Early-onset epileptic encephalopathy in a girl carrying a truncating mutation of the ARX gene: rethinking the ARX phenotype in females

Severe early onset epilepsy is due to a number of known causes although a clear etiology is not identifiable in up to a third of all the cases. Pathogenic sequence variations in the ARX gene have been described almost exclusively in males, while heterozygous female relatives, such as mothers, sisters and even grandmothers have been largely reported as asymptomatic or mildly affected. In order to investigate the pathogenic role of ARX in refractory epilepsy of early onset even in females, we have screened the ARX sequence in a population of 50 female subjects affected with unexplained epileptic encephalopathy with onset in the first year of life. We report the identification of a novel truncating mutation of the coding region of the ARX gene in a girl with a structurally normal brain. Our findings confirm the role of ARX in the pathogenesis of early epilepsy and underline the importance of screening of the ARX gene in both male and female subjects with otherwise unexplained early onset epileptic encephalopathy.