klinika detskej neurológie LF UK a DFNsP Bratislava ¹; Ústav lekárskej biológie, genetiky a klinickej genetiky LF UK a UN Bratislava, oddelenie molekulárnej a biochemickej genetiky, FNsP Bratislava-Staré Mesto ²
Published in the journal: Cesk Slov Neurol N 2013; 76/109(2): 197-202
Category: Short Communication

Summary

Introduction:
X-adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by adrenal insufficiency and neurological manifestations. The disorder is caused by a defect in the ABCD1 gene, leading to inability to degrade very long chain fatty acids (VLCFA) and to their accumulation in tissues and fluids. The disorder is recessively inherited and X-linked with clinical manifestation predominantly in males. Clinical manifestation includes several phenotypes of X-ALD. The aim of the study was to review current knowledge on X-ALD and our options for laboratory, radiological and genetic diagnosis of the disorder and treatment approaches.

Material and methods:
Our study group included 11 patients, five with childhood cerebral form, one with the adolescent cerebral form, two with primary adrenal insufficiency, one with andrenomyeloneuropathy and two symptomatic females. All patients underwent VLCFA testing, brain MRI and DNA analysis of the ABCD1 gene.

Results:
Pathologically elevated VLCFA plasma levels were found in all patients. MRI revealed changes in white matter typically distributed in parietal-occipital areas in all but one patient. Mutation of the ABCD1 gene was confirmed in all patients. All male patients were treated with Lorenzo´s oil. Two patients with cerebral form died within 2 years since the clinical onset of the disease. One patient was successfully transplanted (sibling transplantation of umbilical cord blood).

Conclusion:
The birth rate in Slovakia is about 60 thousand children per year, and the incidence of the X-ALD is from 1 : 16,800 to 1 : 42,000. Therefore, we presume that there will be one to three new cases each year. It is important to recognize the disorder from its typical clinical manifestationa. Due to the close relationship between the disorder and endocrinopathies, education of endocrinologists is considered important, in order to increase their ability to identify possible cases without neurological deficit. Cerebral forms of the disease in their early stages can be succesfully treated with bone marrow or umbilical cord blood transplantation.

Key words:
X-adrenoleukodystrophy – classification – pathogenesis – diagnosis – treatment

Zdroje

1. Raymond GV. X-Linked Adrenoleukdystrophy. In: Raymond GV, Eichler F, Fatemi A et al (eds). Leukodystrophies. London: Mac Keith Press 2011: 75–89.

2. Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA 2005; 294(24): 3131–3134.

3. van Geel BM, Bezman L, Loes DJ, Moser HW, Raymond GV. Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 2001; 49(2): 186–194.

4. Chandoga J, Petrovič R, Futas J, Ďurovčíková D, Štofko J, Jančo S et al. X-viazaná adrenoleukodystrofia – najčastejšia dedičná metabolická porucha peroxizómov. Neurol Prax 2006; 7(2): 90–95.

5. Moser AB, Kreiter N, Bezman L, Lu S, Raymond GV, Naidu S et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999; 45(1): 100–110.

6. Hubbard WC, Moser AB, Tortorelli S, Liu A, Jones D, Moser H. Combined liquid chromatography tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: preliminary findings. Mol Genet Metab 2006; 89(1–2): 185–187.

7. Forss-Petter S, Werner H, Berger J, Lassmann H, Molzer B, Schwab MH et al. Targeted inactivation of the X-linked adrenoleukodystrophy gene in mice. J Neurosci Res 1997; 50(5): 829–843.

8. Kobayashi T, Shinnoh N, Kondo A, Yamada T. Adrenoleukodystrophy protein-deficient mice represent abnormality of very long chain fatty acid metabolism. Biochem Biophys Res Commun 1997; 232(3): 631–636.

9. Lu JF, Lawler AM, Watkins PA, Powers JM, Moser AB, Moser HW et al. A mouse model for X-linked adrenoleukodystrophy. Proc Natl Acad Sci USA 1997; 94(17): 9366–9371.

10. Paintlia AS, Gilg AG, Khan M, Singh AK, Barbosa E, Singl I. Correlation of very long chain fatty acid accumulation and inflammatory disease progression in childhood X-ALD: implications for potential therapies. Neurobiol Dis 2003; 14(3): 425–439.

11. Powers JM, Pei Z, Heinzer AK, Deering R, Moser AB, Moser HW et al. Adreno-leukodystrophy: oxidative stress of mice and men. J Neuropathol Exp Neurol 2005; 64(12): 1067–1079.

12. Eichler FS, Ren JQ, Cossoy M, Rietsch AM, Nagpal S, Moser AB et al. Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy? Ann Neurol 2008; 63(6): 729–742.

13. Rizzo WB, Leshner RT, Odone A, Dammann AL, Craft DA, Jensen ME et al. Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 1989; 39(11): 1415–1422.

14. Moser HW, Raymond GV, Lu SE, Muenz LR, Moser AB, Xu J et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol 2005; 62(7): 1073–1080.

15. Seidl Z, Vaněčková M, Vítek T, Kron M, Dvořáková L, Zeman J. X-adrenoleukodystrofie-hodnocení lézí mozku modalitou magnetické rezonance pomocí „Loes score“. Cesk Radiol 2007; 61(3): 275–278.

16. Cavaletti G. Current status and future prospective of immunointervantion in multiple sclerosis. Curr Med Chem 2006; 13(19): 2329–2343.

17. Linsen L, Somers V, Stinissen P. Immunoregulation of autoimmunity by natural killer T cells. Hum Immunol 2005; 66(12): 1193–1202.

18. Berger J, Pujol A, Auborg P, Forss-Petter S. Current and future pharmacological treatment strategies in X-linked adrenoleukodystrophy. Brain Pathol 2010; 20(4): 845–856.

19. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I et al. Hematopoetic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009; 326(5954): 818–823.

20. Horáková J, Lukáč J, Šufliarska S, Boďová I, Mydliar M, Sýkora P et al. Transplantácia pupočníkovej krvi u 4-ročného chlapca s adrenoleukodystrofiou viazanou na chromozóm X. Cesk Pediatr 2005; 4: 219–223.

21. Dvorakova L, Storkanova G, Unterrainer G, Hujova J, Kmoch S, Zeman J et al. Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: the first polymorphism causing an amino acid exchange. Hum Mutat 2001; 18(1): 52–60.

22. van der Knaap MS. X-linked adrenoleukodystrophy. In: van der Knaap MS, Valk J (eds). Magnetic Resonance of Myelination and Myelin Disorders. 3rd ed. Berlin Heidelberg New York: Springer 2005: 176–190.