Neurologic phenotypes associated with COL4A1 / 2 mutations

Abstract

ObjectiveTo characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation.MethodsWe analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.ResultsChildhood-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.ConclusionCOL4A1/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.

Cerebral small vessel disease with hemorrhagic stroke related to COL4A1 mutation: A case report

“…Mutational analysis of COL4A1 has demonstrated a guanine to adenosine substitution at bp 2159 in exon 29, leading to the replacement of glycine with aspartic acid at position 720 (p.G720D) in affected patients associated with ocular lesions and SVD . The same mutation was noted in our case . Some of the COL4A1 disease‐causing mutations identified include COL4A1 G498V, COL4A1 G519R, COL4A1 G528 associated with hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome, COL4A1 G562E associated with SVD, COL4A1 G720D with intracerebral hemorrhage and ocular dysgenesis, COL4A1 G755R with cerebrovascular disease, COL4A1 G1236R and COL4A1 G1580R with porencephaly .…”

“…Ocular manifestations in COL4A1 ‐related disorders include bilateral retinal arterial tortuosity, congenital cataract and anterior segment anomaly of Axenfeld–Rieger type in which anterior chamber abnormalities can be seen comprising of congenital iris abnormalities, posterior embryotoxon, microcornea, increased intraocular pressure, and glaucoma . The ocular lesions are often associated with cerebral SVD and porencephaly …”

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

“…She was otherwise a 18 Cerebrovascular manifestations occur from fetal life onward and their severity may range from small vessel brain disease to fatal cerebral hemorrhage. 19 Ocular abnormalities are variably observed and may include pediatric cataract, ASD, or retinal arterial tortuosity. 20 Notably, a family with isolated pediatric cataract has been reported.…”

A Novel COL4A1 Mutation in a Neonate with Intrauterine Intraventricular Hemorrhage and Porencephaly

“…Even in the absence of any cerebrovascular hemorrhage, some patients with COL4A1 mutations display leukoencephalo pathy, calcification, or cerebral micro bleeding. These silent defects might cause physical dis ability and global developmental delay 16) .…”