Non-random X chromosome inactivation in Aicardi syndrome

Abstract

Most females have random X-chromosome inactivation (XCI), deWned as an equal likelihood for inactivation of the maternally-or paternally-derived X chromosome in each cell. Several X-linked disorders have been associated with a higher prevalence of non-random XCI patterns, but previous studies on XCI patterns in Aicardi syndrome were limited by small numbers and older methodologies, and have yielded conXicting results. We studied XCI patterns in DNA extracted from peripheral blood leukocytes of 35 girls with typical Aicardi syndrome (AIC) from 0.25 to 16.42 years of age, using the human androgen receptor assay. Data on 33 informative samples showed non-random XCI in 11 (33%), deWned as a >80:20% skewed ratio of one versus the other X chromosome being active. In six (18%) of these, there was a >95:5% extremely skewed ratio of one versus the other X chromosome being active. XCI patterns on maternal samples were not excessively skewed. The prevalence of non-random XCI in Aicardi syndrome is signiWcantly diVerent from that in the general population (p < 0.0001) and provides additional support for the hypothesis that Aicardi syndrome is an X-linked disorder. We also investigated the correlation between X-inactivation patterns and clinical severity and found that non-random XCI is associated with a high neurological composite severity score. Conversely, a statistically signiWcant association was found between random XCI and the skeletal composite score. Correlations between X-inactivation patterns and individual features were made and we found a signiWcant association between vertebral anomalies and random XCI.

Ophthalmologic findings in Aicardi syndrome

“…This is supported by our data that there is increased skewing of XCI in girls with Aicardi syndrome, compared to the general population. 27 …”

Laterality of Brain and Ocular Lesions in Aicardi Syndrome

“…An X-linked genetic mutation is strongly implicated in the pathogenesis due to the appearance of disease exclusively in females, with the few male cases found to have a 47, XXY genotype [2-6] although reported exceptions exist with an XY genotype [26-28]. Some authors have suggested that X chromosome inactivation may explain the variability and asymmetry seen in the phenotype of this disease, supported by a higher than normal prevalence of skewed X chromosome inactivation in peripheral lymphocytes among Aicardi patients, particularly those with worse neurological status [24, 29]. Known to occur at 5 weeks gestation, X chromosome inactivation would not be expected to lead to developmentally shared lesions in the eye and brain, as these structures have already differentiated from one another by 4 weeks gestation.…”

Aicardi and Turner syndrome in a 45,X0/46,XX female

“…Probably she survived because non-random inactivation of X chromosome. Recently Eble et al [5] showed that X chromosome inactivation is significantly different in AS from that in the general population: according with these authors, the chromosome carrying the putative mutation should be more likely to be inactivated than the normal one.…”