brief introduction on channelopathies..... hypokalemic periodic paralysis hyperkalemic peridic paralysis and more...

1. CHANNELOPATHIE
S
Presenter-Dr. Pradeep katwal

2. Channelopathies
CAUSED BY DEFECTIVE ION CHANNEL.

3. ION CHANNELS
•TRANMEMBRANE GLYCOPROTEIN PORES
oCell excitability
oElectrical signaling
•TYPES
 VOLTAGE GATED CHANNEL
 LIGAND GATED CHANNEL

4. Voltage gated channel
Transmembrane potential
Identified according to principle ion
conducted
Concentrated in different regions

5. Voltage-Gated Ion Channels
• The voltage sensor is a region of the protein bearing charged
amino acids that relocate upon changes in the membrane
electric field.
Segments (S5 and S6) and the pore loop
were found to be responsible for ion conduction.
Lipid bilayer
Transmembrane
segment (cylinder)
Voltage sensor Pore
part of the channel
General architecture of voltage-gated channels (Na+ and Ca2+).The “+” or “-“ signs
indicate charges that have been implicated in voltage sensing.

6. Each alpha1subunit has 4 homologous repeat domains, each comprised of
6 transmembrane segments alpha1 modulated by other subunits

7. Figure 3.Structure of Ion Channels.
Panel A shows a subunit containing six transmembrane-spanning motifs, S1
through S6, that forms the core structure of sodium, calcium, and potassium
channels.
.
Panel B shows four such subunits assembled to form a potassium channel.
12/12/2012

8. Action potential

9. STATES OF ION CHANNEL-
CLOSED, OPEN,INACTIVATED

11. Ion Channels and the AP
2.11

12. Ligand gated channels
• Activated by binding to agonist
– Glycine
– Gamma-aminobutyric acid
– Acetycholine

13. Channel Gating Mechanisms
AChR: Proposed gating mechanism
(Unwin, 1995)
Closed Open

14. • Mutation of ion channel can alter
–activation
–ion selectivity
–Inactivation
Abnormal gain of function
loss of function

15. • PHENOTYPIC HETEROGENICITY
• GENETIC HEREROGENICITY

16. Channelopathies
• INHERITED CHANNELOPATHIES
Neurologial channelopathies
Cardiac channelopathies
• AUTOIMMUNE CHANNELOPATHIES
Mysthenia gravis
Lambert-Eaton mysthenic syndrome
Paraneoplastic cerebellar degenaration
Limbic encephalitis

17. Neurological channelopathies

19. HYPOKALEMIC PERIODIC PARALYSIS
MUTATED GENE CALCL1A3 SCN4A
CHROMOSOME 1q31 17q
DEFECTIVE CALCIUM SODIUM
CHANNEL
MODE OF AUTOSOMAL DOMINANT
INHERITENCE
TYPE 1 TYPE 2

20. Hypokalemic Periodic Paralysis
Pathophysiology
• The mutation slows the activation rate of L-type Ca
current to 30% of NormaL
• Reduced RYR1-mediated Ca release from SER
• Reduced calcium current density
• Impaired E-C coupling
• Ca homeostasis change reduces ATP-dependent K
channel current and leads to abnormal depolarization
(Tricarico D et al 1999)
20

21. HYPOKALEMIC PERIODIC PARALYSIS
PREVELANCE 1:100,000
AGE OF ONSET FIRST AND SECOND DECADE OF
LIFE
SYMPTOMS DURING ATTACKS ACUTE ONSELT FLACCID
PARALYSIS
PROXIMAL >>> DISTAL
SYMPTOMS BETWEEN ATTACKS REGAIN FULL STRENGTH
BETWEEN ATTACKS
TRIGGERS HIGH CARBOHYDRATE,HIGH
SALT,
DRUGS- BETA AGONISTS,
INSULIN
REST FOLLOWING PROLONGED
EXERCISE

22. SERUM POTASSIUM LOW
CONCENTRATION
ECG HYPOKALEMIC CHANGES
MUSCLE BIOPSY SINGLE OR MULTIPLE
CENTRALLY PLACED
VACUOLES
NERVE CONDUCTION TEST REDUCED AMPLITUDE OF
ACTION POTENTIAL
ELECTROMYGRAPHY ELECTRICALLY SILENT
GENETIC STUDY CALCL1A3, SCN4A

23. TREATMENT ORAL KCL
SUPPLEMENTATION
KCL VIA INFUSION
DONOT GIVE IN DEXTROSE
PROPHYLAXIS ACETAZOLAMIDE
(125-1000 Mg)
PROGNOSIS USUALLY GOOD
RARE DEVELOPMENT OF
PROXIMAL MYOPATHY
*Never forget to measure the thyroid hormones.

24. • The mechanism of effect of acetazolamide is not discovered.
Acetazolamide produced a mild metabolic acidosis but did not
have a demonstrable effect on total body sodium, total body
potassium, or thyroid function.
• Acetazolamide is the most effective treatment available for
hypokalemic periodic paralysis.

25. HYPERKALEMIC PERIODIC PARALYSIS
MUTATED GENE SCN4A
CHROMOSOME 17q
DEFECTIVE CHANNEL SODIUM
MODE OF AUTOSOMAL
INHERITENCE DOMINANT

26. Pathophysiology
 In hyperKPP, Na+ channels fail to inactivate and
prolonged openings and depolarization result.
 The result is that persistent Na+ currents are
witnessed, the Na+ current is closer to the
maximum, and Na+ diffuses down its gradient into
the cell which results in a depolarization and a more
positive membrane potential.
 Increased extracellular K+ levels worsen the
inactivation

27. HYPOKALEMIC HYPERKALEMIC
PREVELANCE 1:100,000 1:200,000
AGE OF ONSET FIRST AND SECOND FIRST DECADE
DECADE OF LIFE
SYMPTOMS DURING ACUTE ONSELT FLACCID WEAKNESS OF
ATTACKS PARALYSIS PROXIMAL
PROXIMAL >>> DISTAL MUSCLE,SPARING
BULBAR MUSCLE
SYMPTOMS BETWEEN ASYMPTOMATIC ASYMPTOMATIC
ATTACKS
TRIGGERS HIGH CARBOHYDRATE, REST AFTER EXERCISE
HIGH SALT, STRESS
DRUGS-BETA FATIGUE
AGONISTS, INSULIN FOOD HIGH IN
REST FOLLOWING POTASSIUM
PROLONGED EXERCISE
POSTASSIUM TREATMENT PROVOCATIVE TEST
SUPPLEMENTATION

28. SERUM LOW HIGH, NORMAL
POTASSIUM
CONCENTRATION
ECG HYPOKALEMIC HYPERKALEMIC CHANGES
CHANGES CHANGES
MUSCLE BIOPSY SINGLE OR MULTIPLE SMALLER, LESS
CENTRALLY PLACED NUMEROUS
PERIPHERALLY PLACED
VACUOLES VACUOLES
NERVE CONDUCTION TEST REDUCED REDUCED AMPLITUDE OF
AMPLITUDE OF ACTION POTENTIAL
ACTION POTENTIAL
ELECTROMYGRAPHY ELECTRICALLY SILENT ELECTRICALLY SILENT
MYOTONIC DISCHARGE
BETWEEN ATTACKS
GENETIC STUDY CALCL1A3, SCN4A SCN4A

29. TREATMENT MILD SUSTAINED
EXERCISE
LOW POTASSIUM DIET
BETA AGONIST
THIAZIDES
HIGH SUGAR LOAD
CALCIUM GLUCONATE
PROPHYLAXIS ACETAZOLAMIDE ,
MEXILETINE
(125-1000 Mg)

30. • Abstract
 We studied the effect of acetazolamide on plasma potassium
in normals and in two patients with hyperkalemic periodic
paralysis.
 Administration of acetazolamide for 48 hours lowered mean
plasma potassium in normals from 4.01 to 3.56 mEq per liter
(p less than 0.001) and in the patients from 4.55 to 4.00 mEq
per liter (p less than 0.001).
 This kaliopenic effect of acetazolamide may account for its
therapeutic action in hyperkalemic periodic paralysis.

31. PARAMYOTONIA CONGENITA
MUTATED GENE SCN4A
CHROMOSOME 17q
DEFECTIVE CHANNEL SODIUM
MODE OF INHERITENCE AUTOSOMAL DOMINANT

32. CLINICAL FEATURES
MILD ATTACK
COLD INDUCED OR SPONTENEOUS
PARDOXICAL STIFFNING

33. SERUM POTASSIUM CONCENTRATION VARIABLE
SERUM CK CONCENTRATION MILDY ELEVATED
NERVE CONDUCTION TEST NORMAL
COOLNG OF MUSCLE
DRASTICALLY REDUCES
COMPOUND ACTION
POTENTIAL
ELECTROMYGRAPHY DIFFUSE MYOTONIC
POTENTIAL
GENETIC STUDY SCN4A

34. GLUCOSE
TREATMENT CARBOHYDRATE RICH FOODS
ACETAZOLAMIDE ,
MEXILETINE,
THIAZIDE DIURETICS

35. ANDERSON TAWIL SYNDROME
MUTATED GENE KCNJ2
CHROMOSOME 17q
DEFECTIVE CHANNEL INWARDLY RECTIFYING
POTASSIUM CURRENT
(Kir2.1.)
MODE OF AUTOSOMAL
INHERITENCE DOMINANT

36. EPISODIC WEAKNESS
CARDIAC ARRTHYMIAS
DYSMORPHIC FEARURES
TREATMENT -ACETAZOLAMIDE

37. Figure 1. Andersen's Syndrome Is Characterized by Dysmorphic Features, Cardiac Arrhythmias,
and Periodic Paralysis(A and B) Andersen's patient exhibiting low set ears, hypertelorism,
micrognathia, and (C) clinodactyly of the fifth digits. (D) ECG rhythm strip from an Andersen's
patient demonstrating short runs of polymorphic ventricular tachycardia. (E) Muscle biopsy of an
Andersen's patient exhibiting tubular aggregates commonly seen in periodic paralysis patients

39. MYOTONIA CONGENITA
MUTATED GENE ClCN1
CHROMOSOME 7q35
DEFECTIVE CHANNEL CHLORIDE
MODE OF INHERITENCE AUTOSOMAL DOMINANT-
THOMSOM DISEASE
AUTOSOMAL RECESSIVE -
BECKER DISEASE

40. • INFANCY AND EARLY CHILDHOOD
• STIFFNESS DECREASE WITH ACTIVITY
• WORSEN BY COLD
• MUSCLE HYPERTROPY

41. • USUALLY DONOT REQUIRE TREATMENT
– PHENYTOIN
– MEXILETINE

42. MALIGNAT HYPERTHERMIA
SUSEPTIBILITY
• MHS 1-6
• MUTATION RYR GENE
• CHROMOSOME 19q13
• RYNODINE RECEPTOR PRESENT IN CALCIUM
CHANNEL
• AUTOSOMAL DOMNANT

43. Malignant hyperthermia
Skeletal muscle Rigidity and weakness
Rhabdomyolysis
Muscle spasms especially affecting
masseter, but can
be generalised
Myalgia
Autonomic Sympathetic overactivity
Hyperventilation
Tachycardia
Haemodynamic instability
Cardiac arrhythmia
Laboratory Increased oxygen consumption
Hypercapnia
Lactic acidosis
Raised creatine kinase
Hyperkalaemia

44. Malignant hyperthermia
Full episodes: general anaesthesia (inhalational
Triggers agents— isoflurane, desflurane,) suxamethonium
Milder malignant hyperthermia: exercise in hot
conditions, neuroleptic drugs, alcohol, infections
Dantrolene 2 mg/kg intravenously every 5 minutes to
Treatment a total of 10 mg/kg
Hyperventilation with supplemental oxygen
Sodium bicarbonate
Active cooling
Discontinue anaesthesia
Maintain urine output over 2 ml/kg/hour
Avoid calcium, calcium antagonists, b-blockers

45. THE CONGENITAL MYASTHENIC
SYNDROMES
• GENETIC MUTATION IN ANY COMPONENT OF
NEUROMUSCULAR JUNCTION
Type Genetics
Slow channel Autosomal dominant; AChR mutations
Low-affinity fast channel Autosomal recessive; may be
heteroallelic
Severe AChR deficiencies Autosomal recessive; mutations most
common; many different mutations
AChE deficiency Mutant gene for AChE's collagen
anchor

46. • SYMPTOMS BEGAIN IN INFANCY
• AChR TEST IS PERSITANTLY NEGATIVE
• TREATMENT
 PYRIDOSTGMINE
 3,4 DIAMINOPYRINE

47. CARDIAC CHANNELOPATHIES
LONG QT SYNDROME
SHORT QT SYNDROME
BURGADA SYNDROME
CATECHOLAMINERGIC POLYMORPHIC
VENTRICULAR TACHYCARDIA

50. • ION CHANNEL DEFECT
• CARDIAC REPOLARIZATION

51. BURGADA SYNDROME
 DIMINISHED SODIUM INWARD CURRENT AT REGION
OF RIGHT VENTICULAR OUT FLOW
 RAPID DEPOLARIZATION OF THAT AREA
 TRANSIENT OR CONCEALED ST ELEVATION V1-V3
 PROVOKED WITH NA+ CHANNEL BLOCKING DRUGS
 RISK OF POLYMORPHIC VENTICULAR
TACHYCARDIA

53. CNS CHANNELOPATHY

54. FAMILIAL HEMIPLEGIC MIGRANE
• AUTOSOMAL DOMINANT
• TYPE 1-3
• GENE MUTATED-CACNA1A,ATP1A2,SCN1A
• ION CHANNEL-VOLTAGE DEPENDENT P/Q TYPE
CALCIUM CHANNEL

55. • DIAGNOSTIC CRITERIA
• AT LEAST TWO ATTACKS OF MIGRANE WITH
AURA
• AURA MUST INCLUDE REVERSIBLE MOTOR
DEFICIT
• POSITIVE FAMILIT HISTORY
• TREATMENT- ACETAZOLAMIDE VERAPAMIL

56. EPISODIC ATAXIA

57. SPINOCEREBELLAR ATAXIA TYPE 6
• EXPANSION OF TRINEUCLETIDE CAG REPEAT
• DEFECTIVE SODIUM CHANNEL
• CACNA1A GENE
• CHROMOSOME 19P

58. • ADULT ONSELT
• SLOWINY PROGRESSIVE CEREBELLAR GAIT
ATAXIA
• DYSMETRIA
• DYSARTHRIA
• NYSTAGMUS
• MRI-ISOLATED CEREBELLAR ATROPY

59. EPILEPSY SYNDROMES
 HEREDIITARY HYPEREKPLEXIA
 AUTOSOMAL- DOMINANT NOCTURNAL FRONTAL
LOBE EPILEPSY
 BENING FAMILIAL NEONATAL CONVULSION
 GENERALIZED EPILEPSY WITH FEBRILE SEIZURE PLUS
 JUVENILE MYOCLONIC EPILEPSY
 BENIGN ADULT FAMILIAL MYOCLONIC EPILEPSY
 CHILDHOOD ABSENCE SEIZURE

60. Summary.
 Channel mutations are an increasingly
recognized cause of disease.
 Many channelopathies episodic despite
persistently abnormal channel.
 Triggers recognized for some diseases.
 Abnormalities in same channel may present with
different disease states
 Lesions in different channels may lead to same
disease eg periodic paralysis
 Disease mechanism often unclear despite
identification of mutation.

61. REFRENCES
• Harrison’s principles of internal medicine18th ed
• T d graves, m g hanna, neurological channelopathies,
postgrad med j 2005;81:20–32. Doi: 10.1136/pgmj.
2004.022012
• Bernard and shevell; channelopathies, pediatrneurol.
2007. 09.007
• Mechanisms and clinical management of inherited
channelopathies: long qt syndrome, brugada syndrome,
catecholaminergic polymorphic ventricular tachycardia, and
short qt syndrome; elizabeth s. Kaufman, md, heart rhythm
society, doi:10.1016/j.Hrthm.2009.02.009
• Guyton and hall textbook of medical physiology (12th edn)

62. End
Thank you