Perampanel as precision therapy in rare genetic epilepsies

OBJECTIVE: Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy. METHODS: This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified. RESULTS: A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity. SIGNIFICANCE: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission

Perampanel as Precision Therapy in Rare Genetic Epilepsies

Objective: Perampanel, an antiseizure drug with AMPA-receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Special interest holds epilepsies with loss of GABA inhibition (e.g. SCN1A), overactive excitatory neurons (e.g. SCN2A, SCN8A ), and variants in glutamate receptors (e.g. GRIN2A). We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy. Methods: A multicenter project based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel was collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified. Results: 137 patients, with 79 different etiologies, aged 2 months-61 years (mean 15.48±9.9) were enrolled. The mean dosage was 6.45±2.47 mg, and treatment period was 2.0±1.78 years (1.5 months-8 years). 62 patients (44.9%) were treated for >2 years. 98 patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61±34.36%. 60 patients (43.5%) sustained over 75% reduction in seizure frequency, including 38 (27.5%) with > 90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, NEU1. 11/17 (64.7%) of patients with SCN1A, 35.3% of which had over 90% seizure reduction. Other etiologies remarkable for over 90% reduction in seizures were GNAO1 and PIGA. 14 patients had a CSWS EEG pattern and in 6 subjects perampanel reduced epileptiform activity. Significance: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1 and POLG, suggesting a targeted effect related to glutamate transmission

Unusual variability of PRRT2 linked phenotypes within a family

Background: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene on chromosome 16p11.2 have recently been identified as a cause of paroxysmal kinesigenic dyskinesias (PKD), infantile convulsions and choreoathetosis (ICCA) syndrome or infantile convulsions (IC)

PRRT2 Mutations Are the Major Cause of Benign Familial Infantile Seizures

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone. Hum Mutat 33:1439-1443, 2012. (C) 2012 Wiley Periodicals, Inc

PRRT2 Mutations are the major cause of benign familial infantile seizures

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone. Hum Mutat 33:1439-1443, 2012. (C) 2012 Wiley Periodicals, Inc