Premium
Genetic testing in benign familial epilepsies of the first year of life: Clinical and diagnostic significance
Author(s) -
Zara Federico,
Specchio Nicola,
Striano Pasquale,
Robbiano Angela,
Gennaro Elena,
Paravidino Roberta,
Vanni Nicola,
Beccaria Francesca,
Capovilla Giuseppe,
Bianchi Amedeo,
Caffi Lorella,
Cardilli Viviana,
Darra Francesca,
Bernardina Bernardo Dalla,
Fusco Lucia,
Gaggero Roberto,
Giordano Lucio,
Guerrini Renzo,
Incorpora Gemma,
Mastrangelo Massimo,
Spaccini Luigina,
Laverda Anna Maria,
Vecchi Marilena,
Vanadia Francesca,
Veggiotti Pierangelo,
Viri Maurizio,
Occhi Guya,
Budetta Mauro,
Taglialatela Maurizio,
Coviello Domenico A.,
Vigevano Federico,
Minetti Carlo
Publication year - 2013
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12089
Subject(s) - genetics , epilepsy , medicine , copy number variation , genetic testing , cohort , first degree relatives , biology , pediatrics , gene , family history , psychiatry , genome
Summary Purpose To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures ( BFNS ), benign familial neonatal‐infantile seizures ( BFNIS ), and benign familial infantile seizures ( BFIS ). Methods Families with at least two first‐degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN 2A, KCNQ 2, KCNQ 3, PPRT 2 point mutations were analyzed by direct sequencing of amplified genomic DNA . Genomic deletions involving KCNQ 2 and KCNQ 3 were analyzed by multiple‐dependent probe amplification method. Key Findings A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS , 9 as BFNIS , and 29 as BFIS . Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ 2 , 1 affecting KCNQ 3 , 5 affecting SCN 2A , and 21 affecting PRRT 2 . The detection rate of mutations in the entire cohort was 89%. In BFNS , mutations specifically involve KCNQ 2 . In BFNIS two genes are involved ( KCNQ 2 , six families; SCN 2A , two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT 2 mutation. Significance Our data highlight the important role of KCNQ 2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow‐up is associated with KCNQ 2 mutations and may represent a predictive factor. In addition, we showed that KCNQ 3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K‐channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN 2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT 2 mutations are clustered in families with BFIS . Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT 2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ 2 compared to only 3% of the BFIS families, for which PRRT 2 represents the major gene.