The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the presynaptic neuronal voltage-gated calcium channel Ca v 2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca 2þ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Ca v 2.2 in normal human neurodevelopment.

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We provide a comprehensive review of studies done since 2000 of the newest anticonvulsant medications in the treatment of pediatric epilepsy. Using the PubMed search engine we identified any studies referencing the use of the following eight anticonvulsants in children: brivaracetam, clobazam, ezogabine, felbamate, lacosamide, perampanel, vigabatrin and zonisamide. The papers reviewed included case reports, observational studies, retrospective and randomized-controlled trials between the year 2000 and 2014. Although there is abundant observational data on the safety and efficacy of these eight anticonvulsants in the treatment of pediatric epilepsy, there are only a limited number of randomized, placebo controlled trials of these drugs. Further study in this area is needed.