Ignatia B. Van den Veyver, M.D.
Assistant Professor
Department of Obstetrics and Gynecology
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas
November 23, 2003
Our laboratory is one of very few in the world that performs molecular genetic research on Aicardi syndrome. We are continuing to collaborate with the laboratory of Dr. Huda Zoghbi, who has initiated the studies on Aicardi syndrome many years ago.
Because Aicardi syndrome occurs only in girls, or rarely boys with two X chromosomes (who have Klinefelter syndrome), it has long been hypothesized that the condition must be caused by a genetic change or mutation in a gene on one of the two X chromosomes in these affected children.
Our studies over the past several years were based on the observation that some girls with another condition, called MLS syndrome or microphthalmia with linear skin defects, have many features in common with girls who have Aicardi syndrome. Just like in Aicardi syndrome, only girls are affected with MLS syndrome. They also have problems with the development of the eyes, resulting in small eyes, they have brain defects, such as agenesis of the corpus callosum and they can have seizures. Dr. Zoghbi’s laboratory found, in collaboration with Dr. Andrea Ballabio, that MLS syndrome is caused by a deletion of a small piece of the short arm of one of the X chromosomes (Schaefer et al., 1993; Wapenaar et al., 1993).
We then performed detailed studies of the genes that are missing in girls with MLS deletions to test them as candidate genes for Aicardi syndrome. We analyzed the DNA from many affected girls for changes (mutations) in these genes (Schaefer et al., 1996; Schaefer et al., 1997; Van den Veyver et al., 1998; Prakash et al., 1999). We also made deletions of the same genes in laboratory mice and analyzed their features (Prakash et al., 2002). Unfortunately, we did not find any mutations in the DNA from patients; we also did not find features in the mice that look similar to those of Aicardi syndrome.
Therefore, we had to conclude that Aicardi syndrome and MLS syndrome are likely not related conditions (Van den Veyver, 2002). We are now continuing the searches for the cause of Aicardi syndrome by testing other genes throughout the X chromosome.
A detailed analysis of the pathological findings in two Aicardi syndrome brains was very important to better understand the condition. We made new observations on changes in a particular type of brain cells, called astrocytes, which led us to investigate and exclude a new candidate gene, FLN1 (filamin) (Van den Veyver et al, 2003).
Our current and future research on Aicardi syndrome focuses on three new areas:
We are continuing to look for mutations in several candidate genes on the X chromosome. Studies on two such genes, ARX and M6B are in progress.
We will also perform a detailed clinical study on all the features of Aicardi syndrome. We believe that this will be very important to better understand the pathogenesis of Aicardi syndrome and guide us in our search for its cause. I am very pleased that Dr. Gary Clark and Dr. Richard Lewis, both at Baylor College of Medicine, have agreed to participate in this project. Dr. Clark, a Professor of Pediatric Neurology, is an expert on disorders of brain development. Dr. Lewis, a Professor of Ophthalmology, is an expert in genetics of eye diseases and disorders of development of the eye. Additional detailed information on this study can be found in the Winter 2003/2004 Aicardi Syndrome Newsletter.
We are excited that we will be able to use a new method, microarray hybridization to test the DNA of girls with Aicardi syndrome. This method can detect very small deletions or duplications on the X chromosome that cannot be seen by any other technique currently routinely used. If we can find such a deletion in the DNA of even only one of the affected girls, it will be a big step forward towards finding the cause of Aicardi syndrome
Acknowledegement:
We are grateful for the continued support of the Aicardi Syndrome Foundation and for all the help and enthusiasm of The Aicardi Syndrome Newsletter and all families participating in research.
References:
Schaefer L, Ferrero GB, Grillo A, Bassi MT, Roth EJ, Wapenaar MC, van Ommen GJ, Mohandas TK, Rocchi M, Zoghbi HY, Ballabio A: A high resolution deletion map of human chromosome Xp22. Nat Genet 4:272-279 (1993).
Wapenaar MC, Bassi MT, Schaefer L, Grillo A, Ferrero GB, Chinault AC, Ballabio A, Zoghbi HY: The genes for X-linked ocular albinism (OA1) and microphthalmia with linear skin defects (MLS): cloning and characterization of the critical regions. Hum Mol Genet 2:947-952 (1993).
Schaefer L, Ballabio A, Zoghbi HY: Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS). Genomics 34:166-172 (1996).
Schaefer L, Prakash S, Zoghbi HY: Cloning and characterization of a novel rho-type GTPase-activating protein gene (ARHGAP6) from the critical region for microphthalmia with linear skin defects. Genomics 46:268-277 (1997).
Van den Veyver IB, Cormier TA, Jurecic V, Baldini A, Zoghbi HY: Characterization and physical mapping in human and mouse of a novel RING finger gene in Xp22. Genomics 51:251-261 (1998).
Prakash SK, Van den Veyver IB, Franco B, Volta M, Ballabio A, Zoghbi HY: Characterization of a novel chromo domain gene in Xp22.3 with homology to Drosophila msl-3. Genomics 59:77-84 (1999).
Prakash SK, Cormier TA, McCall AE, Garcia JJ, Sierra R, Haupt B, Zoghbi HY, Van den Veyver IB: Loss of holocytochrome c-type synthetase causes the male lethality of X- linked dominant microphthalmia with linear skin defects (MLS) syndrome. Hum Mol Genet 11:3237-3248 (2002).
Van den Veyver IB. MLS, Aicardi and Goltz syndrome: Are they related X-linked dominant male-lethal disorders. Cytogenet Genome Res 99: 289-96 (2002).
Van den Veyver IB, Panichkul P, Antallfy B, Sun Y, Hunter JV, Armstrong DD. Aicardi syndrome is associated with Filamin-positive inclusions in astrocytes. (Pediatr Neurol, 2003, in Press)