Epilepsia.: co-auth.: group Reymond

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Epilepsia. 2022 Feb 18. doi: 10.1111/epi.17173. Online ahead of print.

PIGN encephalopathy: Characterizing the epileptology

Allan Bayat 1 2, Guillem de Valles-Ibáñez 3, Manuela Pendziwiat 4 5, Alexej Knaus 6, Kerstin Alt 7, Elisa Biamino 8, Annette Bley 9 10, Sophie Calvert 11, Patrick Carney 12, Alfonso Caro-Llopis 13, Berten Ceulemans 14, Janice Cousin 15, Suzanne Davis 3, Vincent des Portes 16, Patrick Edery 17, Eleina England 18, Carlos Ferreira 19, Jeremy Freeman 20 21, Blanca Gener 22, Magali Gorce 23, Delphine Heron 24, Michael S Hildebrand 25 26, Aleksandra Jezela-Stanek 27, Pierre-Simon Jouk 28, Boris Keren 24, Katja Kloth 29, Gerhard Kluger 7, Marius Kuhn 7, Johannes R Lemke 30 31, Hong Li 32, Francisco Martinez 13, Caroline Maxton 33, Heather C Mefford 34, Giuseppe Merla 8, Hanna Mierzewska 35, Alison Muir 34, Sandra Monfort 36, Joost Nicolai 36, Jennifer Norman 37, Gina O’Grady 38, Barbara Oleksy 39, Carmen Orellana 36, Laura Elena Orec 40, Charlotte Peinhardt 32, Ewa Pronicka 41, Monica Rosello 36, Fernando Santos-Simarro 42, Eva Maria Christina Schwaibold 43, Alexander P A Stegmann 44, Constance T Stumpel 45, Elzbieta Szczepanik 39, Iwona Terczyńska 46, Julien Thevenon 47, Andreas Tzschach 48, Patrick Van Bogaert 23, Roberta Vittorini 8, Sonja Walsh 48, Sarah Weckhuysen 49 50, Barbara Weissman 40, Lynne Wolfe 19, Alexandre Reymond 51, Pasquelena De Nittis 51, Annapurna Poduri 52, Heather Olson 52, Pasquale Striano 53, Gaetan Lesca 17, Ingrid E Scheffer 25 54, Rikke S Møller 1 2, Lynette G Sadleir 3 Affiliations expand

Abstract

Objective: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy.

Methods: We recruited patients with epilepsy due to biallelic PIGN variants 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.

Results: Twenty 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.

Significance: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Keywords: GPI-anchoring disorder; congenital disorder of glycosylation; developmental and epileptic encephalopathy; epilepsy; intellectual disability.