PIGNencephalopathy: Characterizing the epileptology
Authors: Bayat Allan , de Valles‐Ibáñez Guillem , Pendziwiat Manuela , Knaus Alexej , Alt Kerstin , Biamino Elisa , Bley Annette , Calvert Sophie , Carney Patrick , Caro‐Llopis Alfonso , Ceulemans Berten , Cousin Janice , Davis Suzanne , des Portes Vincent , Edery Patrick , England Eleina , Ferreira Carlos , Freeman Jeremy , Gener Blanca , Gorce Magali , Heron Delphine , Hildebrand Michael S. , Jezela‐Stanek Aleksandra , Jouk Pierre‐Simon , Keren Boris , Kloth Katja , Kluger Gerhard , Kuhn Marius , Lemke Johannes R. , Li Hong , Martinez Francisco , Maxton Caroline , Mefford Heather C. , Merla Giuseppe , Mierzewska Hanna , Muir Alison , Monfort Sandra , Nicolai Joost , Norman Jennifer , O'Grady Gina , Oleksy Barbara , Orellana Carmen , Orec Laura Elena , Peinhardt Charlotte , Pronicka Ewa , Rosello Monica , Santos‐Simarro Fernando , Schwaibold Eva Maria Christina , Stegmann Alexander P. A. , Stumpel Constance T. , Szczepanik Elzbieta , Terczyńska Iwona , Thevenon Julien , Tzschach Andreas , Van Bogaert Patrick , Vittorini Roberta , Walsh Sonja , Weckhuysen Sarah , Weissman Barbara , Wolfe Lynne , Reymond Alexandre , De Nittis Pasquelena , Poduri Annapurna , Olson Heather , Striano Pasquale , Lesca Gaetan , Scheffer Ingrid E. , Møller Rikke S. , Sadleir Lynette G. 
Published: February 2022

AbstractObjectiveEpilepsy is common in patients withPIGNdiseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology ofPIGNencephalopathy.MethodsWe recruited patients with epilepsy due to biallelicPIGNvariants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified.ResultsTwenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic–atonic (1/26), and generalized tonic–clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug‐resistant epilepsy, compared to 4/6 ID+E patients, who were seizure‐free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty‐seven of 34 variants were novel. Variants were truncating (n= 7), intronic and predicted to affect splicing (n= 7), and missense or inframe indels (n= 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures.SignificancePIGNencephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.