The Neurological Channelopathies

1. The Neurological Channelopathies Dimitri Kullmann Institute of Neurology UCL

2. 1: Disorders of muscle

3. 2: Disorders of neurons

4. 3: Disorders of glial cells

5. Cooper & Jan 1999

6. Voltage-gated channels

7. Na+ channelopathies

8. Skeletal muscle Na+ channel NaV1.4

9. Na+ channel activation, deactivation and inactivation

11. Potassium-aggravated myotonia mutations affect single channel behaviour

12. Skeletal muscle Na+ channel NaV1.4 mutations • Most muscle Na+ channelopathies are: • dominantly inherited • associated with high serum [K+] • caused by impaired fast inactivation (mutations around III-IV linker, or cytoplasmic receptor) • Mild impairment of fast inactivation  myotonia • Severe impairment  Na+ channels enter slow inactivated state • Hypokalaemic periodic paralysis can result from loss of function of Na+ channel (mutations cluster in S4 voltage sensor)

14. Computer model of myotonia and paralysis Cannon, 1997

15. Na+ channelopathies

16. GEFS+: Generalised epilepsy with febrile seizures plus

17. CNS Na+ channel mutations associated with GEFS+

18. SCN1B mutation interferes with the ability of the  subunit to modulate channel gating Wallace et al (1998)

19. GEFS+-associated NaV1.1 mutations also interfere with fast inactivation Lossin et al (2002)

20. Remaining questions for Na+ channel mutations: • How do S4 mutations associated with hypokalaemic periodic paralysis cause membrane depolarisation and  [K+]? • What triggers seizure onset? • Why do some SCN1A mutations that affect other kinetic parameters cause epilepsy • Why is the phenotype so variable within GEFS+ families? • How do truncation mutations of SCN1A cause severe myoclonic epilepsy of infancy (SMEI)?

21. Ca2+ channelopathies

22. 2   1 Ca2+ channel structure

23. Skeletal muscle Ca2+ channel mutations

24. Hypokalaemic periodic paralysis-associated mutations of CaV1.1 reduce Ica, shift voltage sensitivity and slow channel kinetics … but why do they result in depolarisation and episodic paralysis? Morrill & Cannon (1999)

25. Malignant hyperthermia and central core disease are associated with mutations of the ryanodine receptor gene RYR1 (CACNA1S mutations also found in MH)

26. Ca2+ channelopathies 4 subunit mutations also reported in association with epilepsy/episodic ataxia

27. Familial hemiplegic migraine: • Severe, autosomal dominant, associated with reversible weakness • Other associations: progressive cerebellar ataxia, coma, neuromuscular junction defect • Molecular pathogenesis: •  or  current density • left-shifted activation threshold

28. Familial hemiplegic migraine: mouse knock-in model P/Q-type Ca2+ channel-dependent neuromuscular transmission  van den Maagdenberg et al, 2004

29. Familial hemiplegic migraine: mouse knock-in model Cortical spreading depression  van den Maagdenberg et al, 2004

30. Episodic ataxia type 2 Prolonged attacks of cerebellar inco-ordination Associated with progressive cerebellar degeneration Autosomal dominant

31. EA2: premature stops, splice-site mutations, mis-sense mutations non-functional channel Jouvenceau et al (2000)

32. Spinocerebellar ataxia type 6 Site of CAG expansion Normal allele: 4-18 SCA6: 19-30 • Disease mechanism: • nuclear protein deposition? • altered channel density and activation threshold also reported

33. Cl- channelopathies

34. ClC1: • homodimeric with two pores, • major determinant of resting membrane potential

36. Muscle fibres from myotonic goats: • repetitive discharges in response to small depolarising currents • myotonia results from loss of channel function Membrane potential Control Myotonic Adrian & Bryant (1974)

37. Dominant or recessive behaviour of CLCN1 mutations is reflected in co-expression studies Dominant Recessive Kubisch et al (1998)

38. Loss of function CLCN2 mutations in idiopathic generalised epilepsy Haug et al (2003)

39. K+ channelopathies

40. Muscle K+ channelopathies Loss of function  dominant negative effect Association with hypokalaemia poorly understood

42. Episodic ataxia type 1 Brief attacks of cerebellar incoordination Associated with neuromyotonia Autosomal dominant

43. Pore loop Extracellular + Intracellular N C Kinetics Permeation K+ Targeting Translation Assembly EA1: Loss of function Variable dominant negative effects

44. KCNQ2 mutation in BFNC causes decreased IK Biervert et al (1998)

45. KCNQ2+KCNQ3 heteromultimers make IM channels Wang et al (1998) 25% reduction in IM current is sufficient to cause disease (Schroeder et al (1998)

46. Nicotinic receptor channelopathies

47. Nicotinic receptor at the neuromuscular junction • Nicotinic receptor mutations affect: • channel opening • receptor occupancy • expression of the fetal  subunit

48. Slow channel syndrome Sine et al (1995)

49. Fast channel syndrome can be associated with congenital joint deformities (arthrogryposis multiplex) Brownlow et al (2001)

50. Nicotinic receptorchannelopathies