title: A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females.
abstract: OBJECTIVE
  ARX, the aristaless-related homeobox gene, is implicated in cerebral, testicular, and pancreatic development. ARX mutations are associated with various forms of epilepsy, developmental delay, and ambiguous genitalia in humans. A mouse model that recapitulates X-linked lissencephaly with ambiguous genitalia (XLAG) is far from elucidating the substrate for phenotypes that different ARX mutations cause. Moreover, despite phenotypic pleomorphism associated with X-linked dominant ARX mutations, heterozygous female carriers have not been thoroughly studied. Reviewing records of patients with ARX mutations, infantile epilepsies, and psychomotor retardation, we analyzed a family harboring a novel ARX mutation with different phenotypes in males and females, including Ohtahara syndrome.
  
  
  METHODS
  Children's Hospital Boston patient records were retrospectively screened for patients with infantile epileptic encephalopathies who underwent ARX sequencing based on clinical suspicion. Identified families were analyzed for genetic and neuropsychiatric phenomena.
  
  
  RESULTS
  The proband was a male with Ohtahara syndrome, ambiguous genitalia, psychomotor delay, and central nervous system dysgenesis due to a novel ARX mutation in exon 5, causing a frameshift in the aristaless domain. Heterozygous females demonstrated neurocognitive/psychiatric phenomena including learning difficulties, anxiety, depression, and schizophrenia.
  
  
  CONCLUSIONS
  This is the first reported case of Ohtahara syndrome with abnormal genital and psychomotor development in the setting of this novel ARX mutation in exon 5. Based on the unique phenotype of the proband and on the presence of heterozygous females with neurocognitive/psychiatric ailments, this study describes the potential roles for ARX mutations in epilepsy and neuropsychiatric disease, underscoring the importance of ARX in interneuron development, cerebral electrical activity, cognition, and behavior.
authors.affiliation: Department of Neurology, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
authors.forename: Yaman Z
authors.initials: YZ
authors.lastname: Ekşioğlu
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Pong
authors.forename: Masanori
authors.initials: M
authors.lastname: Takeoka
mesh_terms: D000328:Adult; D002648:Child; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D012734:Disorders of Sex Development / Q000175:diagnosis / Q000235:genetics*; D000089662:Doublecortin Protein; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005801:Genes, Homeobox / Q000235:genetics*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D001523:Mental Disorders / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017678:Sex Distribution; D013036:Spasms, Infantile / Q000235:genetics; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C469264:ARX protein, human; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D014157:Transcription Factors