This case series found significant asymmetry of both ocular and brain lesions of Aicardi syndrome. Previous case series have documented laterality of ocular findings [7
]. Similar to one previous study, this study found marked asymmetry in all patients with microphthalmos [7
]. Eighteen percent of subjects in the current study had monocular lacunae. Other studies have demonstrated completely monocular chorioretinal lacunae in 8% to 21% of patients with Aicardi syndrome [1
]. An association between brain and eye lesion laterality has not been previously assessed. Sidedness of microphthalmos was associated with sidedness of brain lesions in this series. A correlation between overall sidedness of ocular and brain disease is more difficult to ascertain due to the lack of adequate fundus examination in 4 subjects (3 of whom had microphthalmos, which can be associated with a high rate of posterior disease). We suspect that a correlation exists (T = 2.19, P = 0.04, when assuming maximal posterior segment disease in all subjects lacking a view of the fundus), but this would likely be largely due to microphthalmos as no other ocular findings were independently correlated with brain MRI laterality.
This study found a predilection for right-sided brain lesions on MRI. Periventricular heterotopias are known to occur more commonly in the right hemisphere, due to later migration of right-sided neuroblasts [16
]. A previous study characterizing 23 brain MRI’s of children with Aicardi syndrome noted that polymicrogyria tended to be asymmetric; however, that study found lesions most commonly in the left frontal lobe, rather than the right. That study also found asymmetric periventricular heterotopias in all subjects, although not with a particular side preference [9
]. Put together, these studies strongly suggest that asymmetric brain involvement is a common finding in Aicardi syndrome. Asymmetric specification of function is known to occur in the brains of normal individuals, for example with semantic language centers most commonly occurring on the left side, and language prosody localized more heavily to the right hemisphere. This may be secondary in part to asymmetric gene expression of the right and left hemispheres during development, as evidenced by asymmetric cortical mRNA expression seen in embryonic human brains in one prior study [17
]. Development of asymmetric abnormal pathology may therefore reflect timing of disease development when normal asymmetric gene expression is occurring.
The frequency of ocular findings in this study was similar to that of the series of 14 patients reported by Menezes et al
, except for a higher frequency of ocular colobomas in the present study (10/24, 42% in the present study compared to 3/14, 21% from the Menezes et al
]. (see ). Menezes et al
did not report iris colobomas while the present study found 2 cases, including one that was temporally located, which has not been previously reported in Aicardi syndrome. Brain anomalies on MRI were found at a similar rate in the present study compared to recent previous reports [9
]. (see Table 3) The lower quality of MRI’s prior to 2000 may explain a decreased frequency of lesions reported in the literature prior to 2000 [20
A wide range of severity in neurological functioning was seen in this case series, as has been seen in prior reports of patients with Aicardi syndrome [1
]. (see ) Fifty-three percent (10/19) of subjects with measurable motor or language impairment scores had severe or profound impairment in one or both categories. An age dependent scale was used in the present study, which is likely more accurate than other scales in determining language and motor impairment among widely disparate ages. Interestingly, severity of MRI findings did not always correlate with severity of phenotypic outcomes, as best illustrated by subject number 7 and subject number 9, both of whom had MRI severity scores that did not match the severity of language and motor findings. Such findings suggest that other factors may contribute to functional outcomes, which are not detectable by MRI, such as possible deficits in interneuron development.
Although a purported gene has not been identified to date, a genetic origin for Aicardi syndrome is suspected. 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
] although reported exceptions exist with an XY genotype [26
]. 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
]. 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. In this study, microphthalmos was associated with sidedness of Aicardi associated brain lesions, however X chromosome inactivation may still play a role in other Aicardi associated ocular and brain anomalies. We hypothesize that the developmental process that is disrupted in Aicardi syndrome is occurring broadly within the developing neuraxis primarily at 3-4 weeks gestation. At this time, the optic cup is forming from what will become the diencephalon, and the prosencephalon is forming more generally from the anterior neuraxis. It is possible that inducing structures like the anterior visceral endoderm (AVE) and signaling molecule families like Wnt’s, retinoids and fibroblast growth factors (FGF) may play a role [30
]. Thus, microphthalmos and colobomata likely relate to this early disruption of development. In contrast, the variable pattern and location of chorioretinal lacunae and other Aicardi associated lesions may occur at a later time because of X chromosome inactivation.
There were some limitations to this study. Patients were selected for this study based on a clinical definition of Aicardi syndrome, rather than a molecular definition, therefore we have no certainty that all children in our series had the same pathogenesis of disease. In addition, Aicardi syndrome may be caused by a mutation in more than one gene or variable isolated mutations of the same gene, therefore heterogeneous genotypes and phenotypes may confuse the outcomes of this study. Subjects recruited from the Aicardi Syndrome conferences may introduce selection bias if, for example, families who choose to participate tend to have children with more severe disease. Prior studies with other recruitment methods had similar rates of ocular and brain MRI findings, suggesting that selection bias is less significant. Finally, although Aicardi associated lesions are thought to be static with time, at least one previous study documents changes in the size of fundus lesions over time with disappearance of a lacunae and development of a new retinal coloboma in one patient [31
]. Colobomas are known to represent failed embryonic optic fissure closure, calling into question the validity of an observed acquired coloboma later in life. Nonetheless, without longitudinal follow up, it is not known if some of the subjects in the present study would have growing or shrinking lesions as they age which may alter asymmetry over time.
In conclusion, this study is the largest series to our knowledge of Aicardi syndrome patients with both ophthalmologic and brain MRI findings reported [22
]. These results substantiate prior smaller case series looking at ophthalmologic and brain MRI Aicardi associated lesions. A correlation between brain disease and microphthalmos sidedness was seen in this case series. This work expands our understanding of phenotypic variance in other X linked disorders. Knowledge gained from this study may assist future work in gene discovery in other disorders as well as in Aicardi syndrome. Identifying the responsible gene in Aicardi syndrome is important for prenatal diagnosis, prognosis, and future development of medical therapies.