Author:
Zagaglia Sara,Selch Christina,Nisevic Jelena Radic,Mei Davide,Michalak Zuzanna,Hernandez-Hernandez Laura,Krithika S.,Vezyroglou Katharina,Varadkar Sophia M.,Pepler Alexander,Biskup Saskia,Leão Miguel,Gärtner Jutta,Merkenschlager Andreas,Jaksch Michaela,Møller Rikke S.,Gardella Elena,Kristiansen Britta Schlott,Hansen Lars Kjærsgaard,Vari Maria Stella,Helbig Katherine L.,Desai Sonal,Smith-Hicks Constance L.,Hino-Fukuyo Naomi,Talvik Tiina,Laugesaar Rael,Ilves Pilvi,Õunap Katrin,Körber Ingrid,Hartlieb Till,Kudernatsch Manfred,Winkler Peter,Schimmel Mareike,Hasse Anette,Knuf Markus,Heinemeyer Jan,Makowski Christine,Ghedia Sondhya,Subramanian Gopinath M.,Striano Pasquale,Thomas Rhys H.,Micallef Caroline,Thom Maria,Werring David J.,Kluger Gerhard Josef,Cross J. Helen,Guerrini Renzo,Balestrini Simona,Sisodiya Sanjay M.
Abstract
ObjectiveTo characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation.MethodsWe analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.ResultsChildhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge.ConclusionCOL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.
Publisher
Ovid Technologies (Wolters Kluwer Health)