Role of X chromosome inactivation in Chinese women carrying the mutation causing adrenoleukodystrophy

Written on Wednesday 26 February 2014

X-linked adrenoleukodystrophy (ALD) is a hereditary neurodegenerative disease caused by a mutation in the ABCD1 gene located on the X chromosome. Approximately 20% of ALD women carrying the mutation can develop neurologic symptoms.
Men and women differ in their sexual chromosomes, women having two X chromosomes and men an X and a Y chromosome. Shorter than the X chromosome, the Y chromosome encodes for a smaller number of genes. In order to balance gene expression between men and women sexual chromosomes, a particular biologic process, called X chromosome inactivation, takes place in women. This process leads to the inactivation in women of one of the two chromosomes, either the X chromosome from paternal or maternal origin depending on the cells. The inactivated X chromosome remains silent.
In ALD, skewed X chromosome inactivation could influence the apparition of symptoms in carrier women. Data from the literature published to date is contradictory. To better understand the impact of skewed X chromosome inactivation, a genetic study was carried out on a Chinese family covering three generations and suffering from ALD.
In this family, two of five carrier women showed neurologic symptoms. Four women out of five showed skewed X chromosome inactivation: two symptomatic women, one asymptomatic woman and one woman mutation-free.
The results suggest skewed X chromosome inactivation in a carrier woman does not necessarily imply a negative influence. However, the majority of inactivated X chromosomes in the two symptomatic women from this family are of paternal origin, thus letting the maternal X chromosomes carrying the mutation express themselves freely. The opposite is observed for the asymptomatic woman. Skewed X chromosome inactivation favoring the mutated ABCD1 gene expression seems to be associated to manifestation of symptoms.
Presence of unfavorable skewed X chromosome inactivation could allow early screening of carriers at high risk of becoming symptomatic, for whom a preventive therapy would be justified. X chromosome inactivation analysis could be useful for women showing atypical presentations of adrenoleukodystrophy in the long run.
The possible role played by X chromosome inactivation on clinical manifestations of the disease should be told during disease counseling, along with the possibility of performing specific tests.

Disease: Adrenoleukodystrophy
Subjects: Chinese women with an history of the disease in the family
Type of study: Genetics
Laboratory: Dr. F. Lan, Research Center for Molecular Diagnosis of Genetic Diseases, Fuzhou General Hospital, Fuzhou, China.

Source: Z. Wang, A. Yan, Y. Lin, H. Xie, C. Zhou, F. Lan. Familial skewed X chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a Chinese pedigree. PLoS One. 2013, 8(3):e57977.

Scientific information provided in collaboration with the INIST-CNRS Institute, Institute for Scientific and Technical Information