Data from: Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease

Objective: To characterize the neurological 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 anti-epileptic 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
co-localized 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 non-specific findings, in particular
periventricular leukoencephalopathy and ventricular asymmetry. Analysis of
fifteen 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. Conclusions
COL4A1/COL4A2 mutations typically cause a severe neurological 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, whilst
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.