EVIDENCE THAT SKEWED X-INACTIVATION IS NOT NEEDED FOR THE PHENOTYPIC-EXPRESSION OF AICARDI-SYNDROME

Aicardi syndrome is a rare disorder characterized by absent corpus cal losum, infantile spasms, and chorioretinal lacunae. It is sporadic in nature and affects only females, resulting in severe mental and physic al handicap. It has been suggested that the disease is caused by a dom inant X-linked mutation which occurs de novo in females, and is lethal in hemizygous male embryos. This mode of inheritance has been observe d in a number of other rare syndromes. In these syndromes, when X inac tivation is studied, a non-random pattern is usually found. We have st udied the X inactivation pattern in ten female patients with Aicardi s yndrome and their parents using the highly polymorphic, differentially methylated androgen receptor gene. The results showed an unexpected r andom X-inactivation pattern in these patients. Previous clinical and cytogenetic evidence suggests that Aicardi syndrome is caused by an X- linked dominant mutation, de novo in females and lethal in males. Howe ver, unlike most other known X-linked disorders inherited in this fash ion, Aicardi syndrome patients have a normal (i.e., random) X-inactiva tion pattern. A number of possible explanations is proposed for this a pparently contradictory evidence.