Objective: To investigate whether the combination of the X-linked dystonia-parkinsonism (XDP) haplotype and skewed X-chromosome inactivation (XCI) underlies the penetrance of XDP in women.

Background: XDP is a combined dystonia-parkinsonism (DYT/PARK) syndrome inherited in an X-linked recessive manner, thus affecting almost exclusively men. However, rare cases of women who present predominantly with late-onset, isolated PARK have been described. We previously reported skewed XCI as the likely molecular cause of PARK in a single heterozygous mutation carrier [1]. Nevertheless, the role of this epigenetic factor in the penetrance of XDP in women has not yet been comprehensively examined.

Method: We estimated the XCI ratio using the androgen receptor gene methylation status [2] in blood of 78 heterozygous XDP haplotype carriers. Furthermore, we performed cDNA sequencing to analyze whether XCI favors the expression of the wild-type (WT) or mutant allele in 4 affected women. Also, a comprehensive DYT/PARK gene panel was used to investigate the presence of other genetic factors that could cause movement disorders.

Results: We found 13 affected women out of 78 XDP haplotype carriers, all of whom fit well into the clinical spectrum of XDP, including female patients with predominant DYT and age at onset (AAO) similar to males. These women include six heterozygotes with (extremely) skewed XCI, one of whom unexpectedly exhibited preferential expression of the WT allele. Surprisingly, seven women showed random XCI but still manifested the disorder. One such woman was heterozygous for a pathogenic PINK1 change and a TOR1A variant of unknown significance, while another carried a likely pathogenic change in PRKN, suggesting that other genetic factors could cooperate with the XDP haplotype to cause movement disorders. Conversely, the observation that some heterozygotes, with both skewed XCI and preferential expression of the mutant allele, can be asymptomatic raises the possibility that there are genetic factors that confer protection against the XDP haplotype.

Conclusion: DYT is a clinical feature of female XDP, and the AAO can be similar to males. Further, skewed XCI may not be a requirement for the manifestation of XDP in women. Careful neurological examination of XDP families should thus include female mutation carriers, who exhibit the disease with considerably lower penetrance compared to their male counterparts.

References: [1] Domingo A, Lee L V., Brüggemann N, et al. Woman With X-Linked Recessive Dystonia-Parkinsonism. JAMA Neurol. 2014;71(9):1177. doi:10.1001/jamaneurol.2014.56. [2] Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992;51(6):1229-1239. http://www.ncbi.nlm.nih.gov/pubmed/1281384.

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-x-chromosome-inactivation-in-the-penetrance-of-x-linked-dystonia-parkinsonism-in-women/