Paroxysmal hypnogenic dyskinesia is associated with mutations in the PRRT2 gene

Abstract

Objective: To explore the potential causative genes of paroxysmal hypnogenic dyskinesia (PHD), which was initially considered a subtype of paroxysmal dyskinesia and has been recently considered a form of nocturnal frontal lobe epilepsy (NFLE).

Methods: Eleven patients with PHD were recruited. Mutations in proline-rich region transmembrane protein-2 (PRRT2), myofibrillogenesis regulator 1 (MR-1), solute carrier family 2, member 1 (SLC2A1), calcium-activated potassium channel alpha subunit (KCNMA1), cholinergic receptor, nicotinic, alpha 4 (CHRNA4), cholinergic receptor, nicotinic, beta 2 (CHRNB2), cholinergic receptor, nicotinic, alpha 2 (CHRNA2), and potassium channel subfamily T member 1 (KCNT1) were screened by direct sequencing.

Results: Two PRRT2 mutations were identified in patients with typical PHD. A mutation of c.649dupC (p.Arg217ProfsX8) was identified in a patient with PHD and his father who was diagnosed with paroxysmal kinesigenic dyskinesia. An additional mutation of c.640G>C (p.Ala214Pro) was identified in a sporadic patient and his asymptomatic mother. No mutations were found in the other screened genes.

Conclusions: The present study identified PRRT2 mutations in PHD, extending the phenotypic spectrum of PRRT2 and supporting the classification of PHD as a subtype of paroxysmal dyskinesia but not NFLE. Based on the results of this study, screening for the PRRT2 mutation is recommended in patients with PHD.

Figure 1. Genetic data on the patients with paroxysmal hypnogenic dyskinesia (PHD) with gene mutations in PRRT2

(A) The pedigree (left) and PRRT2 sequence (right) of the patient with mutation of c.649dupC (patient 1). The patient carried the heterozygous mutation of the PRRT2 gene c.649dupC (p.Arg217ProfsX8), inherited from his father with paroxysmal kinesigenic dyskinesia (PKD). (B) The pedigree (left) and PRRT2 sequence (right) of the patient with mutation c.640G>C (patient 2). The patient carried the heterozygous mutation of the PRRT2 gene c.640G>C (p.Ala214Pro), inherited from his asymptomatic mother. (C) The amino acid sequence alignment of the PRRT2 family showed the evolutionary conservation of the residues. Ala214 and Arg217 were highly conserved in various species.

Figure 2. EEG changes in the patients with paroxysmal hypnogenic dyskinesia with PRRT2 mutations

(A) Interictal EEG of patient 1 obtained at the age of 20 years showed irregular delta activities in the bifrontal lobe, more dominant in the right frontal lobe. (B) Ictal EEG of patient 1. The attack started with rhythmic convulsions during non-REM sleep (NREM) stage II accompanied by muscle artifacts on EEG recording. It lasted 12 seconds, followed by slow waves in the bifrontal lobe, and returned to the sleeping background (NREM-IV) 1 minute later. (C) Interictal EEG of patient 2 obtained at the age of 10 years showed irregular generalized spikes and slow waves and (D) focal spike and waves in the right posterior temporal lobe. (E) Ictal recording of patient 2 showed that the patient awakened suddenly from NREM-II and presented irregular bilateral arm and leg choreoathetoid movements, accompanied by movement artifacts and generalized low- and medium-voltage theta slowing. The movements lasted 26 seconds, and the slowing continued for 1 minute.