A study of incidence, causative factors, symptoms, and prognosis in epilepsy with onset in the first two years of life

Background: The motivation to start this thesis work came from the meetings with infants just having presented with epileptic seizures and from speaking to their parents. I found two issues to be particularly urgent. The first was to give the parents, and myself, an overall map of the situation. A map that had to address questions like: What are the implications of the seizures in this specific infant? What should be done next? What are the alternative future scenarios and their respective probabilities? When the population-based studies in this thesis started, the knowledge-base to answer such questions was poor, studies were few and the numbers of infants studied were small. The second issue concerned the cause of disease in the individual child. For decades the cause of epilepsy has been revealed in only a minority of cases. Especially in severe disease, like drug-resistant epilepsy, not knowing the cause places a heavy psychological burden on the family. In addition, treatment will be symptomatic, not directed at the (unknown) disease mechanisms and often ineffective.

Methods: Two circumstances offered the opportunity to deal with these issues. The Stockholm Incidence Registry of Epilepsy (SIRE) registered all new cases of epilepsy in the Northern Stockholm region from September 2001 and onwards. All children with epilepsy in this area are managed at the Karolinska University Hospital. This provides a population-based perspective, which is the best way to study a disease and all aspects of it including etiology, clinical characteristics, and outcome. The other favorable condition was the development of genetic diagnostics, in particular massively parallel DNA sequencing, where Science for Life Laboratory was very early to establish whole exome and whole genome sequencing for both research and clinical healthcare purposes, in a close collaboration between the Clinical Genomic facility and the Karolinska University Laboratory.

Results: The population-based studies of this thesis include 116 children with onset of epilepsy during the first 2 years of life. A majority of the cases could be assigned to an epilepsy syndrome and have the etiology revealed. Massively parallel sequencing contributed substantially to reveal genetic etiologies. About half of the children were diagnosed with intellectual disability and half of the cases were in seizure remission for 2 years or longer at age 7 years. Type of etiology is the main predictor of outcome. Two new disease genes, closely related and both with a central role in neuronal inhibition-excitation, were uncovered and described as part of the thesis.

Significance: Together with a few other recent population-based studies, this thesis contributes to a firm knowledge-base when managing infants with epilepsy and counselling their parents. The important role of massively parallel DNA sequencing in revealing monogenic etiologies in early onset epilepsy has been clearly shown. In addition to enabling genetic counselling and prenatal diagnostics, the inclusion of genetic diagnostics in the work-up of children with epilepsy, will henceforth further the development of more effective and even curative precision medicine treatments of epilepsy.

List of scientific papers

I. Epilepsy syndromes, etiologies, and the use of next-generation sequencing in epilepsy presenting in the first 2 years of life: A population-based study. Stödberg, T. Tomson, T. Barbaro, M. Stranneheim, H. Anderlid, B. M. Carlsson, S. Åmark, P. Wedell, A. Epilepsia. 2020 Nov;61(11):2486-2499.
https://doi.org/10.1111/epi.16701

II. Outcome at age 7 of epilepsy presenting in the first 2 years of life. A population-based study. Stödberg, T. Tomson, T. Anderlid, BM. Andersson, T. Henry, O. Åmark, P. Wedell, A. [Submitted]

III. Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Stödberg, T⁎. McTague, A⁎. Ruiz, A. J. Hirata, H. Zhen, J. Long, P. Farabella, I. Meyer, E. Kawahara, A. Vassallo, G. Stivaros, S. M. Bjursell, M. K. Stranneheim, H. Tigerschiöld, S. Persson, B. Bangash, I. Das, K. Hughes, D. Lesko, N. Lundeberg, J. Scott, R. C. Poduri, A. Scheffer, I. E. Smith, H. Gissen, P. Schorge, S. Reith, M. E. Topf, M. Kullmann, D. M. Harvey, R. J. Wedell, A#. Kurian, M. A#. Nat Commun. 2015 Sep 3;6:8038. ⁎Shared first authorship, #Shared last authorship.
https://doi.org/10.1038/ncomms9038

IV. SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia. Stödberg, T⁎. Magnusson, M⁎. Lesko, N. Wredenberg, A. Martin Munoz, D. Stranneheim, H. Wedell, A. Neurol Genet. 2020 Jul 2;6(4):e478. ⁎Shared first authorship.
https://doi.org/10.1212/NXG.0000000000000478