PIGN encephalopathy: Characterizing the epileptology

TY - JOUR

T1 - PIGN encephalopathy: Characterizing the epileptology

AU - Bayat, Allan

AU - de Valles-Ibáñez, Guillem

AU - Pendziwiat, Manuela

AU - Knaus, Alexej

AU - Alt, Kerstin

AU - Biamino, Elisa

AU - Bley, Annette

AU - Calvert, Sophie

AU - Carney, Patrick

AU - Caro-Llopis, Alfonso

AU - Ceulemans, Berten

AU - Cousin, Janice

AU - Davis, Suzanne

AU - des Portes, Vincent

AU - Edery, Patrick

AU - England, Eleina

AU - Ferreira, Carlos

AU - Freeman, Jeremy

AU - Gener, Blanca

AU - Gorce, Magali

AU - Heron, Delphine

AU - Hildebrand, Michael S

AU - Jezela-Stanek, Aleksandra

AU - Jouk, Pierre-Simon

AU - Keren, Boris

AU - Kloth, Katja

AU - Kluger, Gerhard

AU - Kuhn, Marius

AU - Lemke, Johannes R

AU - Li, Hong

AU - Martinez, Francisco

AU - Maxton, Caroline

AU - Mefford, Heather C

AU - Merla, Giuseppe

AU - Mierzewska, Hanna

AU - Muir, Alison

AU - Monfort, Sandra

AU - Nicolai, Joost

AU - Norman, Jennifer

AU - O'Grady, Gina

AU - Oleksy, Barbara

AU - Orellana, Carmen

AU - Orec, Laura Elena

AU - Peinhardt, Charlotte

AU - Pronicka, Ewa

AU - Rosello, Monica

AU - Santos-Simarro, Fernando

AU - Schwaibold, Eva Maria Christina

AU - Stegmann, Alexander P A

AU - Stumpel, Constance T

AU - Szczepanik, Elzbieta

AU - Terczyńska, Iwona

AU - Thevenon, Julien

AU - Tzschach, Andreas

AU - Van Bogaert, Patrick

AU - Vittorini, Roberta

AU - Walsh, Sonja

AU - Weckhuysen, Sarah

AU - Weissman, Barbara

AU - Wolfe, Lynne

AU - Reymond, Alexandre

AU - De Nittis, Pasquelena

AU - Poduri, Annapurna

AU - Olson, Heather

AU - Striano, Pasquale

AU - Lesca, Gaetan

AU - Scheffer, Ingrid E

AU - Møller, Rikke S

AU - Sadleir, Lynette G

N1 - © 2022 International League Against Epilepsy.

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - Drug Resistant Epilepsy

KW - Electroencephalography

KW - Epilepsy/diagnostic imaging

KW - Female

KW - Humans

KW - Intellectual Disability/diagnostic imaging

KW - Phenotype

KW - Seizures/genetics

U2 - 10.1111/epi.17173

DO - 10.1111/epi.17173

M3 - SCORING: Journal article

C2 - 35179230

VL - 63

SP - 974

EP - 991

JO - EPILEPSIA

JF - EPILEPSIA

SN - 0013-9580

IS - 4

ER -