Neurologic phenotypes associated with COL4A1/2 mutations

Zagaglia, Sara and Selch, Christina and Nisevic, Jelena R. and Mei, Davide and Michalak, Zuzanna and Hernandez-Hernandez, Laura and Krithika, S. and Vezyroglou, Katharina and Varadkar, Sophia M. and Pepler, Alexander and Biskup, Saskia and Leão, Miguel and Gärtner, Jutta and Merkenschlager, Andreas and Jaksch, Michaela and Møller, Rikke S. and Gardella, Elena and Kristiansen, Britta S. and Hansen, Lars K. and Vari, Maria S. and Helbig, Katherine L. and Desai, Sonal and Smith-Hicks, Constance L. and Hino-Fukuyo, Naomi and Talvik, Tiina and Laugesaar, Rael and Ilves, Pilvi and Õunap, Katrin and Körber, Ingrid and Hartlieb, Till and Kudernatsch, Manfred and Winkler, Peter and Schimmel, Mareike and Hasse, Anette and Knuf, Markus and Heinemeyer, Jan and Makowski, Christine and Ghedia, Sondhya and Subramanian, Gopinath M. and Striano, Pasquale and Thomas, Rhys H. and Micallef, Caroline and Thom, Maria and Werring, David J. and Kluger, Gerhard J. and Cross, J. Helen and Guerrini, Renzo and Balestrini, Simona and Sisodiya, Sanjay M. (2018) Neurologic phenotypes associated with COL4A1/2 mutations. Neurology, 91 (22). e2078-e2088. ISSN 1526-632X

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Official URL: https://doi.org/10.1212/WNL.0000000000006567

Abstract

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results: Childhood-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. Conclusion: COL4A1/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.

Item Type: Journal Article
Keywords: Infarction, Epilepsy surgery, Partial seizures
Faculty: Faculty of Science & Engineering
Depositing User: Lisa Blanshard
Date Deposited: 30 Jul 2020 13:19
Last Modified: 30 Jul 2020 13:19
URI: http://arro.anglia.ac.uk/id/eprint/705733

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