December 15, 2008
Dear Aicardi Syndrome Newsletter Families and Friends,
Thank you so much for your invaluable support for our research studies. It was a pleasure to have the opportunity to provide an update of our research at the Aicardi syndrome family conference in July 2008. This year has been productive and rewarding. One of our Aicardi projects reached completion and has been submitted for publication and we have several on-going projects that are progressing well. We continue our search for the genetic changes that cause Aicardi syndrome, as well as our efforts to advance awareness about Aicardi syndrome among health care providers.
The neuroimaging features of Aicardi syndrome have been studied and further characterized with help from our collaborators, Dr. Bobbi Hopkins and Dr. Gary Clark. Their findings have now been published and the paper will be posted online soon. To summarize, we looked at neuroimages from 23 girls with Aicardi syndrome and found that in 100% of these girls there was cerebral asymmetry and polymicrogyria, meaning many small brain folds. The polymicrogyria appears more prominent in the front than in the back. Agenesis of the corpus callosum was another common finding. The agenesis was found to be complete in 68% and partial in 32% of girls. Heterotopias, or mislocalized nodules of brain cells, were another common finding as were cysts which were present in 95% of girls. We describe new changes in a structure called tectum and in the cerebellum. Better characterization of the neuroimaging features of Aicardi syndrome will aid in the diagnosis of the condition, and may be especially helpful in establishing a diagnosis for girls who do no not have all features of the classic Aicardi triad (agenesis of the corpus callosum, infantile spasms, chorioretinal lacunae).
Another project has been the study of X chromosome inactivation in Aicardi syndrome. Typically females have two X chromosomes and males have one X and one Y chromosome. Females compensate for this difference by “turning off” or inactivating one of their X chromosomes. For most people, in each cell one of the X chromosomes is turned off at random, so in 50% of cells one X is inactivated and the other X is inactivated in the remaining 50% of cells. Further information can be found in our primer on XCI on the Aicardi syndrome website. Our hypothesis was that X inactivation is not random in girls with Aicardi syndrome and indeed we found that the pattern of X chromosome inactivation in girls with Aicardi syndrome is skewed, meaning we see a greater percentage of one X inactivated compared to the other. The findings of this project have been submitted for publication. The results provide further support for the long-standing hypothesis that Aicardi syndrome results from a mutation in a gene on the X chromosome and puts to rest some controversy in the medical literature on this topic.
We are also using microarray CGH to search for the gene associated with this condition. This process involves comparing the genetic material of girls with Aicardi syndrome to control samples. We are looking for differences in copy number in the genetic instructions. For example, in girls we would expect to see two copies at each location along the X chromosome because girls have two X chromosomes. If we were to see only one copy at a particular location in a sample then we would know that there was a deletion of genetic instructions at that location. This is an unbiased approach that will allow us to narrow the region on the X chromosome where we should search for the Aicardi syndrome gene. Depending on the size or position of the change in copy number the results may point towards one or several genes for further study. This method can find even very small changes in the amount of DNA that is extra or missing. While we believe the genetic change responsible for Aicardi syndrome is on the X chromosome, to be as comprehensive as possible we are currently using microarray CGH on the whole genome, meaning all of the chromosomes, not just the X chromosome. We continue using this approach to identify the gene associated with Aicardi syndrome but have not yet found a significant change.
The array CGH approach to locating a gene responsible for a given condition has been used successfully in our laboratory with another of our projects. In 2007 we identified PORCN as the gene associated with Goltz syndrome. This is a condition causing skin, skeletal and eye defects along with facial dysmorphism and asymmetry. Using array CGH we determined that there was a loss of copy number at a specific region on the X chromosome in a sample from one of our study participants. We did not see the same loss in that individual’s parents or in other samples from healthy individuals. We found that there were seven candidate genes in that region on the X chromosome and soon after determined that one of these, PORCN, is associated with Goltz syndrome. Now individuals who are suspected to have Goltz syndrome can have mutation analysis to try to confirm their diagnosis. We hope that our work in this area on Aicardi syndrome will yield similar results.
Our efforts to further awareness about Aicardi syndrome and our research have included creating a laboratory webpage and registering with ClinicalTrials.gov. Our website can be reached at http://www.bcm.edu/genetics/vandenveyver/ and provides information about our current research, publications and lab members as well as direct links to contact us. As we are now registered with ClinicalTrials.gov, healthcare professionals and families from around the world can find out how to enroll in our study if they go to ClinicalTrials.gov and search for Aicardi syndrome. We have had several new families enroll in our research after locating us in this manner.
We will continue to forge ahead with our work to better understand Aicardi syndrome, to locate the gene responsible for the condition and to spread awareness among healthcare professionals. Our future efforts will include more high-throughput sequencing of candidate genes on the X chromosome and the analysis of genes expressed in the cell cultures that we made from blood samples of girls with Aicardi syndrome. Your support and participation have been essential for our progress to date and we look forward to continuing our partnership.
Sincerely,
Ignatia Van den Veyver, MD
Principal Investigator
Tanya Eble, MS, CGC
Aicardi Syndrome Study Coordinator