Unraveling the Disease Mechanisms in Progressive Myoclonus Epilepsy, EPM1

Principal Investigators: ANNA-ELINA LEHESJOKI1, REETTA KÄLVIÄINEN2
Researcher: Saara Tegelberg1

1Folkhälsan Institute of Genetics and Neuroscience Center, University of Helsinki, 2Kuopio University Hospital

The topic of research in our consortium is an autosomal recessive epilepsy syndrome, progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). It is characterized by onset at 6-18 years of age, invalidating action myoclonus, tonic-clonic epileptic seizures and progressive ataxia. Mutations in the gene encoding cystatin B (CSTB) underlie EPM1. The physiological function of CSTB and the molecular pathogenesis of EPM1, however, remain to be elucidated. Preliminary analysis of the Cstb-/- knock-out mouse model for EPM1 suggests that CSTB is needed for maintaining neuronal architecture and size and that CSTB can prevent apoptotic death of specific neuronal cells. The long-term goal of our research is to understand the molecular pathogenesis of EPM1, which will allow the development of novel treatments for the disease. Within this consortium, we work towards this goal with four specific aims. First, we aim to characterize the variability in the clinical phenotype and individual course of the disease in Finnish EPM1 patients by a comprehensive clinical and neuropsychological evaluation. These studies include electrophysiological and brain magnetic imaging analyses, which will ultimately give new insight into to the pathophysiological mechanisms in EPM1. Second, utilizing the relevant target tissues of the EPM1 mouse model, we will use genome-wide approaches to identify metabolically linked genes and proteins that are associated with EPM1 pathogenesis. Third, we will characterize the role of CSTB in neuronal survival in cellular and tissue models of EPM1. Finally, we will combine neuroanatomical, neurophysiological and magnetic imaging data of the mouse brain to get insight into the anatomical and cellular basis of altered neuronal excitability in EPM1. To approach these goals, we have created a network of collaborations that will bring special expertise to our consortium.

Contact: anna-elina.lehesjoki(at)helsinki.fi,tel. +358 9 191 25072