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.
CHANNELOPATHIE S Presenter-Dr. Pradeep katwal
ChannelopathiesCAUSED BY DEFECTIVE ION CHANNEL.
ION CHANNELS•TRANMEMBRANE GLYCOPROTEIN PORESoCell excitabilityoElectrical signaling•TYPES VOLTAGE GATED CHANNEL LIGAND GATED CHANNEL
Voltage gated channelTransmembrane potentialIdentified according to principle ion conductedConcentrated in different regions
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.
Each alpha1subunit has 4 homologous repeat domains, each comprised of 6 transmembrane segments alpha1 modulated by other subunits
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
HYPOKALEMIC PERIODIC PARALYSISMUTATED GENE CALCL1A3 SCN4ACHROMOSOME 1q31 17qDEFECTIVE CALCIUM SODIUMCHANNELMODE OF AUTOSOMAL DOMINANTINHERITENCE TYPE 1 TYPE 2
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
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
SERUM POTASSIUM LOWCONCENTRATIONECG HYPOKALEMIC CHANGESMUSCLE BIOPSY SINGLE OR MULTIPLE CENTRALLY PLACED VACUOLESNERVE CONDUCTION TEST REDUCED AMPLITUDE OF ACTION POTENTIALELECTROMYGRAPHY ELECTRICALLY SILENTGENETIC STUDY CALCL1A3, SCN4A
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.
• 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.
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
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
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
• 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.
CLINICAL FEATURESMILD ATTACKCOLD INDUCED OR SPONTENEOUSPARDOXICAL STIFFNING
SERUM POTASSIUM CONCENTRATION VARIABLESERUM CK CONCENTRATION MILDY ELEVATEDNERVE CONDUCTION TEST NORMAL COOLNG OF MUSCLE DRASTICALLY REDUCES COMPOUND ACTION POTENTIALELECTROMYGRAPHY DIFFUSE MYOTONIC POTENTIALGENETIC STUDY SCN4A
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
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
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
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
• SYMPTOMS BEGAIN IN INFANCY• AChR TEST IS PERSITANTLY NEGATIVE• TREATMENT PYRIDOSTGMINE 3,4 DIAMINOPYRINE
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
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.
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)