channelopathies
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brief introduction on channelopathies.....

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

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  • Now we know that there is a mutation in the skeletal muscle ca channel which slows the rate of channel activation and therefore ca influx. As mentioned earlier this receptor also acts as a voltage sensor leading to reduced ryanodine receptor medicated ca release from the SER leading to reduced calcium current leading to impaired E-C coupling. The exact role of hypokalemia is not well understood. As with other forms of paralysis, muscle fibres are depolarized and inexcitable during the attack. In vitro, muscle fibres from pts with hypoKPP exposed to low K shows paradoxical depolarization. Hence hypothesizing that cal channel mutation leads to changes in calcium homeostasis which reduces ATP dependent K current creating a hypokalemic state which leads to abnormal depolarization.One of the theoriesα subunit of the voltage-gated calcium channel, Cav1.1 (also known as the skeletal muscle L-type calcium channel, and the dihydropyridine receptor HypoPP is most commonly associated with mutation of CACNA1S (type I HypoPP), which encodes the α subunit of the voltage-gated calcium channel, Cav1.1 (also known as the skeletal muscle L-type calcium channel, and the dihydropyridine receptor). Cav1.1 in the T-tubular membraneis attached to the ryanodine receptor of sarcoplasmic reticulum, for which it acts as a voltage sensor. About 10% of HypoPP is associated with mutations in SCN4A (type 2 HypoPP), which encodes the skeletal muscle sodium channel.

channelopathies Presentation Transcript

  • 1. CHANNELOPATHIE S Presenter-Dr. Pradeep katwal
  • 2. ChannelopathiesCAUSED BY DEFECTIVE ION CHANNEL.
  • 3. ION CHANNELS•TRANMEMBRANE GLYCOPROTEIN PORESoCell excitabilityoElectrical 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, S1through S6, that forms the core structure of sodium, calcium, and potassiumchannels..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
  • 10. Ion Channels and the AP 2.11
  • 11. Ligand gated channels• Activated by binding to agonist – Glycine – Gamma-aminobutyric acid – Acetycholine
  • 12. Channel Gating Mechanisms AChR: Proposed gating mechanism (Unwin, 1995) Closed Open
  • 13. • Mutation of ion channel can alter –activation –ion selectivity –InactivationAbnormal gain of functionloss of function
  • 14. • PHENOTYPIC HETEROGENICITY• GENETIC HEREROGENICITY
  • 15. Channelopathies• INHERITED CHANNELOPATHIESNeurologial channelopathiesCardiac channelopathies• AUTOIMMUNE CHANNELOPATHIESMysthenia gravisLambert-Eaton mysthenic syndromeParaneoplastic cerebellar degenarationLimbic encephalitis
  • 16. Neurological channelopathies
  • 17. HYPOKALEMIC PERIODIC PARALYSISMUTATED GENE CALCL1A3 SCN4ACHROMOSOME 1q31 17qDEFECTIVE CALCIUM SODIUMCHANNELMODE OF AUTOSOMAL DOMINANTINHERITENCE TYPE 1 TYPE 2
  • 18. 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
  • 19. HYPOKALEMIC PERIODIC PARALYSISPREVELANCE 1:100,000AGE OF ONSET FIRST AND SECOND DECADE OF LIFESYMPTOMS DURING ATTACKS ACUTE ONSELT FLACCID PARALYSIS PROXIMAL >>> DISTALSYMPTOMS BETWEEN ATTACKS REGAIN FULL STRENGTH BETWEEN ATTACKSTRIGGERS HIGH CARBOHYDRATE,HIGH SALT, DRUGS- BETA AGONISTS, INSULIN REST FOLLOWING PROLONGED EXERCISE
  • 20. SERUM POTASSIUM LOWCONCENTRATIONECG HYPOKALEMIC CHANGESMUSCLE BIOPSY SINGLE OR MULTIPLE CENTRALLY PLACED VACUOLESNERVE CONDUCTION TEST REDUCED AMPLITUDE OF ACTION POTENTIALELECTROMYGRAPHY ELECTRICALLY SILENTGENETIC STUDY CALCL1A3, SCN4A
  • 21. TREATMENT ORAL KCL SUPPLEMENTATION KCL VIA INFUSION DONOT GIVE IN DEXTROSEPROPHYLAXIS ACETAZOLAMIDE (125-1000 Mg)PROGNOSIS USUALLY GOOD RARE DEVELOPMENT OF PROXIMAL MYOPATHY*Never forget to measure the thyroid hormones.
  • 22. • 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.
  • 23. HYPERKALEMIC PERIODIC PARALYSISMUTATED GENE SCN4ACHROMOSOME 17qDEFECTIVE CHANNEL SODIUMMODE OF AUTOSOMALINHERITENCE DOMINANT
  • 24. 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
  • 25. HYPOKALEMIC HYPERKALEMICPREVELANCE 1:100,000 1:200,000AGE OF ONSET FIRST AND SECOND FIRST DECADE DECADE OF LIFESYMPTOMS DURING ACUTE ONSELT FLACCID WEAKNESS OFATTACKS PARALYSIS PROXIMAL PROXIMAL >>> DISTAL MUSCLE,SPARING BULBAR MUSCLESYMPTOMS BETWEEN ASYMPTOMATIC ASYMPTOMATICATTACKSTRIGGERS HIGH CARBOHYDRATE, REST AFTER EXERCISE HIGH SALT, STRESS DRUGS-BETA FATIGUE AGONISTS, INSULIN FOOD HIGH IN REST FOLLOWING POTASSIUM PROLONGED EXERCISEPOSTASSIUM TREATMENT PROVOCATIVE TESTSUPPLEMENTATION
  • 26. SERUM LOW HIGH, NORMALPOTASSIUMCONCENTRATIONECG HYPOKALEMIC HYPERKALEMIC CHANGES CHANGES CHANGESMUSCLE BIOPSY SINGLE OR MULTIPLE SMALLER, LESS CENTRALLY PLACED NUMEROUS PERIPHERALLY PLACED VACUOLES VACUOLESNERVE CONDUCTION TEST REDUCED REDUCED AMPLITUDE OF AMPLITUDE OF ACTION POTENTIAL ACTION POTENTIALELECTROMYGRAPHY ELECTRICALLY SILENT ELECTRICALLY SILENT MYOTONIC DISCHARGE BETWEEN ATTACKSGENETIC STUDY CALCL1A3, SCN4A SCN4A
  • 27. TREATMENT MILD SUSTAINED EXERCISE LOW POTASSIUM DIET BETA AGONIST THIAZIDES HIGH SUGAR LOAD CALCIUM GLUCONATEPROPHYLAXIS ACETAZOLAMIDE , MEXILETINE (125-1000 Mg)
  • 28. • 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.
  • 29. PARAMYOTONIA CONGENITAMUTATED GENE SCN4ACHROMOSOME 17qDEFECTIVE CHANNEL SODIUMMODE OF INHERITENCE AUTOSOMAL DOMINANT
  • 30. CLINICAL FEATURESMILD ATTACKCOLD INDUCED OR SPONTENEOUSPARDOXICAL STIFFNING
  • 31. SERUM POTASSIUM CONCENTRATION VARIABLESERUM CK CONCENTRATION MILDY ELEVATEDNERVE CONDUCTION TEST NORMAL COOLNG OF MUSCLE DRASTICALLY REDUCES COMPOUND ACTION POTENTIALELECTROMYGRAPHY DIFFUSE MYOTONIC POTENTIALGENETIC STUDY SCN4A
  • 32. GLUCOSETREATMENT CARBOHYDRATE RICH FOODS ACETAZOLAMIDE , MEXILETINE, THIAZIDE DIURETICS
  • 33. ANDERSON TAWIL SYNDROMEMUTATED GENE KCNJ2CHROMOSOME 17qDEFECTIVE CHANNEL INWARDLY RECTIFYING POTASSIUM CURRENT (Kir2.1.)MODE OF AUTOSOMALINHERITENCE DOMINANT
  • 34. EPISODIC WEAKNESSCARDIAC ARRTHYMIASDYSMORPHIC FEARURESTREATMENT -ACETAZOLAMIDE
  • 35. Figure 1. Andersens Syndrome Is Characterized by Dysmorphic Features, Cardiac Arrhythmias,and Periodic Paralysis(A and B) Andersens patient exhibiting low set ears, hypertelorism,micrognathia, and (C) clinodactyly of the fifth digits. (D) ECG rhythm strip from an Andersenspatient demonstrating short runs of polymorphic ventricular tachycardia. (E) Muscle biopsy of anAndersens patient exhibiting tubular aggregates commonly seen in periodic paralysis patients
  • 36. MYOTONIA CONGENITAMUTATED GENE ClCN1CHROMOSOME 7q35DEFECTIVE CHANNEL CHLORIDEMODE OF INHERITENCE AUTOSOMAL DOMINANT- THOMSOM DISEASE AUTOSOMAL RECESSIVE - BECKER DISEASE
  • 37. • INFANCY AND EARLY CHILDHOOD• STIFFNESS DECREASE WITH ACTIVITY• WORSEN BY COLD• MUSCLE HYPERTROPY
  • 38. • USUALLY DONOT REQUIRE TREATMENT – PHENYTOIN – MEXILETINE
  • 39. MALIGNAT HYPERTHERMIA SUSEPTIBILITY• MHS 1-6• MUTATION RYR GENE• CHROMOSOME 19q13• RYNODINE RECEPTOR PRESENT IN CALCIUM CHANNEL• AUTOSOMAL DOMNANT
  • 40. Malignant hyperthermiaSkeletal muscle Rigidity and weakness Rhabdomyolysis Muscle spasms especially affecting masseter, but can be generalised MyalgiaAutonomic Sympathetic overactivity Hyperventilation Tachycardia Haemodynamic instability Cardiac arrhythmiaLaboratory Increased oxygen consumption Hypercapnia Lactic acidosis Raised creatine kinase Hyperkalaemia
  • 41. Malignant hyperthermia Full episodes: general anaesthesia (inhalationalTriggers agents— isoflurane, desflurane,) suxamethonium Milder malignant hyperthermia: exercise in hot conditions, neuroleptic drugs, alcohol, infections Dantrolene 2 mg/kg intravenously every 5 minutes toTreatment 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
  • 42. THE CONGENITAL MYASTHENIC SYNDROMES • GENETIC MUTATION IN ANY COMPONENT OF NEUROMUSCULAR JUNCTIONType GeneticsSlow channel Autosomal dominant; AChR mutationsLow-affinity fast channel Autosomal recessive; may be heteroallelicSevere AChR deficiencies Autosomal recessive; mutations most common; many different mutationsAChE deficiency Mutant gene for AChEs collagen anchor
  • 43. • SYMPTOMS BEGAIN IN INFANCY• AChR TEST IS PERSITANTLY NEGATIVE• TREATMENT  PYRIDOSTGMINE  3,4 DIAMINOPYRINE
  • 44. CARDIAC CHANNELOPATHIESLONG QT SYNDROMESHORT QT SYNDROMEBURGADA SYNDROMECATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA
  • 45. • ION CHANNEL DEFECT• CARDIAC REPOLARIZATION
  • 46. 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
  • 47. CNS CHANNELOPATHY
  • 48. FAMILIAL HEMIPLEGIC MIGRANE• AUTOSOMAL DOMINANT• TYPE 1-3• GENE MUTATED-CACNA1A,ATP1A2,SCN1A• ION CHANNEL-VOLTAGE DEPENDENT P/Q TYPE CALCIUM CHANNEL
  • 49. • DIAGNOSTIC CRITERIA• AT LEAST TWO ATTACKS OF MIGRANE WITH AURA• AURA MUST INCLUDE REVERSIBLE MOTOR DEFICIT• POSITIVE FAMILIT HISTORY• TREATMENT- ACETAZOLAMIDE VERAPAMIL
  • 50. EPISODIC ATAXIA
  • 51. SPINOCEREBELLAR ATAXIA TYPE 6• EXPANSION OF TRINEUCLETIDE CAG REPEAT• DEFECTIVE SODIUM CHANNEL• CACNA1A GENE• CHROMOSOME 19P
  • 52. • ADULT ONSELT• SLOWINY PROGRESSIVE CEREBELLAR GAIT ATAXIA• DYSMETRIA• DYSARTHRIA• NYSTAGMUS• MRI-ISOLATED CEREBELLAR ATROPY
  • 53. 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
  • 54. 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.
  • 55. 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)
  • 56. End Thank you