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

Zagaglia S¹, Selch C¹, Nisevic JR¹, Mei D¹, Michalak Z¹, Hernandez-Hernandez L¹, Krithika S¹, Vezyroglou K¹, Varadkar SM¹, Pepler A¹, Biskup S¹, Leão M¹, Gärtner J¹, Merkenschlager A¹, Jaksch M¹, Møller RS¹, Gardella E¹, Kristiansen BS¹, Hansen LK¹, Vari MS¹, Helbig KL¹, Desai S¹, Smith-Hicks CL¹, Hino-Fukuyo N¹, Talvik T¹, Laugesaar R¹, Ilves P¹, Õunap K¹, Körber I¹, Hartlieb T¹, Kudernatsch M¹, Winkler P¹, Schimmel M¹, Hasse A¹, Knuf M¹, Heinemeyer J¹, Makowski C¹, Ghedia S¹, Subramanian GM¹, Striano P¹, Thomas RH¹, Micallef C¹, Thom M¹, Werring DJ¹, Kluger GJ¹, Cross JH¹, Guerrini R¹, Balestrini S¹, Sisodiya SM².

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.