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Progressive myoclonus epilepsies – on the way to precision medicine?
Published on Sep 22, 2017923 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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Chapter list
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 (EPM designation in OMIM)09:51
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