Central nervous system malformations and epilepsy in children : genetic, imaging, and clinical aspects

Malformations of cortical development frequently lead to neurodevelopmental disabilities and epilepsy in children. Nevertheless, comprehensive prevalence data based on population studies are scarce. The objective of this thesis was to expand our knowledge of the genetic causes of malformations in cortical development using new genetic methods, relate these findings to imaging and to clinical phenotypes, and reveal the prevalence and incidence rates of polymicrogyria in a population-based paediatric cohort.

This thesis comprises three study populations with brain malformations: 86 children with various brain malformations and drug-resistant epilepsy in study I; 20 individuals with lissencephaly spectrum malformations and epilepsy in study II; and 109 children with polymicrogyria in studies III and IV.

In all studies, CT and MRI scans underwent re-evaluation, and malformations were classified according to the current classification systems. Clinical data were collected from medical records. Molecular analysis using array-based comparative genomic hybridization in study I, and next generation sequencing in studies II–IV, were performed in cases without a known aetiology. Genetic, imaging, and clinical correlations were analysed. The prevalence and yearly incidence were calculated for polymicrogyria.

Pathogenic structural variants were detected in 7 of 76 (9.2%) genetically tested children with various brain malformations and epilepsy. Among the included 86 children, 11.6% had lissencephaly spectrum malformation and 18.6% polymicrogyria. Pathogenic structural variants were disclosed in 10% of the lissencephaly spectrum group, and in 20% of the polymicrogyria group.

A molecular aetiology was uncovered in all 20 individuals with lissencephaly spectrum malformation in study II. The most prevalent genetic findings were variants in PAFAH1B1 or microdeletions of 17p13.3, involving PAFAH1B1. Posterior predominant pachygyria with thick cerebral cortex was the most common imaging finding.

In studies III and IV, a population-based paediatric cohort with polymicrogyria was analysed. The prevalence was 2.3 per 10,000 children, and the annual incidence rate was 1.9 cases per 10,000 person-years. A confirmed or presumed genetic cause was revealed in 32% of the total cohort, and in 39% of those who underwent genetic testing. In addition, congenital infection was diagnosed in 4.5% of children, and in 5.5% the aetiology was assumed to be vascular. The classification of polymicrogyria based on the pattern indicated that polymicrogyria with periventricular nodular heterotopia was the most prevalent condition, accounting for 24% of all cases, followed by perisylvian polymicrogyria, which accounted for 21%. Epilepsy occurred in 54% of cases.

In conclusion, the use of next generation sequencing significantly increases the diagnostic yield in malformations of cortical development. The cause of lissencephaly spectrum malformation was possible to disclose in all individuals in our cohort. We could demonstrate a confirmed or strongly suspected aetiology in 42% of children with polymicrogyria. Furthermore, our results indicate that epilepsy has a stronger correlation with the genetic cause of polymicrogyria than to its distribution. Finally, we performed the first study on the prevalence and incidence of polymicrogyria in a population-based paediatric cohort.

List of scientific papers

I. Copy number variations in children with brain malformations and refractory epilepsy. Wincent J*, Kolbjer S*, Martin D, Luthman A, Åmark P, Dahlin M. Anderlid BM. Am J Med Genet A. 2015 Mar; 167 A(3):512–23. *authors contributed equally to the study.
https://doi.org/10.1002/ajmg.a.36886

II. Lissencephaly in an epilepsy cohort: Molecular, radiological and clinical aspects. Kolbjer S, Martin DA, Pettersson M, Dahlin M*, Anderlid BM*. Eur J Paediatr Neurol. 2021 Jan 8;30:71–81. *authors contributed equally to the study.
https://doi.org/10.1016/j.ejpn.2020.12.011

III. Polymicrogyria: epidemiology, imaging, and clinical aspects in a population-based cohort. Kolbjer S, Martin Muñoz DA, Örtqvist AK, Pettersson M, Hammarsjö A, Anderlid BM*, Dahlin M*. Brain Commun. 2023; 5(4):fcad213. *authors contributed equally to the study.
https://doi.org/10.1093/braincomms/fcad213

IV. Genetic-neuroimaging correlations in polymicrogyria: Precision diagnosis through massive parallel sequencing in a Swedish population-based cohort. Kolbjer S, Martin Muñoz DA, Pettersson M, Hammarsjö A, Taylan F, Nordgren A, Dahlin M*, Anderlid BM*. *authors contributed equally to the study. [Manuscript]