Abstract
Mutations in the PRRT2 (proline-rich transmembrane protein 2) gene have been identified as the main cause of an expanding spectrum of disorders, including paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy, which places this gene at the border between epilepsy and movement disorders. The clinical spectrum has largely expanded to include episodic ataxia, hemiplegic migraine, and complex neurodevelopmental disorders in cases with biallelic mutations. Prior to the discovery of PRRT2 as the causative gene for this spectrum of disorders, the sensitivity of paroxysmal kinesigenic dyskinesia to anticonvulsant drugs regulating ion channel function as well as the co-occurrence of epilepsy in some patients or families fostered the hypothesis this could represent a channelopathy. However, recent evidence implicates PRRT2 in synapse functioning, which disproves the “channel hypothesis” (although PRRT2 modulates ion channels at the presynaptic level), and justifies the classification of these conditions as synaptopathies, an emerging rubric of brain disorders. This review aims to provide an update of the clinical and pathophysiologic features of PRRT2-associated disorders.
Highlights
Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder with a prevalence estimated at 1:150,000 [1], characterized by recurrent, brief attacks of chorea, dystonia, ballism, or a combination thereof, with preserved consciousness
PRRT2 mutations have been described in cases with isolated paroxysmal hypnogenic dyskinesia (PHD) [16], a fourth paroxysmal dyskinesia (PxD) form in which attacks occur during sleep without identifiable triggers, which has been increasingly discarded as a PxD subtype following the evidence that autosomal dominant frontal lobe epilepsy (ADFLE) was the underlying etiology in most cases [17]
The importance of this observation is 2-fold: [1] it brought the re-inclusion of PHD as an additional PxD subtype, beyond PKD, paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED)[3]; and [2] it demonstrated that additional clinical features beyond the trigger of the attacks might be predictive of the underlying genetic deficits
Summary
Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder with a prevalence estimated at 1:150,000 [1], characterized by recurrent, brief attacks of chorea, dystonia, ballism, or a combination thereof, with preserved consciousness. PKD is the most frequent subtype of paroxysmal dyskinesia (PxD), in which the attacks are by definition triggered by the initiation of voluntary movements, kinesigenic, but may be further precipitated by non-kinesigenic triggers [2] and usually last
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