CHANNELOPATHIES

Presenter-Dr. Pradeep katwal

Channelopathies

CAUSED BY DEFECTIVE ION CHANNEL.

ION CHANNELS

•TRANMEMBRANE GLYCOPROTEIN PORES

oCell excitabilityoElectrical signaling

•TYPES VOLTAGE GATED CHANNEL LIGAND GATED CHANNEL

Voltage gated channel

Transmembrane potential

Identified according to principle ion conducted

Concentrated in different regions

Voltage-Gated Ion Channels

General architecture of voltage-gated channels (Na+ and Ca2+).The “+” or “-“ signs indicate charges that have been implicated in voltage sensing.

Transmembrane segment (cylinder)

PoreVoltage sensor part of the channel

Lipid bilayer

• 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.

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

04/12/2023

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.

Action potential

STATES OF ION CHANNEL- CLOSED, OPEN,INACTIVATED

Ion Channels and the AP

2.11

Ligand gated channels

• Activated by binding to agonist– Glycine– Gamma-aminobutyric acid– Acetycholine

Channel Gating Mechanisms AChR: Proposed gating mechanism

(Unwin, 1995)

OpenClosed

• Mutation of ion channel can alter –activation–ion selectivity–Inactivation

Abnormal gain of functionloss of function

• PHENOTYPIC HETEROGENICITY

• GENETIC HEREROGENICITY

Channelopathies

• INHERITED CHANNELOPATHIESNeurologial channelopathiesCardiac channelopathies• AUTOIMMUNE CHANNELOPATHIESMysthenia gravisLambert-Eaton mysthenic syndromeParaneoplastic cerebellar degenarationLimbic encephalitis

Neurological channelopathies

HYPOKALEMIC PERIODIC PARALYSISMUTATED GENE CALCL1A3 SCN4A

CHROMOSOME 1q31 17q

DEFECTIVE CHANNEL

CALCIUM SODIUM

MODE OF INHERITENCE

AUTOSOMAL DOMINANT

TYPE 1 TYPE 2

20

• 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)

Hypokalemic Periodic ParalysisPathophysiology

HYPOKALEMIC PERIODIC PARALYSISPREVELANCE 1:100,000AGE OF ONSET FIRST AND SECOND DECADE OF

LIFESYMPTOMS DURING ATTACKS ACUTE ONSELT FLACCID

PARALYSISPROXIMAL >>> DISTAL

SYMPTOMS BETWEEN ATTACKS REGAIN FULL STRENGTH BETWEEN ATTACKS

TRIGGERS HIGH CARBOHYDRATE,HIGH SALT, DRUGS- BETA AGONISTS, INSULINREST FOLLOWING PROLONGED EXERCISE

SERUM POTASSIUM CONCENTRATION

LOW

ECG HYPOKALEMIC CHANGESMUSCLE BIOPSY SINGLE OR MULTIPLE

CENTRALLY PLACED VACUOLES

NERVE CONDUCTION TEST REDUCED AMPLITUDE OF ACTION POTENTIAL

ELECTROMYGRAPHY ELECTRICALLY SILENTGENETIC STUDY CALCL1A3, SCN4A

TREATMENT ORAL KCL SUPPLEMENTATIONKCL VIA INFUSIONDONOT GIVE IN DEXTROSE

PROPHYLAXIS ACETAZOLAMIDE(125-1000 Mg)

PROGNOSIS USUALLY GOODRARE 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.

HYPERKALEMIC PERIODIC PARALYSIS

MUTATED GENE SCN4A

CHROMOSOME 17q

DEFECTIVE CHANNEL SODIUM

MODE OF INHERITENCE

AUTOSOMAL DOMINANT

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 HYPERKALEMIC

PREVELANCE 1:100,000 1:200,000AGE OF ONSET FIRST AND SECOND

DECADE OF LIFEFIRST DECADE

SYMPTOMS DURING ATTACKS

ACUTE ONSELT FLACCID PARALYSISPROXIMAL >>> DISTAL

WEAKNESS OF PROXIMAL MUSCLE,SPARING BULBAR MUSCLE

SYMPTOMS BETWEEN ATTACKS

ASYMPTOMATIC ASYMPTOMATIC

TRIGGERS HIGH CARBOHYDRATE,HIGH SALT,DRUGS-BETA AGONISTS, INSULINREST FOLLOWING PROLONGED EXERCISE

REST AFTER EXERCISESTRESSFATIGUEFOOD HIGH IN POTASSIUM

POSTASSIUM SUPPLEMENTATION

TREATMENT PROVOCATIVE TEST

SERUM POTASSIUM CONCENTRATION

LOW HIGH, NORMAL

ECG HYPOKALEMIC CHANGES

HYPERKALEMIC CHANGES CHANGES

MUSCLE BIOPSY SINGLE OR MULTIPLE CENTRALLY PLACED VACUOLES

SMALLER, LESS NUMEROUS PERIPHERALLY PLACED VACUOLES

NERVE CONDUCTION TEST REDUCED AMPLITUDE OF ACTION POTENTIAL

REDUCED AMPLITUDE OF ACTION POTENTIAL

ELECTROMYGRAPHY ELECTRICALLY SILENT ELECTRICALLY SILENTMYOTONIC DISCHARGE BETWEEN ATTACKS

GENETIC STUDY CALCL1A3, SCN4A SCN4A

TREATMENT MILD SUSTAINED EXERCISELOW POTASSIUM DIETBETA AGONISTTHIAZIDESHIGH SUGAR LOADCALCIUM GLUCONATE

PROPHYLAXIS ACETAZOLAMIDE , MEXILETINE(125-1000 Mg)

• 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.

PARAMYOTONIA CONGENITA

MUTATED GENE SCN4A

CHROMOSOME 17q

DEFECTIVE CHANNEL SODIUM

MODE OF INHERITENCE AUTOSOMAL DOMINANT

CLINICAL FEATURES

MILD ATTACK

COLD INDUCED OR SPONTENEOUS

PARDOXICAL STIFFNING

SERUM POTASSIUM CONCENTRATION VARIABLE

SERUM CK CONCENTRATION MILDY ELEVATEDNERVE CONDUCTION TEST NORMAL

COOLNG OF MUSCLE DRASTICALLY REDUCES COMPOUND ACTION POTENTIAL

ELECTROMYGRAPHY DIFFUSE MYOTONIC POTENTIAL

GENETIC STUDY SCN4A

TREATMENT GLUCOSECARBOHYDRATE RICH FOODS

ACETAZOLAMIDE ,MEXILETINE,THIAZIDE DIURETICS

ANDERSON TAWIL SYNDROME

MUTATED GENE KCNJ2

CHROMOSOME 17q

DEFECTIVE CHANNEL INWARDLY RECTIFYING POTASSIUM CURRENT (Kir2.1.)

MODE OF INHERITENCE

AUTOSOMAL DOMINANT

EPISODIC WEAKNESS

CARDIAC ARRTHYMIAS

DYSMORPHIC FEARURES

TREATMENT -ACETAZOLAMIDE

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

MYOTONIA CONGENITAMUTATED GENE ClCN1

CHROMOSOME 7q35

DEFECTIVE CHANNEL CHLORIDE

MODE OF INHERITENCE AUTOSOMAL DOMINANT- THOMSOM DISEASE

AUTOSOMAL RECESSIVE -BECKER DISEASE

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

• USUALLY DONOT REQUIRE TREATMENT

– PHENYTOIN– MEXILETINE

MALIGNAT HYPERTHERMIA SUSEPTIBILITY

• MHS 1-6• MUTATION RYR GENE• CHROMOSOME 19q13• RYNODINE RECEPTOR PRESENT IN CALCIUM

CHANNEL• AUTOSOMAL DOMNANT

Malignant hyperthermiaSkeletal muscle Rigidity and weakness

RhabdomyolysisMuscle spasms especially affecting masseter, but canbe generalisedMyalgia

Autonomic Sympathetic overactivityHyperventilationTachycardiaHaemodynamic instabilityCardiac arrhythmia

Laboratory Increased oxygen consumptionHypercapniaLactic acidosisRaised creatine kinaseHyperkalaemia

Malignant hyperthermia

Triggers Full episodes: general anaesthesia (inhalationalagents— isoflurane, desflurane,) suxamethoniumMilder malignant hyperthermia: exercise in hotconditions, neuroleptic drugs, alcohol, infections

Treatment Dantrolene 2 mg/kg intravenously every 5 minutes toa total of 10 mg/kgHyperventilation with supplemental oxygenSodium bicarbonateActive coolingDiscontinue anaesthesiaMaintain urine output over 2 ml/kg/hourAvoid calcium, calcium antagonists, b-blockers

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

• SYMPTOMS BEGAIN IN INFANCY

• AChR TEST IS PERSITANTLY NEGATIVE

• TREATMENT PYRIDOSTGMINE 3,4 DIAMINOPYRINE

CARDIAC CHANNELOPATHIES

LONG QT SYNDROME

SHORT QT SYNDROME

BURGADA SYNDROME

CATECHOLAMINERGIC POLYMORPHIC

VENTRICULAR TACHYCARDIA

• ION CHANNEL DEFECT• CARDIAC REPOLARIZATION

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

CNS CHANNELOPATHY

FAMILIAL HEMIPLEGIC MIGRANE

• AUTOSOMAL DOMINANT• TYPE 1-3• GENE MUTATED-CACNA1A,ATP1A2,SCN1A• ION CHANNEL-VOLTAGE DEPENDENT P/Q TYPE

CALCIUM CHANNEL

• DIAGNOSTIC CRITERIA• AT LEAST TWO ATTACKS OF MIGRANE WITH

AURA• AURA MUST INCLUDE REVERSIBLE MOTOR

DEFICIT• POSITIVE FAMILIT HISTORY• TREATMENT- ACETAZOLAMIDE VERAPAMIL

EPISODIC ATAXIA

SPINOCEREBELLAR ATAXIA TYPE 6

• EXPANSION OF TRINEUCLETIDE CAG REPEAT• DEFECTIVE SODIUM CHANNEL• CACNA1A GENE • CHROMOSOME 19P

• ADULT ONSELT• SLOWINY PROGRESSIVE CEREBELLAR GAIT

ATAXIA• DYSMETRIA• DYSARTHRIA• NYSTAGMUS

• MRI-ISOLATED CEREBELLAR ATROPY

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

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)

End

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