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Progressive myoclonus epilepsies – on the way to precision medicine?
Published on 2017-09-22935 Views
During the past two decades, significant progress has been made in understanding the molecular genetic basis of human genetic diseases, the current next-generation sequencing technologies allowing gen
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Presentation
Progressive Myoclonus Epilepsies – on the way to precision medicine?00:00
Outline02:56
Progressive Myoclonus Epilepsies PMEs03:44
Unverricht-Lundborg disease (ULD / EPM1): clinical features05:48
Evolution of gene identification07:41
PME genes: neuronal ceroid lipofuscinoses10:33
PME genes: other10:54
Diagnostic yield in large PME series11:08
Unsolved PME Cases: Phase 1 Whole Exome Sequencing (WES)12:00
Variant analysis strategy12:45
Unsolved PME Cases: Phase 1 WES13:39
A recurrent missense mutation in KCNC1 is a new cause of PME - 115:22
A recurrent missense mutation in KCNC1 is a new cause of PME - 216:55
Arg320His has a dominant-negative loss-offunction effect on Kv3.1 K+ channel function - 117:47
Arg320His has a dominant-negative loss-offunction effect on Kv3.1 K+ channel function - 218:05
The Arg320His mutation in KCNC1 defines a new PME syndrome: MEAK18:51
MEAK has a clinical presentation similar to Unverricht-Lundborg disease19:41
PME genes (EPM designation in OMIM)20:30
Potential therapy for KCNC1 associated PME?20:39
PME genetics – before and after WES phase 122:14
Molecular genetic diagnosis of PMEs - 123:09
Molecular genetic diagnosis of PMEs - 224:37
EPM1: loss-of function mutations in the CSTB gene25:26
Homozygous stop/fs mutations in CSTB associated with a neonatal onset severe encephalopathy27:28
EPM1: CSTB protein - 128:52
EPM1: CSTB protein - 230:12
EPM1: CSTB protein - 331:17
Cstb-/- mouse model for EPM131:45
Cystatin B deficiency sensitizes neurons to oxidative stress32:56
Cathepsin B mediates oxidative stress-induced neuronal death downstream of Cystatin B33:46
Cystatin B deficiency disrupts cerebellar redox homeostasis34:54
Disease progression in the Cstb-/- mouse model for EPM1 - 136:34
Disease progression in the Cstb-/- mouse model for EPM1 - 236:48
Disease progression in the Cstb-/- mouse model for EPM1 - 337:10
Disease progression in the Cstb-/- mouse model for EPM1 - 437:15
Disease progression in the Cstb-/- mouse model for EPM1 - 537:19
Disease progression in the Cstb-/- mouse model for EPM1 - 637:34
Disease progression in the Cstb-/- mouse model for EPM1 - 738:07
Early microgliosis in Cstb-/- mice38:12
Altered functional properties of Cstb-/- microglia in vitro - 138:12
Altered functional properties of Cstb-/- microglia in vitro - 238:53
Increased apoptosis and compromised phagocytosis in hippocampus of P14 Cstb-/- mice39:04
Cstb-/- mouse microglia are polarized towards the pro-inflammatory phenotype40:05
Increased expression of inflammatory markers in Cstb-/- mouse cortex40:24
Neuroinflammation in Cstb-/- mouse brains40:36
Elevated pro-inflammatory cytokine levels in Cstb-/- mouse serum41:07
Cstb-/- mice are more sensitive to LPS-induced lethal endotoxemia42:02
LPS induces secretion of pro-inflammatory cytokines in serum of Cstb-/- mice42:34
Altered inflammasome and IL-1β pathway activation in Cstb-/- macrophages43:09
Is EPM1 an autoinflammatory disease?43:43
Alterations in GABAergic signaling in cerebellum of pre-symptomatic Cstb-/- mice44:04
Hypothesis - 145:11
Hypothesis - 245:21
Hypothesis - 345:22
Hypothesis - 445:23
Hypothesis - 545:23
Hypothesis - 645:37
Hypothesis - 745:39
Hypothesis - 845:44
Hypothesis - 945:46
Hypothesis - 1045:51
Hypothesis - 1145:56
Unifying pathophysiological mechanisms? EPM1 and MEAK46:04
Hopes for Precision Medicine Approaches46:50
Conclusions48:04
Acknowledgements48:59