Abstracts

Rationale: Koolen-de Vries syndrome (KdVS, OMIM #610443) is a multisystem genetic disorder commonly involving intellectual disability, hypotonia, amiable personality and dysmorphic facial features. Individuals may also have cardiac and renal/urologic malformations, cryptorchidism and skin pigmentation abnormalities. The syndrome may occur with 17q21.31 microdeletions or heterozygous mutations in KANSL1, the critical gene within the common deletion region. Although half of the individuals with KdVS are reported to have seizures, the electroclinical phenotype of this genetic epilepsy syndrome has not been studied. Methods: Individuals with KdVS and seizures were recruited at an international KdVS family gathering, with additional participants enrolling after social media family support groups brought attention to the research project. Thirty people met inclusion criteria. In each case, primary caregivers were interviewed by a pediatric neurologist who obtained a comprehensive neurologic, developmental and general medical history. Medical records and results of genetic, EEG and MRI testing were obtained. Phenotypic data were analysed to determine the electroclinical phenotype of KdVS. Results: Thirty individuals (10 male) were studied, aged 2-35 years (mean 9.8 years). Mean age of seizure onset was 4.4 years (range 4 months to 24 years), and the vast majority of patients had either refractory (12/30; 41%) or delayed resolution (12/30; 41%) course, based on Brodie classification. Focal seizures with impaired awareness were the most frequent seizure type occurring in 19 individuals (63%), usually with prominent autonomic features. The latter led some patients to receive diagnoses of Panayiotopoulos syndrome. Twenty patients (67%) had prolonged seizures (> 10 minutes) which were often medically refractory. EEG showed focal/multifocal epileptiform discharges in 18/23 cases (78%), sometimes with features of Panayiotopoulos syndrome or childhood epilepsy with centrotemporal spikes (CECTS). Only 7/15 patients had reduction in seizure frequency with levetiracetam, while clinical response appeared to be better with valproic acid, benzodiazepines and sodium channel antagonists. Neuroimaging showed abnormalities in 15/22 (68%) cases. Dilated ventricles and dysgenesis or partial agenesis of the corpus callosum were most common, seen in 13 (59%) and seven (32%) cases, respectively. Periventricular nodular heterotopia, malrotated hippocampi, focal cortical dysplasia and dysmorphic cerebellar hemispheres were also observed. Conclusions: The electro-clinico-radiologic phenotype of KdVS typically begins with childhood-onset focal seizures that are prolonged and have prominent autonomic features. EEG shows multifocal epileptiform discharges in most cases. MRI brain is usually abnormal with dilated ventricles a common finding and can be mistaken for periventricular leukomalacia. Some patients have presentations reminiscent of the "benign" focal epilepsies, Panayiotopoulos and CECTS, suggesting KANSL1 could be a candidate gene for these common childhood focal epilepsy syndromes. Funding: This study was supported by funding from an Australian National Health and Medical Research Council (NHMRC) Program Grant.