Potassium Channelopathies: Consequences and Impact on Treatment December 4, 2010

Transcription

1 Potassium Channelopathies: Consequences and Impact on Treatment December 4, 2010 Karen S. Wilcox, Ph.D. Department of Pharmacology & Toxicology Anticonvulsant Drug Development Program University of Utah American Epilepsy Society Annual Meeting

2 Disclosure No Conflicts to Disclose Funding: NINDS: RC1 NS (KSW & JAW), NS41673 (KSW), NS44210 (HSW); Dumke Foundation (KSW), Primary Children s Research Foundation (KSW) American Epilepsy Society Annual Meeting

3 Potassium Channelopathies and Epilepsy Variety of seizure disorders and syndromes Inherited channelopathy De novo channelopathy Acquired or transcriptional channelopathy Loss AND gain of function mutations

4 Inward Rectifier Family KCNJ1 6, 8 16 KCNJ10 EAST Syndrome KCNJ11 DEND Syndrome 6 Transmembrane K + Channels Twin Pore Channels KCNK1 7, 9 18 S1 S0 S2 S3 S4 S5 S6 Voltage Activated K + Channels KCNN1 4 Ca 2+ Activated K + Channels KCNT1 2 Na + Activated K + Channels Shaker related Family KCNA1 7, 10 (Shaker) KCNB1 2 (Shab) KCNC1 4 (Shaw) KCND1 3 (Shal) KCNA1 Episodic Ataxia 1, Partial Seizures, SUDEP? KCND2 Temporal Lobe Epilepsy Eag related family KCNH1 8 KvLQT related family KCNQ1 5 KCNQ1 LQTS/SUDEP? KCNQ2, KCNQ3 Benign Familial Neonatal Convulsions Slo related family KCNMA1 Ca 2+ and Voltage Activated Channels KCNU1 ph sensitive channel KCNMA1 Generalized Epilepsy and Paroxysmal Dyskinesia Brenner and Wilcox, in press

5 Mutations in KCNQ2 and KCNQ3 Benign Familial Neonatal Convulsions (BFNC) S1 S0 S2 S3 S4 S5 S6 Generalized and partial seizures Onset usually within first few days and can be as late as 13 months Incomplete penetrance Can also occur de novo Spontaneous resolution (with or without anticonvulsant treatment) Normal psychomotor skill, development, and learning ability in most, but not all patients Greatly increased risk of developing adult onset epilepsy BENIGN???? Seizure susceptibility gene? (Singh et al, Charlier et al*) (Biervert et al, Schroeder et al, Lerche et al)

6 KCNQ2 and KCNQ3 Subunits Co Assemble to Form the M channel Unique channel that is gated by voltage and GPCRs Muscarinic ACh receptor activation will close channel and depolarize cell Helps set and maintain resting membrane potential Influences action potential firing rates Mechanism of action for retigabine (Ezogabine ) Cooper, E. C. et al. Arch Neurol 2003;60:

7 69 Mutations in KCNQ2 Have Been Identified in Families with BFNC S105del3 E119G Q78delC K69insC K21delGGTG M1V,M1T,Del E1 E5 S122L 129splice Del E3 E11, Dup E3 E12 R153del1 195insT,195del10insA A196V L243F R207W R207Q M208V D212G R214W H228Q 562ins5bp Singh et al., in Animal Models of Epilepsy: Methods and Innovations, Ed. S. C. Baraban, (2009) V250G S247W S247X N258S Del E9 3'utr P387insC 398del2 405splice P410fs12X 416splice R581X G271V W269X Y284C 283insGT A306T Q323X L339R 372 splice R353G Del E9 E17 T359K R448X Del E13 E15 E509splice E526D 522del13 544splice R553Q K554N 653del1 644delT R588splice L637R V589X 709delT R333Q,R333W 867ins GGGCC 866delG

8 Only Four Mutations Have Been Identified in the KCNQ3 Gene in Families with BFNC Singh et al., in Animal Models of Epilepsy: Methods and Innovations, Ed. S. C. Baraban, (2009)

9 KCNQ2 Is Highly Concentrated at the Axon Initial Segment (AIS) Pan et al., J Neurosci 26: , 2006

10 Neurons in Mice With a Kcnq2 Haploinsufficiency Are More Excitable B6 control Szt1 S1 S0 S2 S3 S4 S5 S6 normalized frequency Szt1 control B6 control interstimulus interval number * Otto et al, J.Neurosci., (2006)

11 Retigabine Is Not as Effective in Mice With a Kcnq2 Haploinsufficiency B6 wildtype Szt1 S1 S0 S2 S3 S4 S5 S6 10 um RGB control 150 ms 15 pa 10 um RGB control 150 ms 15 pa 140 pa 400 ms Otto et al, J.Neurosci., (2006)

12 Retigabine Is Less Potent In Mice With a Kcnq2 Haploinsufficiency Otto et al, Epilepsia, (2004)

13 Therapeutic Implications of Mutations in KCNQ2 and KCNQ3 Increased seizure susceptibility Are patients at risk following insults? Altered pharmacology has implications for clinical trials The right compound for the right patient: pharmacogenomics

14 Potassium Channelopathies and Sudden Unexplained Death in Epilepsy (SUDEP) KCNQ1 (Kv 7.1): expressed in heart and CNS KCNA1 (Kv 1.1): expressed mainly in CNS S1 S2 S3 S4 S5 S6 S0

15 SUDEP Patients with epilepsy die unexpectedly at a rate up to 24 times greater than the general population SUDEP may account for up to 18% of all deaths in patients with epilepsy AES & EFA Joint Task force recommends discussing SUDEP with patients and families Clinical risk factors for SUDEP: early onset intractable epilepsy males, aged years generalized seizures exposure to multiple anticonvulsant medications poor compliance with medications

16 Potential Mechanisms Hypothesized to Result in SUDEP Intrinsic cardiac problem, e.g. LQTS mutations Cardiac failure mediated by autonomic dysregulation Apnea due to central respiratory depression

17 Loss of Function Mutations in KCNQ1 Result in Long QT Syndrome and Cause Seizures in Mice T311I S1 S2 S3 S4 S5 S6 S0 < A340E Slow delayed rectifier potassium current (I KS ) in human cardiac myocytes Not thought to be expressed in CNS

18 KCNQ1 Potassium Channels and Seizures in Mouse Forebrain Goldman et al., Sci Trans Med, 2009

19 KCNQ1 Potassium Channels in Mouse Vagal Nerve Nuclei n. X n.xi Cortical Discharges Often Trigger Cardiac Asystole Goldman et al., Sci Trans Med, 2009

20 KCNQ1 Potassium Channel Mutations in Heart and Brain Hundreds of LQTS mutations have been identified for KCNQ1 Loss of function Seizure disorders have been observed with greater than expected frequency in patients with LQTS Excessive autonomic activity can influence cardiorespiratory function T311I S1 S2 S3 S4 S5 S0 S6 < A340E

21 Loss of Function Mutations in KCNA1 (Kv1.1) Can Result in Epilepsy T226R and A242P mutations in KCNA1 result in partial epilepsy reduce expression or trafficking of channels Kcna1 knockout mice have seizures and die prematurely Enhanced excitability related to axonal repolarization and propagation T226R A242P S1 S2 S3 S4 S5 S0 S6

22 EEG ECG Recordings Reveal Interictal and Ictal Cardiac Abnormalities in Kcna1 / Glasscock, E. et al. J. Neurosci. 2010;30:

23 KCNA1 Is Present In Vagus Nerve Axons: Enhanced Parasympathetic Activity in Knockout Mice? Glasscock, E. et al. J. Neurosci. 2010;30:

24 Therapeutic Implications of Potassium Channelopathies and SUDEP Screen for heart rhythm disorders to reduce the risk Follow up with genetic screening and pharmacotherapy where indicated

25 KCNJ11 (K IR 6.2; K ATP ) Channelopathy: Delay, Epilepsy, and Neonatal Diabetes (DEND) Syndrome Gain of function mutation Neonatal onset diabetes Developmental delay Neonatal seizures Infantile spasms Intractable seizures Shimomura, K. et al. Neurology 2007;69:

26 K ATP Gating Shimomura, K. et al. Neurology 2007;69:

27 Treatment for DEND with Glibenclamide Binds to the SUR receptor Closes the channel Depolarizes cells in pancreas and allows insulin release Seizures come under control Development resumed J Physiol (2006) Shimomura, K. et al. Neurology 2007;69:

28 Potassium Channelopathies: Consequences and Impact on Treatment A large number of familial and de novo channelopathies in potassium channels underlie, or are associated with, many types of epilepsy Both loss of function and paradoxically, gain of function mutations: Missense/nonsense Splicing mutations Small and gross deletions Small and gross insertions Indels

29 Potassium Channelopathies: Consequences and Impact on Treatment Recent advances in genetics and animal models provide information to guide treatment Reduce risk of SUDEP Identify seizure susceptibility genes Many forms of epilepsy likely to be multifactorial Novel drug targets and personal pharmacogenomics Basic mechanisms underlying epilepsy

30 ARS question to be placed here (if applicable)