SUMMARYPurpose: Glut 1 deficiency syndrome (DS) is defined by hypoglycorrhachia with normoglycemia, acquired microcephaly, episodic movements, and epilepsy refractory to standard antiepileptic drugs (AEDs). Gold standard treatment is the ketogenic diet (KD), which provides ketones to treat neuroglycopenia. Our purpose is (1) to describe epilepsy phenotypes in a large Glut 1 DS cohort, to facilitate diagnosis; and (2) to describe cases in which non-KD agents achieved seizure freedom (SF), highlighting potential adjunctive treatments. Methods: Retrospective review of 87 patients with Glut 1 DS (45% female, age range 3 months-35 years, average diagnosis 6.5 years) at Columbia University, from 1989 to 2010. Key Findings: Seventy-eight (90%) of 87 patients had epilepsy, with average onset at 8 months. Seizures were mixed in 68% (53/78): generalized tonic-clonic (53%), absence (49%), complex partial (37%), myoclonic (27%), drop (26%), tonic (12%), simple partial (3%), and spasms (3%). We describe the first two cases of spasms in Glut 1 DS. Electrophysiologic abnormalities were highly variable over time; only 13 (17%) of 75 had exclusively normal findings. KD was used in 82% (64/78); 67% (41/61) were seizure-free and 68% of seizure-free patients (28/41) resolved in <1 week and 76% (31/41) in <1 month. Seven patients achieved SF with broad agents only. Significance: Glut 1 DS is a genetic metabolic encephalopathy with variable focal and multifocal seizure types and electroencephalographic findings. Infants with seizures, spasms, or paroxysmal events should be tested for Glut 1 DS. Evidence is insufficient to recommend specific AEDs as alternatives to KD. Early diagnosis and initiation of KD and prevention of unnecessary AED trials in Glut 1 DS are important goals for the treatment of children with epilepsy.

The contribution of genetics to both rare and common epilepsies is rapidly being elucidated, and neurologists are routinely considering genetic testing in the work-up of several epilepsy syndromes of both known and unknown cause. Simultaneously, advances in molecular technology foreshadow additional discoveries in epilepsy etiology, implying a greater role than ever before for genetics in the epilepsy clinic. Genetic testing can be valuable not only for diagnosis but also for guiding treatment and for informing reproductive choices. In this Review, we outline the principles of genetic evaluation and counseling, and describe how to interpret genetic test results for epilepsy in the following five common clinical scenarios: Dravet syndrome, infantile spasms, epilepsy with cortical malformation, epilepsy with mental retardation, and idiopathic epilepsy syndromes. We differentiate clinical situations in which genetic testing is of high and low utility, and predict future areas for the application of genetics in epilepsy practice.

SUMMARYPurpose: 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.Key Findings: 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. Significance: 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.