Der Einfluss genetischer Faktoren auf kognitive Fähigkeiten in der Juvenilen Myoklonischen Epilepsie
Zusammenfassung der Projektergebnisse
Juvenile myoclonic epilepsy (JME) is a highly heritable idiopathic generalised epilepsy syndrome, characterised by myoclonic jerks, which are frequently triggered by cognitive effort. By definition, clinical brain scans are normal. However, recent studies reported functional and structural abnormalities within the medial and dorsolateral prefrontal cortex and thalami in JME patients. Findings are corroborated by reports of impaired frontal lobe cognitive functions in patients, as well as their unaffected siblings. In a recent functional magnetic resonance imaging study at our centre, abnormal co-activation of the motor cortex and increased functional connectivity between the motor system and prefrontal cognitive networks during a working memory paradigm were reported in JME. This may provide a disease mechanism for both cognitively triggered jerks and impairment of cognitive functions. Imaging studies in similarly presumed neurodevelopmental and heritable diseases, such as autism or schizophrenia, have identified intermediate phenotypes, so called endophenotypes, which are closer related to the genotype than the final phenotype, and thus may help to identify disease culprit genes in polygenetic disorders and at the same time may help to understand genetically determined disease underlying mechanisms. In this project at the UCL Institute of Neurology, we employed the same functional MRI working memory task in 15 unaffected siblings of 11 juvenile myoclonic epilepsy patients and compared functional magnetic resonance imaging activations with 20 age and gender matched healthy controls. Similarly to patients, unaffected siblings show abnormal motor system co-activation with cognitive networks during the task, as well as increased taskrelated functional connectivity between motor and prefrontal cognitive networks. Surprisingly, activation patterns between the disease-affected patients and their unaffected siblings did not differ significantly. This study controls for the impact of seizures and medication by studying unaffected siblings. Therefore, our finding suggests that altered motor system activation and functional connectivity represents a potential underlying mechanism for impairment of frontal lobe functions in both, patients and unaffected siblings. In addition, it most likely reflects an imaging endophenotype of juvenile myoclonic epilepsy that represents the shared underlying risk of disease-affected and unaffected siblings. The results of this study are an important step forward to further understand diseaseunderlying mechanisms in juvenile myoclonic epilepsy. Similarly to genetic imaging studies in schizophrenia, this imaging endophenotype of JME may be used in the future as a quantitative trait in a probabilistic approach for gene discovery in conjunction with genomewide association studies and may increase the yield of genetic studies for identifying culprit genes for JME, which so far has proven difficult.
Projektbezogene Publikationen (Auswahl)
- Risk-taking behavior in juvenile myoclonic epilepsy. Epilepsia 2013;54(12):2158-65
Wandschneider B, Centeno M, Vollmar C, Stretton J, O'Muircheartaigh J, Thompson PJ, Kumari V, Symms M, Barker GJ, Duncan JS, Richardson MP, Koepp MJ
(Siehe online unter https://doi.org/10.1111/epi.12413) - Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain Volume 137, Issue 9, 1 September 2014, Pages 2469–2479
Wandschneider B, Centeno M, Vollmar C, Symms M, Thompson PJ, Duncan JS, Koepp MJ
(Siehe online unter https://doi.org/10.1093/brain/awu175)
