The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

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.

Keywords: benign familial infantile seizures; cerebellum; hemiplegic migraine; paroxysmal kinesigenic dyskinesia; synaptic dysfunction.

Figure 1

The clinical spectrum of PRRT2-associated disorders by onset age. The curves on the background reflect the empirical distribution of age at onset for the two commonest phenotypes (i.e., epilepsy in blue and paroxysmal dyskinesia in red) based on references (10, 26, 27).

Figure 2

(A) Estimated transcript abundance in different cell lines, ordered by organ of phenotypic resemblance, showing that PRRT2 is mostly expressed in brain cell lines. (B) PRRT2 RNA expression levels in 10 brain areas obtained by combining data from two transcriptomics dataset (GTEx and FANTOM5), showing that PRRT2 is highly expressed in the cerebellum, cerebral cortex, and basal ganglia. (C) Subcellular location of PRRT2 obtained in AF22 cell line by indirect immunofluorescence microscopy (i.e., an antibody-based protein-visualization technique, in which nucleus is stained in blue, microtubules in red and the protein of interest in green) showing that PRRT2 localizes to the plasma membrane, as depicted in the cartoon. NX = consensus normalized expression. For details see https://www.proteinatlas.org/.