Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease

Sara Zagaglia, Christina Selch, Jelena Radic Nisevic, Davide Mei, Zuzanna Michalak, Laura Hernandez-Hernandez, S. Krithika, Katharina Vezyroglou, Sophia M. Varadkar, Alexander Pepler, Saskia Biskup, Miguel Leão, Jutta Gärtner, Andreas Merkenschlager, Michaela Jaksch, Rikke S. Møller, Elena Gardella, Britta Schlott Kristiansen, Lars Kjærsgaard Hansen, Maria Stella VariKatherine L. Helbig, Sonal Desai, Constance L. Smith-Hicks, Naomi Hino-Fukuyo, Tiina Talvik, Rael Laugesaar, Pilvi Ilves, Katrin Õunap, Ingrid Körber, Till Hartlieb, Manfred Kudernatsch, Peter Winkler, Mareike Schimmel, Anette Hasse, Markus Knuf, Jan Heinemeyer, Christine Makowski, Sondhya Ghedia, Gopinath M. Subramanian, Pasquale Striano, Rhys H. Thomas, Caroline Micallef, Maria Thom, David J. Werring, Gerhard Josef Kluger, J. Helen Cross, Renzo Guerrini, Simona Balestrini, Sanjay M. Sisodiya

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)e2078-e2088
Issue number22
StatePublished - 2018

ASJC Scopus subject areas

  • Clinical Neurology


Dive into the research topics of 'Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease'. Together they form a unique fingerprint.

Cite this