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X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management

Marc Engelen*, Stephan Kemp, Marianne de Visser, Björn M van Geel, Ronald JA Wanders, Patrick Aubourg and Bwee Tien Poll-The

Orphanet Journal of Rare Diseases 2012, 7:51  doi:10.1186/1750-1172-7-51

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Women with X-ALD: is it a matter of age?

Ettore Salsano   (2012-12-07 09:39)  Istituto Neurologico "C. Besta" email

The mechanisms underlying the development of clinical manifestations in women with X-ALD are the subject of two articles, one by Maier et al [1], the other by Salsano et al [2], whereas the data by Naidu et al on the topic [3] were unfortunately reported only as congress abstract, making impossible any comparison of results.
According to Maier et al, the development of clinical manifestations in X-ALD female carriers largely depends on the skewed X chromosome inactivation (XCI), leading to the predominant expression of the mutant ABCD1 gene [1]. In contrast, Salsano et al found that the skewed XCI cannot explain the development of symptoms in X-ALD female carriers [2].
In the section ��Women with X-ALD�� of their review on X-ALD [4], Engelen et al state that the different result of the work by Salsano et al may be attributable to ��differences in mean age between the symptomatic and asymptomatic group��.
Here, I��d like to stress that our different result should be primarily attributable to the "different methodologies used", as indicated in our article [2]. In fact, the mean age at onset of the symptomatic women is comparable with the mean age at evaluation of the asymptomatic ones (46.0��10.4 vs. 47.5��14.1 years; p = 0.7276, Mann-Whitney test). It is the age at evaluation that was significantly higher in the symptomatic women (62.0��12.1 vs. 47.5��14.1years; p = 0.0199, Mann-Whitney test), but the age at evaluation was significantly higher also in the group of symptomatic women investigated by Maier et al [51.6��9.4 vs. 35��18 years; p=0.0241, Mann-Whitney test] [1]. Moreover, this difference should not cause a significant bias in both the studies, although a growing number of X-ALD women may become symptomatic with increasing age.
It is likely that Maier et al underestimated the degree of XCI skewing in the blood of their cohort of X-ALD females. Actually, the XCI seems to be skewed in the majority of X-ALD females, and - for unknown reasons - the expression of the mutant ABCD1 allele seems to be favored in vivo [2]. This might explain why X-ALD women are more prone to become symptomatic than female carriers of other X-linked diseases, and why Engelen et al have found that ��the real incidence of AMN in heterozygous women is likely to be close to 65% by the age of 60��years�� [4].
However, only a minority of X-ALD women suffer from overt AMN-like symptoms with onset in the 4th or 5th decades. Hence, the development of clinical manifestations should be largely dependent from factors other than the skewed XCI, and it is not surprising that we found a 63-year-old female who was asymptomatic, despite the predominant (93%) expression of the mutant ABCD1 allele (in lymphocytes), and a 73-year-old female who was wheelchair-bound, despite the predominant (62%) expression of the wild-type ABCD1 allele [2].

[1] Maier EM, Kammerer S, Muntau AC, Wichers M, Braun A, Roscher AA. Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation. Ann Neurol. 2002, 52:683-688.

[2] Salsano E, Tabano S, Sirchia SM, Colapietro P, Castellotti B, Gellera C, Rimoldi M, Pensato V, Mariotti C, Pareyson D, Miozzo M, Uziel G. Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms. Orphanet J Rare Dis. 2012, 7:10.

[3] Naidu S, Washington C, Thirumalai S, Smith KD, Moser HW, Watkins PA: X chromosome inactivation in symptomatic heterozygotes of X-linked adrenoleukodystrophy. Ann Neurol 1997, 42:498a

[4] Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg PA, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012, 7:51.

Competing interests

No competing interests.


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