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Objective: Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies., Methods: We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage-gated sodium channel subunit Nav 1.1. We genetically deleted 1 or 2 Tau alleles in mice carrying an Nav 1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, electroencephalographic recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays., Results: Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug-induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only 1 Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance., Interpretation: Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies., (© 2014 American Neurological Association.)

Cortical hyperexcitability is a feature of "familial cortical myoclonic tremor with epilepsy" (FCMTE). However, neuropathological investigations in a single FCMTE patient showed isolated cerebellar pathology. Pathological investigations in a second FCMTE patient, reported here, confirmed cerebellar Purkinje cell degeneration and a normal sensorimotor cortex. Subsequently, we sought to explore the nature of cerebellar and motor system pathophysiology in FCMTE. Eye movement recordings and transcranial magnetic stimulation performed in six related FCMTE patients showed impaired saccades and smooth pursuit and downbeat nystagmus upon hyperventilation, as in patients with spinocerebellar ataxia type 6. In FCMTE patients short-interval intracortical inhibition (SICI) was significantly reduced. Resting motor threshold, recruitment curve, silent period, and intracortical facilitation were normal. The neuropathological and ocular motor abnormalities indicate cerebellar involvement in FCMTE patients. Decreased SICI is compatible with intracortical GABA(A)-ergic dysfunction. Cerebellar and intracortical functional changes could result from a common mechanism such as a channelopathy. Alternatively, decreased cortical inhibition may be caused by dysfunction of the cerebello-thalamo-cortical loop as a result of primary cerebellar pathology., (2007 Movement Disorder Society)

Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder characterized by bilateral myoclonic jerks. An 8-year-old boy presenting with early onset, medically intractable, MDS due to a mutation in the epsilon-sarcoglycan gene (SGCE) underwent chronic bilateral stimulation of the globus pallidus internus, which eliminates both myoclonus and dystonia. We conclude that deep brain stimulation can be an effective and safe treatment for MDS., (Copyright 2004 Movement Disorder Society)