Neurologic phenotypes associated with <i>COL4A1</i> / <i>2</i> mutations

Abstract

<h3>Objective</h3> To characterize the neurologic phenotypes associated with <i>COL4A1/2</i> mutations and to seek genotype–phenotype correlation. <h3>Methods</h3> We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with <i>COL4A1/COL4A2</i> mutations. <h3>Results</h3> 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 <i>COL4A1</i> and a clear genotype–phenotype correlation did not emerge. <h3>Conclusion</h3> <i>COL4A1/COL4A2</i> 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 <i>COL4A1/COL4A2</i> 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.