Pathophysiology of Paroxysmal Dyskinesias

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

The paroxysmal dyskinesias are an important category of movement disorders characterized by the sudden onset of involuntary movements that may include one or more of the following: dystonia, chorea, athetosis and ballism. The paroxysmal dyskinesias are divided into three major types: PKD (paroxysmal kinesigenic dyskinesias), PNKD (paroxysmal non-kinesigenic dyskinesias), and paroxysmal exertion-induced dyskinesias (PED). Precipitating factors are included within the name of each type: kinesigenic (sudden movements), non-kinesigenic (triggered by stress or alcohol), and exertion- or exercise-induced. The paroxysmal dyskinesias may be familial (hereditary), sporadic, or secondary to other neurological or metabolic disorder. The paroxysmal dyskinesias show overlap with other paroxysmal neurological disorders (e.g., epilepsy, migraines) in terms of genetics and triggers. Overall, dystonia is the foremost involuntary movement manifest by patients with PKD, PNKD and PED, and PKD due to mutations in PRRT2 is the most common cause of hereditary paroxysmal dystonia. Conditional knock-out (cKO) mouse models of PKD (Prrt2) offer the distinct possibility of exposing the functional network pathobiology of dystonia and paroxysmal disorders given the high penetrance of PRRT2 mutations in humans and robust phenotypes seen in our Prrt2 mouse models. Moreover, paroxysmal neurological disorders are ideal model systems for studying neural function by allowing for direct comparisons of ictal and inter-ictal states. Our major objectives are to define the neuroanatomical substrates of dystonia using mouse models of PKD and identify the in vivo and in vitro neurophysiological abnormalities that drive dystonia. We will detail the anatomical distribution of Prrt2/PRRT2 and ultrastructural localization of PRRT2, examine the effects of simple KO using a collection of behavioral and morphological assessments, determine if the neuroanatomical origin of dystonia and/or other paroxysmal dyskinesias can be narrowed down to specific brain regions (e.g., cerebellum) and neuronal populations (e.g., cerebellar granule cells, Purkinje cells or deep cerebellar neurons), and examine neural networks activated by paroxysmal dystonia. Neurophysiological studies will be used to characterize the synaptic function of PRRT2 and the signature cellular and network neurophysiological abnormalities the generate dystonic posturing. Our proposed experiments will answer fundamental questions related to the pathogenesis of dystonia, paroxysmal disorders of the nervous system, and biology of PRRT2.