Focal cortical malformations in children with early infantile epilepsy and PCDH19 mutations: case report
Mary Kurian1, Christian M Korff1, Emmanuelle Ranza2
1Pediatric Neurology Unit, Child and Adolescent Department, University Hospitals, Geneva, Switzerland.
Insights
Protocadherin 19 (PCDH19) gene variants are linked to early infantile epilepsy and cortical malformations in girls. Molecular testing for PCDH19 is recommended for early-onset, drug-resistant epilepsy with fever-sensitive seizures.
Area of Science:
- Neuroscience
- Genetics
- Pediatrics
Background:
- Epilepsy in early infancy can be associated with genetic factors and structural brain abnormalities.
- Protocadherin 19 (PCDH19) gene variants are implicated in certain epilepsy syndromes, particularly in females.
Observation:
- This case report details five female children with pharmacoresistant epilepsy, early onset in infancy, fever-sensitive seizures, and cognitive impairment.
- All patients exhibited cortical malformations on imaging, confirmed by histology in two cases.
- Genetic analysis revealed pathogenic variants in PCDH19 in four patients and a microdeletion encompassing PCDH19 in one patient.
Findings:
- Pathogenic variants or deletions in PCDH19 were identified in all evaluated patients with early infantile epilepsy and cortical malformations.
- The clinical presentation included early-onset epilepsy, fever sensitivity, clustered seizures, and cognitive deficits.
- Cortical malformations were a consistent finding in this cohort with PCDH19-related epilepsy.
Implications:
- Molecular testing for PCDH19 should be considered in children with early-onset, pharmacoresistant epilepsy, especially those with fever sensitivity and seizure clusters.
- The presence of structural brain lesions should be investigated in patients with identified PCDH19 pathogenic variants.
- PCDH19 gene analysis is valuable in epilepsy surgery evaluations, even when cerebral structural lesions are already detected.
Abstract:
In this case report we assess the occurrence of cortical malformations in children with early infantile epilepsy associated with variants of the gene protocadherin 19 (PCDH19). We describe the clinical course, and electrographic, imaging, genetic, and neuropathological features in a cohort of female children with pharmacoresistant epilepsy. All five children (mean age 10y) had an early onset of epilepsy during infancy and a predominance of fever sensitive seizures occurring in clusters. Cognitive impairment was noted in four out of five patients. Radiological evidence of cortical malformations was present in all cases and, in two patients, validated by histology. Sanger sequencing and Multiplex Ligation-dependent Probe Amplification analysis of PCDH19 revealed pathogenic variants in four patients. In one patient, array comparative genomic hybridization showed a microdeletion encompassing PCDH19. We propose molecular testing and analysis of PCDH19 in patients with pharmacoresistant epilepsy, with onset in early infancy, seizures in clusters, and fever sensitivity. Structural lesions are to be searched in patients with PCDH19 pathogenic variants. Further, PCDH19 analysis should be considered in epilepsy surgery evaluation even in the presence of cerebral structural lesions.
What This Paper Adds:
Focal cortical malformations and monogenic epilepsy syndromes may coexist. Structural lesions are to be searched for in patients with protocadherin 19 (PCDH19) pathogenic variants with refractory focal seizures.
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