Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

Efficacy and safety of levetiracetam in pediatric migraine.

BACKGROUND: Headache is a frequent occurrence among children and adolescents. Chronic headaches can be severe and disabling, and require prophylactic treatment; however, additional data on the use of prophylactic medications for migraine in children are needed. OBJECTIVE: To review the efficacy and safety of levetiracetam (Keppra) in pediatric patients with a history of recurrent headache. DESIGN/METHODS: Data from 19 pediatric patients were retrospectively reviewed. The initial dose of levetiracetam was usually 125 or 250 mg twice daily, but varied depending upon clinical judgment. RESULTS: Charts of 9 girls and 10 boys (mean age, 11.9 years) were reviewed. A variety of medications, including triptans, had been used before initiating treatment with levetiracetam. Mean headache frequency before treatment was 6.3 per month (standard deviation [SD], 3.8; confidence interval [CI], 4.4 to 8.1). Duration of headaches ranged from 0.25 to 8 years. Migraine (63.2%) and migraine with aura (15.8%) were the most common types of headache reported. Most patients (89.5%) had headaches that were severe. After treatment, the mean headache frequency decreased to 1.7 per month (SD, 2.7; CI, 0.4 to 3.0), representing a reduction compared with baseline (P <.0001). Levetiracetam eliminated headaches in 10 patients (52.6%), and 7 patients (36.8%) had less severe and less frequent headaches. Levetiracetam did not have an effect on headaches in 2 patients (10.5%). Mean duration of treatment with levetiracetam was 4.1 months. Doses ranged from 125 to 750 mg twice daily. Sixteen patients (84.2%) reported no side effects on levetiracetam. One patient experienced asthenia/somnolence and dizziness, and irritable, hyperactive, and hostile behavior led to discontinuation of levetiracetam in another patient. A third patient experienced irritability and moodiness that attenuated after 1 month of treatment and did not require discontinuation. CONCLUSIONS: In this small retrospective review, levetiracetam was found to be generally well tolerated and appears to be a promising candidate for additional evaluation in well-controlled clinical trials of pediatric patients with migraine.