Yonsei Med J.  2014 May;55(3):676-682. 10.3349/ymj.2014.55.3.676.

Clinical and Genetic Aspects in Twelve Korean Patients with Adrenomyeloneuropathy

• Park HJ
• Shin HY
• Kang HC
• Choi BO
• Suh BC
• Kim HJ
• Choi YC
• Lee PH
• Kim SM

• KMID: 2068677
• DOI: http://doi.org/10.3349/ymj.2014.55.3.676

Abstract

PURPOSE
This study was designed to investigate the characteristics of Korean adrenomyeloneuropathy (AMN) patients.
MATERIALS AND METHODS
We retrospectively selected 12 Korean AMN patients diagnosed by clinical analysis and increased plasma content of very long chain fatty acids.
RESULTS
All 12 patients were men. Patient ages at symptom onset ranged from 18 to 55 years. Family history was positive in two patients. The phenotype distributions consisted of AMN without cerebral involvement in seven patients, AMN with cerebral involvement in two patients, and the spinocerebellar phenotype in three patients. Nerve conduction studies revealed abnormalities in four patients and visual evoked tests revealed abnormalities in three patients. Somatosensory evoked potential tests revealed central conduction defects in all of the tested patients. Spinal MRI showed diffuse cord atrophy or subtle signal changes in all 12 patients. Brain MRI findings were abnormal in six of the nine tested patients. These brain abnormalities reflected the clinical phenotypes. Mutational analysis identified nine different ABCD1 mutations in 10 of 11 tested patients. Among them, nine have been previously reported and shown to be associated with various phenotypes; one was a novel mutation.
CONCLUSION
In conclusion, the present study is the first to report on the clinical and mutational spectrum of Korean AMN patients, and confirms various clinical presentations and the usefulness of brain MRI scan.

Keyword

Adrenoleukodystrophy; adrenomyeloneuropathy; ataxia; very long chain fatty acid; ABCD1

MeSH Terms

ATP-Binding Cassette Transporters/genetics
Adolescent
Adrenoleukodystrophy/*diagnosis/*genetics
Adult
Brain/pathology
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Republic of Korea
Young Adult

Figure

• 

  Fig. 1 Brain MRI scans of Korean adrenomyeloneuropathy patients. (A) Patient 8 showed T2 hyperintense lesion involving the corticospinal tract, right temporo-occipital subcortex and right cerebellum. (B) Patient 9 showed T2 hyperintense lesions of the splenium and corticospinal tract. (C) Patient 10 showed bilateral lesions around the dentate nucleus. (D) Patient 12 showed a T2 high signal intense area involving the corticospinal tract.

• 

  Fig. 2 Localization of different mutations within the ABCD1 gene in Korean adrenomyeloneuropathy patients.

Reference

1. Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007; 3:140–151.

2. Jang J, Kim HS, Kang JW, Kang HC. The genetically modified polysialylated form of neural cell adhesion molecule-positive cells for potential treatment of X-linked adrenoleukodystrophy. Yonsei Med J. 2013; 54:246–252.

3. Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993; 361:726–730.

4. 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; 49:186–194.

5. Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta. 2012; 1822:1465–1474.

6. Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, et al. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat. 2001; 18:499–515.

7. Suk SH, Sohn YH, Choi YC, Kim JS, Chi JG. A case of adrenomyeloneuropathy. J Korean Neurol Assoc. 1991; 9:262–268.

8. Jeong JP, Kim CH, Lee SA. A case of adrenomyeloneuropathy. J Korean Neurol Assoc. 2001; 19:431–434.

9. Lee KS, Park EK, Hyun YS, Lee HJ, Chung KW, Koo HS, et al. Cerebral adrenomyeloneuropathy with Trp77-Leu82del mutation in ABCD1 gene. J Korean Neurol Assoc. 2011; 29:356–360.

10. Park HJ, Koh IS, Lee SH, Kwon HK, Cho PZ, Sunwoo IN. A case of adrenomyeloneuropathy confirmed by serum very long chain fatty acids level. J Korean Neurol Assoc. 2001; 19:427–430.

11. Kim YC, Park BH, Yu TY, Jin AR, Noh HJ, Yang CY, et al. A case of adult-onset adrenoleukodystrophy combined with Moyamoya disease. J Korean Endocr Soc. 2009; 24:58–62.

12. Boehm CD, Cutting GR, Lachtermacher MB, Moser HW, Chong SS. Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy. Mol Genet Metab. 1999; 66:128–136.

13. Sutovský S, Petrovic R, Chandoga J, Turcáni P. Adult onset cerebral form of X-linked adrenoleukodystrophy with dementia of frontal lobe type with new L160P mutation in ABCD1 gene. J Neurol Sci. 2007; 263:149–153.

14. Kok F, Neumann S, Sarde CO, Zheng S, Wu KH, Wei HM, et al. Mutational analysis of patients with X-linked adrenoleukodystrophy. Hum Mutat. 1995; 6:104–115.

15. Ligtenberg MJ, Kemp S, Sarde CO, van Geel BM, Kleijer WJ, Barth PG, et al. Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. Am J Hum Genet. 1995; 56:44–50.

16. Powers JM, DeCiero DP, Ito M, Moser AB, Moser HW. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol. 2000; 59:89–102.

17. Soardi FC, Esquiaveto-Aun AM, Guerra-Júnior G, Lemos-Marini SH, Mello MP. Phenotypic variability in a family with x-linked adrenoleukodystrophy caused by the p.Trp132Ter mutation. Arq Bras Endocrinol Metabol. 2010; 54:738–743.

18. Sobue G, Ueno-Natsukari I, Okamoto H, Connell TA, Aizawa I, Mizoguchi K, et al. Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins. Ann Neurol. 1994; 36:912–915.

19. Matsumoto H, Hanajima R, Terao Y, Hamada M, Yugeta A, Shirota Y, et al. Efferent and afferent evoked potentials in patients with adrenomyeloneuropathy. Clin Neurol Neurosurg. 2010; 112:131–136.

20. Restuccia D, Di Lazzaro V, Valeriani M, Oliviero A, Le Pera D, Barba C, et al. Abnormalities of somatosensory and motor evoked potentials in adrenomyeloneuropathy: comparison with magnetic resonance imaging and clinical findings. Muscle Nerve. 1997; 20:1249–1257.

21. Chaudhry V, Moser HW, Cornblath DR. Nerve conduction studies in adrenomyeloneuropathy. J Neurol Neurosurg Psychiatry. 1996; 61:181–185.

22. 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.

23. Kobayashi T, Noda S, Umezaki H, Goto I, Suzuki S, Kitaguchi T, et al. Familial spinocerebellar degeneration as an expression of adrenoleukodystrophy. J Neurol Neurosurg Psychiatry. 1986; 49:1438–1440.

24. Ohno T, Tsuchida H, Fukuhara N, Yuasa T, Harayama H, Tsuji S, et al. Adrenoleukodystrophy: a clinical variant presenting as olivopontocerebellar atrophy. J Neurol. 1984; 231:167–169.

25. Waragai M, Takaya Y, Hayashi M, Shibata N, Kobayashi M. MRI of adrenoleukodystrophy involving predominantly the cerebellum and brain stem. Neuroradiology. 1996; 38:788–791.

26. Tan EK, Lim SH, Chan LL, Wong MC, Tan KP. X-linked adrenoleukodystrophy: spinocerebellar variant. Clin Neurol Neurosurg. 1999; 101:137–140.

27. Ochi K, Noda K, Kawakami H, Oka M, Imon Y, Mimori Y, et al. Dentato-rubral tract involvement in adult-onset adrenoleukodystrophy. AJNR Am J Neuroradiol. 1998; 19:1904.

28. Takemoto Y, Suzuki Y, Tamakoshi A, Onodera O, Tsuji S, Hashimoto T, et al. Epidemiology of X-linked adrenoleukodystrophy in Japan. J Hum Genet. 2002; 47:590–593.

29. Poll-The BT, Engelen M. Peroxisomal leukoencephalopathy. Semin Neurol. 2012; 32:42–50.