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

27. November 2018

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.



To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation.


We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.


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.


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.