Abstracts

The Aristaless-related homeobox gene, ARX, is a transcription factor with a crucial role in the development of forebrain, pancreas and testes. Located in the X chromosome (Xp22.13), ARX mutations cause a pleiomorphic array of phenotypes such as mental retardation, lissencephaly, infantile spasms, and abnormal genitalia in males. Based on human genetics and loss-of-function studies in mice, ARX appears to be crucial in the regulation of GABAergic interneuron development and maintenance of circuitry. Ohtahara syndrome consists of epileptic encephalopathy, suppression-burst EEG-pattern and refractory epilepsy with tonic spasms in young infants. Despite reports of neonatal epilepsy, Ohtahara syndrome has not been previously described in infants with ARX mutations., We describe a boy with Ohtahara syndrome who presents with refractory seizures since day-1-of-life caused by a novel mutation in the ARX-gene. His initial presentation with startle and jerking movements, evolve into brief tonic seizures, refractory to multiple antiepileptic drugs including phenobarbital, zonisamide and levetiracetam. Despite a normal MRI, EEG reveals suppression-burst-pattern. He is normocephalic without dysmorphism, except for micropenis and bilateral cryptorchidism, in addition to diffuse hypotonia without weakness. Later, he develops infantile spasms with partial response to vigabatrin., ARX nucleotide sequence analysis, by Athena diagnostics (Worcester, MA), including entire coding regions and intronic sequences of exon-intron splice junctions, revealed that the proband was hemizygous for a novel mutation comprising 1 base pair insertion of C after nucleotide position 1471, resulting in a frameshift at codon 491. Analysis of mother[apos]s DNA revealed that she was heterozygous for the same mutation in ARX-gene, hence, demonstrating her as a carrier(City of Hope Clinical Molecular Diagnostic Laboratory, Duarte, CA)., This is the first reported case of Ohtahara syndrome as consequence of a novel mutation in exon 5 of the ARX-gene. Insertion of a C after position 1471 in the ARX gene leads to a frameshift that completely changes the structure of the ARX protein from amino acid 491, affecting the composition of the C terminal end. This leads to the disruption of the aristaless-domain, which is known to play crucial role in central nervous system regionalization with respect to its potential role in transactivation activity. The molecular pathology observed in this novel mutation reflects the complexity associated with ARX protein structure and function. The aristaless domain, localized to exon 5 in the C terminal end of the ARX protein, stands out as an important region in ARX protein signaling. Hence, further genetic/molecular studies are necessary to better understand the function of the aristaless-domain and its association with the Ohtahara syndrome in our patient with this novel mutation.,