Inherited erythromelalgia mutations in Na v 1.7

Transcription

1 Inherited erythromelalgia mutations in Na v 1.7 I II III IV A863P N F216S S241T N395K L1 I848T L858F L858H L2 F1449V L3 C Mutation V 1/2 Activation V 1/2 Inactivation Slow Inactivation Deactivation Ramp Current Repriming Ref F216S mv 0 Enhanced Slower (~2x) Larger (~2x) Unchanged Choi et al 2006 S241T mv 0 Enhanced Slower (~4x) Larger (~5x) Unchanged N395K -7.7 mv 0 Impaired Slower ND ND I848T mv 0 Impaired Slower (~3x) Larger (3X) ND L858H mv 0 Enhanced Slower (~10x) Larger (4.5X) ND Lampert et al 2006 Sheets et al SFN 2006 (727.10) Cummins et al 2004 Cummins et al 2004 L858F mv +3.0 mv Unchanged Slower (~18x) Larger (4.5X) Faster Han et al 2006 A863P -8.0 mv +10 mv Steep VD Slower (~6x) Larger (~10x) Faster F1449V mv +4.3 mv Enhanced Unchanged Unchanged Faster (~3X) Harty et al SFN 2006 (727.9) Dib-Hajj et al 2005

2 42 y.o. male with history of RRMS 28 y.o.: Hemibody numbness, followed by optic neuritis, bilateral leg numbness, bladder dysfunction: all resolved MRI: cerebral and spinal cord demyelination 40 y.o.: Tonic-clonic seizure; started on phenytoin 100 mg TID Sl. Spasticity. Rebif started 42 y.o.: Fell into Medicare "donut hole". Unable to afford medications. DC'ed phenytoin, Rebif Two weeks later: Found unresponsive after apparent seizure Admitted comatose to ICU, awoke over 1 wk with paraparesis, urinary sx MRI: increased, extensive bihemispheric demyelination Rebif, phenytoin restarted Persistent spastic ataxic gait, urinary dysfunction, memory difficulties

3

4 Na V 1.7 and Na V 1.8 accumulate in injured axon tips in Painful Human Neuromas Black et al, Annals of Neurology, 2008

5 Mean Firing Frequencey (Hz) A C AP A863P 350 pa 310 pa 120 pa 95 pa 0 mv 0 mv 300 pa 90 pa 20 mv 20 mv 15 ms 20 ms B RMP -55 1x threshold D RMP -49 1x E AP 2x 2x x -50 3x Current Step (pa)

6 F216S 3 5 I N395K II III IV 7 A863P I136V 8 N S241T L1 12 L858F L858H 11 I848T 16 P610T L F1449V L3 24 hna 1.7 v C

7 Na V 1.7 and Na V 1.8 are Up-regulated in models of Acquired Inflammatory Pain control Na v 1.7 carrageenan control carrageenan A B A B

8 DRG neurons express multiple Na channels I II III Na6 hne/pn1 SNS NaN NaG NaG(S)

9 Yale University School of Medicine Center for Neuroscience & Regeneration Research of Yale University, VA Medical Center, West Haven, CT A Collaboration of the Paralyzed Veterans of America and United Spinal Association with Yale University Harnessing the molecular revolution to preserve and restore function after injury to the brain and spinal cord Established 1986

10 I am 25 years old, tetraplegic (C5) after a ski accident. And I have constant burning pain. On the internet I read about research. I'd like to know if I can keep my dream of taking some steps and living without pain some day. Yours truly E..

11 Na V 1.7 and Na V 1.8 are important in Acquired Pain Joel Black, PhD Ted Cummins, PhD Sulayman Dib-Hajj, PhD Collaborators (Human Neuromas): Troels Jensen, MD,PhD (Denmark) Lone Nikolajsen, MD, PhD (Denmark) Shujun Liu, MA Andy Hudmon, PhD Jin Choi, PhD Steve Waxman, MD, PhD

12 M.C. Previously healthy female accountant 22 y.o.: Optic neuritis. VA 20/20 20/200 Remission p 4 wks. VA 20/20 24 y.o.: Diplopia, slurred speech, face numbness Remission: nearly full recovery p 5 wks 28 y.o.: Numbness, weakness of legs Numbness resolves. Weakness persists 29 y.o.: Persistent, unpleasant paraesthesia in legs 31 y.o.: Trigeminal neuralgia. Rx: Carbamazepine 33 y.o.: Intention tremor, cerebellar ataxia

13 Firing Frequency (Hz) I/Imax G/Gmax I/Imax B1 B2 B3a 1nA 10ms V 1/2,fast-inact -69.5±1.7mV -68.8±1.4mV V 1/2,act -22.9±1.6mV -23.0±1.5mV V 1/2,slow-inact -62.0±1.7mV -61.6±1.4mV B4 RMP (mv) -55.8±1.5; n=24 (-57.5±1.3; n=24) =+1.7 Threshold (pa) 94±12; n=24 (131±21; n=24) =-28% B Voltage (mv) 2.9 ± ± = 1.8x B3b B Voltage (mv) 250pA 20ms 1.34 ± 2% 5/25 (20%) 1.65 ± % 13/27 (48%) Input Current (pa)

14 Firing Frequency (Hz) I/Imax G/Gmax I/Imax A1 A2 A3 2nA 2ms A4 A5 2.8 ± A610 RMP (mv) -50.5±1.4; n =23 (-55.4±1.2; n=32) =+4.9 Threshold (pa) 106±14; n=23 (172±18; n=32) =-38% V -75.0±1.3mV -74.6±1.1mV Voltage (mv) 5.8 ± 1.2 = 2.1x V -25.0±mV -25.4±1.3mV V -63.5±1.6mV -57.7±2.0mV Voltage (mv) A7 7/3023 ; % (/; 2346 %) =+17% Input Current (pa) 2.8 ± 0.7 Hz

15 APs/500 ms RMP (mv) Current Threshold (pa) I/Imax G/Gmax I/Imax A1 A2 A3a 2nA 2ms V½,fast-inact -69.5±1.7mV -68.8±1.4mV V½,act -22.9±1.6mV -23.0±1.5mV V ½,slow-intact -62.0±1.7mV -61.6±1.4mV A A Voltage (mv) A3b A Voltage (mv) 250pA 20ms 1.34± 2% 5/25 (20%) 1.65± % 13/27 (48%) Stimulus (pa)

16 RMP (mv) Current Threshold (pa) APs/500 ms I/Imax G/Gmax I/Imax A1 A2 A3 2nA 2ms V ½,fast-inact -75.0±1.3mV -74.6±1.1mV V ½,act -25.0±mV -25.4±1.3mV V ½,slow-intact -63.5±1.6mV -57.7±2.0mV Voltage (mv) A4 A5 A A7 Voltage (mv) =+17% Stimulus (pa) 7/30; 23% (2/3; 6%) 2.8 ± 0.7 Hz

17

18 Small Fiber Neuropathy Dysfunction of small myelinated and unmyelinated nerve fibers: Burning pain (feet > hands) Autonomic sx (orthostatic hypotension, impotence, palpitations etc) Diagnosis: Normal neurol. exam (DTR s, Vibr. Sensation, Muscle Str.) EMG, NCV: no abnormalities Diagnosis confirmed by: Reduced IENFD on Biopsy Quant. Sensory Testing (warm sensation, cold sensation, heat pain)

19 Voltage-gated Na Channels Na channels are diverse Multiple genes, different properties, selective expression Na channel expression is dynamic In both normal and injured neurons Mis-expression of Na channels can cause signs and symptoms Some Na channel subtypes represent therapeutic targets