Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the aristaless-related homeobox gene

Mutations in the Aristaless-related homeobox (ARX) gene are associated with a broad spectrum of disorders including X-linked lissencephaly with abnormal genitalia (XLAG) and absent corpus callosum. Here, we describe a family with two male infants suffering from agenesis of the corpus callosum (ACC), intractable epilepsy, and abnormal genitalia. The phenotype of both affected patients differed in severity of the cerebral malformation with one showing no obvious evidence for lissencephaly. Both infants lacked any psychomotor development and died at the age of 17 weeks and 18 months, respectively. Genetic analysis of the ARX gene revealed a novel frameshift mutation in exon 4 (nt1419_1420insAC) leading to a shortened protein lacking the aristaless domain. In summary, analysis of the ARX gene should not only be considered in male patients with typical features of XLAG but also in those presenting with early onset epilepsy, ACC, and abnormal genitalia without obvious neuroradiological features of lissencephaly.