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The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

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.

SUBMITTER: Doring JH

PROVIDER: S-EPMC7719266 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

Döring Jan Henje JH Saffari Afshin A Bast Thomas T Brockmann Knut K Ehrhardt Laura L Fazeli Walid W Janzarik Wibke G WG Kluger Gerhard G Muhle Hiltrud H Møller Rikke S RS Platzer Konrad K Santos Joana Larupa JL Bache Iben I Bertsche Astrid A Bonfert Michaela M Borggräfe Ingo I Broser Philip J PJ Datta Alexandre N AN Hammer Trine Bjørg TB Hartmann Hans H Hasse-Wittmer Anette A Henneke Marco M Kühne Hermann H Lemke Johannes R JR Maier Oliver O Matzker Eva E Merkenschlager Andreas A Opp Joachim J Patzer Steffi S Rostasy Kevin K Stark Birgit B Strzelczyk Adam A von Stülpnagel Celina C Weber Yvonne Y Wolff Markus M Zirn Birgit B Hoffmann Georg Friedrich GF Kölker Stefan S Syrbe Steffen S

Biomedicines 20201028 11

Pathogenic variants in <i>PRRT2</i>, 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 det ...[more]

PMID: 33126500

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Project description:BackgroundParoxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder, characterized by attacks of involuntary movements triggered by sudden action. Variants in proline-rich transmembrane protein 2 (PRRT2) are the most common genetic cause of PKD.ObjectiveThe objective was to investigate the clinical and genetic characteristics of PKD and to establish genotype-phenotype correlations.MethodsWe enrolled 219 PKD patients, documented their clinical information and performed PRRT2 screening using Sanger sequencing. Whole exome sequencing was performed on 49 PKD probands without PRRT2 variants. Genotype-phenotype correlation analyses were conducted on the probands.ResultsAmong 219 PKD patients (99 cases from 39 families and 120 sporadic cases), 16 PRRT2 variants were identified. Nine variants (c.879+4A>G, c.879+5G>A, c.856G>A, c.955G>T, c.884G>C, c.649C>T, c.649dupC, c.649delC and c.696_697delCA) were previously known, while seven were novel (c.367_403del, c.347_348delAA, c.835C>T, c.116dupC, c.837_838insC, c.916_937del and c.902G>A). The mean interval from onset to diagnosis was 7.94 years. Compared to patients without PRRT2 variants, patients with the variants were more likely to have a positive family history, an earlier age of onset and a higher prevalence of falls during pre-treatment attacks (27.14% versus 8.99%, respectively). Patients with truncated PRRT2 variants tend to have bilateral attacks. We identified two transmembrane protein 151A (TMEM151A) variants including a novel variant (c.368G>C) and a reported variant (c.203C>T) in two PRRT2-negative probands with PKD.ConclusionThese findings provide insights on the clinical characteristics, diagnostic timeline and treatment response of PKD patients. PKD patients with truncated PRRT2 variants may tend to have more severe paroxysmal symptoms. This study expands the spectrum of PRRT2 and TMEM151A variants. Carbamazepine and oxcarbazepine are both used as a first-line treatment choice for PKD patients.

Dataset Information

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

Publications

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

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