Aim of the Study: COL4A1/COL4A2 mutations have been associated with neurologic, renal and ophthalmologic diseases. Aim of this study was to describe the phenotype of drug-resistant COL4A1/COL4A2 associated pediatric epilepsy, by considering clinical, neuroimaging and histological findings, and to discuss pathogenic mechanisms in this condition. Moreover, it was aimed to evaluate epilepsy surgery outcome in affected patients.
Patients and Methods: Retrospective analysis of findings in children with drug-resistant COL4A1/COL4A2 associated epilepsy (in Pat1–3 at t>6 months after epilepsy surgery, in Pat4–9 with conservative treatment) in the Epilepsy Center for Children and Adolescents Vogtareuth.
Results: 9/9 patients showed microcephaly and severe developmental delay. In 2/9 patients, maternal inheritance of COL4A1 mutation was found, in 4/9 de novo COL4A1 or COL4A2 mutation was detected, in 3/9 genetic analysis of the parents was not available. Neuroimaging (MRI) showed in 9/9 patients ventriculomegaly, periventricular white matter abnormalities and cortical changes, in 3/9 patients multiple small hemosiderin depositions indicated past microhemorrhage. Operative outcome was classified as Engel 3a after a two-step surgical approach (resection left t-p-o; hemispherotomy) in Pat1. After multilobar surgery, outcome Engel 3a (Pat2) and after hemispherotomy, outcome Engel Ia (Pat3) were reported. Depending on respective surgical approach, available samples were histologically examined. Focal Cortical Dysplasia IIID with a gliotic scar was observed in Pat1. In Pat2, a mild Malformation of Cortical Development Type II was observed and in Pat3, a blurring of the Gray-White-matter Junction was found.
Discussion: Increased frailty of vessels has been discussed in literature as a cause of cerebral infarctions and bleedings in COL4A1 mutations.The gliotic scar in Pat1, and neuroimaging findings in this cohort demonstrate underlying cerebral lesions. Infarctions or microbleeds during cerebral development can lead to cortical malformations as a possible cause of COL41/COL4A2 associated epilepsy. Up to now, epilepsy surgery has been reported in three COL4A1 patients in literature. In one COL4A2 patient of our cohort, seizure freedom was observed (Pat3), while in Pat1 (COL4A1 mutation) and Pat2 (COL4A2 mutation), seizure outcome was less favourable but neurocognitive improvement was achieved after surgery.
Conclusion: We reported the severe clinical courses in COL4A1/COL4A2 pediatric epilepsy patients. In this cohort, developmental delay and microcephaly were observed. Neuroimaging revealed various cerebral lesions as potential reasons for COL4A1/COL4A2 associated epilepsy. Depending on timing and localisation of the cerebral lesion, different clinical courses are to be expected. Curative or non-curative epilepsy surgery should be considered in severe, drug-resistant focal COL4A1/COL4A2 associated epilepsy.
