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PRRT2-related disorders: further PKD and ICCA cases and review of the literature |
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| Authors: | Felicitas Becker Julian Schubert Pasquale Striano Anna-Kaisa Anttonen Elina Liukkonen Eija Gaily Christian Gerloff Stephan Müller Nicole Heußinger Christoph Kellinghaus Angela Robbiano Anne Polvi Simone Zittel Tim J von Oertzen Kevin Rostasy Ludger Schöls Tom Warner Alexander Münchau Anna-Elina Lehesjoki Federico Zara Holger Lerche Yvonne G Weber |
| Institution: | 1. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Strasse 3, 72076, Tübingen, Germany 12. Pediatric Neurology and Muscular Diseases Unit, G. Gaslini Institute, Department of Neurosciences, University of Genova, Genoa, Italy 2. Folkh?lsan Institute of Genetics, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland 3. Neuroscience Center and Haartman Institute, Medical Genetics and Research Program’s Unit, Molecular Medicine, University of Helsinki, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland 4. Department of Clinical Genetics, Helsinki University Central Hospital, 00029, Helsinki, Finland 5. Epilepsy Unit, Pediatric Neurology, Helsinki University Central Hospital, 00029, Helsinki, Finland 6. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 7. Department of Pediatrics, Friedrich-Alexander University Erlangen-Nuernberg, Erlangen, Germany 8. Klinik für Neurologie, Klinikum Osnarbrück, Osnarbrück, Germany 13. Laboratory of Neurogenetics, G. Gaslini Institute, Genoa, Italy 9. St George`s University of London, London, Great Britain 10. Department of Paediatrics, Division of Pediatric Neurology and Inborn Errors of Metabolism, Medical University Innsbruck, Innsbruck, Austria 11. Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 15. German Center of Neurodegenerative Diseases, Tübingen, Germany 14. Department of Clinical Neurosciences, UCL Institute of Neurology, London, Great Britain |
| 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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