Biomedicines (Oct 2020)
The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood
- Jan Henje Döring,
- Afshin Saffari,
- Thomas Bast,
- Knut Brockmann,
- Laura Ehrhardt,
- Walid Fazeli,
- Wibke G. Janzarik,
- Gerhard Kluger,
- Hiltrud Muhle,
- Rikke S. Møller,
- Konrad Platzer,
- Joana Larupa Santos,
- Iben Bache,
- Astrid Bertsche,
- Michaela Bonfert,
- Ingo Borggräfe,
- Philip J. Broser,
- Alexandre N. Datta,
- Trine Bjørg Hammer,
- Hans Hartmann,
- Anette Hasse-Wittmer,
- Marco Henneke,
- Hermann Kühne,
- Johannes R. Lemke,
- Oliver Maier,
- Eva Matzker,
- Andreas Merkenschlager,
- Joachim Opp,
- Steffi Patzer,
- Kevin Rostasy,
- Birgit Stark,
- Adam Strzelczyk,
- Celina von Stülpnagel,
- Yvonne Weber,
- Markus Wolff,
- Birgit Zirn,
- Georg Friedrich Hoffmann,
- Stefan Kölker,
- Steffen Syrbe
Affiliations
- Jan Henje Döring
- Division of Paediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Afshin Saffari
- Division of Paediatric Neurology and Metabolic Medicince, Centre for Paediatric and Adolescent Medicine, University Hospital, 69120 Heidelberg, Germany
- Thomas Bast
- Epilepsy Center Kork, Medical Faculty of the University of Freiburg, 77694 Kehl, Germany
- Knut Brockmann
- Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Children’s Hospital, University Medical Center, 37075 Göttingen, Germany
- Laura Ehrhardt
- Department of Pediatrics, University Medicine Mainz, 55131 Mainz, Germany
- Walid Fazeli
- Pediatric Neurology, Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
- Wibke G. Janzarik
- Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Gerhard Kluger
- Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schoen Clinic Vogtareuth, 83569 Vogtareuth, Germany
- Hiltrud Muhle
- Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, 24105 Kiel, Germany
- Rikke S. Møller
- Danish Epilepsy Centre, 4293 Dianalund, Denmark
- Konrad Platzer
- Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Joana Larupa Santos
- Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
- Iben Bache
- Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet and Department of Cellular and Molecular Medicine, University of Copenhagen, 2100 Copenhagen, Denmark
- Astrid Bertsche
- Centre for Paediatric Research, University Hospital for Children and Adolescents, 04103 Leipzig, Germany
- Michaela Bonfert
- Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, University of Munich, 80337 Munich, Germany
- Ingo Borggräfe
- Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, University of Munich, 80337 Munich, Germany
- Philip J. Broser
- Neuropädiatrie, Ostschweizer Kinderspital, 9006 St. Gallen, Switzerland
- Alexandre N. Datta
- University Children’s Hospital Basel, 4031 Basel, Switzerland
- Trine Bjørg Hammer
- Danish Epilepsy Centre, 4293 Dianalund, Denmark
- Hans Hartmann
- Hannover Medical School, Clinic for Pediatric Kidney, Liver and Metabolic Diseases, 30625 Hannover, Germany
- Anette Hasse-Wittmer
- Klinikum Traunstein, 83278 Traunstein, Germany
- Marco Henneke
- Department of Pediatrics and Adolescent Medicine, University Medical Center, Georg August University, 37075 Göttingen, Germany
- Hermann Kühne
- Children’s Hospital, 84503 Alt-Neuötting, Germany
- Johannes R. Lemke
- Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Oliver Maier
- Department of Child Neurology, Children’s Hospital, 9006 St. Gallen, Switzerland
- Eva Matzker
- Neuropädiatrie, Carl-Thiem-Klinikum Cottbus, 03048 Cottbus, Germany
- Andreas Merkenschlager
- Department of Neuropediatrics, University Hospital of Children, 04103 Leipzig, Germany
- Joachim Opp
- Children’s Hospital, 46047 Oberhausen, Germany
- Steffi Patzer
- Hospital St. Elizabeth and St. Barbara, 06110 Halle, Germany
- Kevin Rostasy
- Department of Pediatric Neurology, Children’s Hospital Datteln, Witten/Herdecke University, 45711 Datteln, Germany
- Birgit Stark
- Kepler Universitätsklinikum, 4020 Linz, Austria
- Adam Strzelczyk
- Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany
- Celina von Stülpnagel
- Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, University of Munich, 80337 Munich, Germany
- Yvonne Weber
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
- Markus Wolff
- Department of Pediatric Neurology, Vivantes Hospital Neukölln, 12351 Berlin, Germany
- Birgit Zirn
- Genetic Counselling and Diagnostic, Genetikum Stuttgart, 70173 Stuttgart, Germany
- Georg Friedrich Hoffmann
- Division of Paediatric Neurology and Metabolic Medicince, Centre for Paediatric and Adolescent Medicine, University Hospital, 69120 Heidelberg, Germany
- Stefan Kölker
- Division of Paediatric Neurology and Metabolic Medicince, Centre for Paediatric and Adolescent Medicine, University Hospital, 69120 Heidelberg, Germany
- Steffen Syrbe
- Division of Paediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
- DOI
- https://doi.org/10.3390/biomedicines8110456
- Journal volume & issue
-
Vol. 8,
no. 11
p. 456
Abstract
Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.
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