Abstract
Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307*, c.388delG/p.Ala130Profs*46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80–100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.
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Acknowledgments
We thank all patients and their relatives for participation in this study and the following clinicians for supporting the recruitment of the Italian patients: Mauro Brunetta, Pediatric Neurology, Ospedale di Cava de `Tirreni, Salerno, Italy; Biayna Sukhudyan, Pediatric Neurology, Arabkir Medical Center, Yerevan, Armenia; Marilena Vecchi, Department of Paediatrics, University of Padua, Padua, Italy; Francesca Vanadia, Child Neuropsychiatry, Ospedale Civico “E.-Benfratelli”, Palermo, Italy; Bernardo Dalla Bernardina, Child Neuropsychiatry Unit, G.B. Rossi Hospital, University of Verona, Verona, Italy. We thank Yasemin Colakoglu and Hella Hellgren for technical assistance with PRRT2 sequencing and Snezana Maljevic for text style corrections. This project was supported by grants from the National Genome Network of the Federal Ministry for Education and Research (BMBF: NGFNplus/01GS08123 to HL), the European Union (Epicure: LSH 037315 to HL, FZ and AEL), the German Research Foundation (DFG Le1030/11-1 to HL). We thank the Italian League Against Epilepsy and the German Society for Epileptology for supporting the recruitment of families.
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F. Becker and J. Schubert are equally contributed to this work.
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Becker, F., Schubert, J., Striano, P. et al. PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol 260, 1234–1244 (2013). https://doi.org/10.1007/s00415-012-6777-y
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DOI: https://doi.org/10.1007/s00415-012-6777-y