Basic Science applied to medicine

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CHANNELOPATHY
INTRODUCTION
Diseases caused by disturbed function of ​ion channel​ ​subunits or the ​proteins​ that regulate them
ION CHANNELS - Ion channels are transmembrane glycoprotein pores.
Responsible for selective movement of a molecule across the membrane
Ion channel - properties –
Selectivity: Each specific ion crosses through specific channels
Gating: transition between states (closed ↔ open ↔Inactivation
Types of Ion Channels
1) Voltage gated- Na, K, Ca
2) Ligand gated- Ach, Epi, Norepi, 5HT
State of ion channel
1) Resting
2) Activated
3) Inactivated
Mutation of ion channel can lead to
1) Loss of Fx
2) Gain of Fx
Function of Ion Channels
• Maintain cell resting membrane potential
• Action potential and Conduction of electrical signal
• Excitation-contraction (E-C) coupling
• Synaptic transmission
• Intracellular transfer of ion, metabolite, propagation: gap junctions
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• Cell volume regulation: Cl channel, aquaporins
• Sensory perception
• Oscillators: pacemaker channels of the heart
• Stimulation-secretion coupling: release of insulin form pancreas (ATP sensitive K channel)
Definition: Disorders of ion channels or ion channel disease Diseases that result from defects in
ion channel function.
TYPES OF CHANNELOPATHIES BASED ON INHERITANCE
INHERITED CHANNELOPATHIES AQUIRED CHANNELOPATHIES
Neurologial channelopathies Lambert-Eaton mysthenic syndrome
Cardiac channelopathies Limbic encephalitis
Diabetes Mellitus: ATP-sensitive K+ channel Paraneoplastic cerebellar degenaration
Cystic fibrosis: CFTR, Cl- channel
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PERIODIC PARALYSIS
Rare neuromuscular disorder, related to a defect in muscle ion channels.
HypoK, HyperK, Andersen Syndrome
HypoKalemic PP -
TYPE 1 TYPE 2
PREVALENCE 70% 30%
GENDER M>F M=F
CHROMOSOME 1q31 17q
ION CHANNEL CALCIUM
DHPR
SODIUM ​SCN4A
INHERITANCE Autosomal Dominant Autosomal dominant
PATHOGENESIS LESS CLEARLY UNDERSTOOD
Slow activation rate of L-type Ca current to
30% of Normal
• Reduced RYR1-mediated Ca release from
SER
MORE CLEARLY UNDERSTOOD
Mutant sodium channels produce an
anomalous current that may cause
aberrant depolarization
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• Reduced calcium current
• Impaired E-C coupling
• Reduced ATP-dependent K
channel current and leads to abnormal
depolarization
C/F More prominent myalgias
younger age of onset
shorter duration of attacks, and less
severe myopathy
MUSCLE BIOPSY vacuoles tubular aggregates
RESPONSE TO
ACETAZOLAMIDE
worsening occur in some
HYPOK HYPERK
PREVELANCE 1:100,000 1:200,000
GENDER M>F M=F
INHERITANCE Autosomal Dominant Autosomal Dominant
AGE OF ONSET late childhood or teenage years 1​ST​
Decade
SYMPTOMS DURING
ATTACKS
Acute onset painless flaccid Paralysis
Areflexia
LL>UL
PROXIMAL >>> DISTAL
Consciousness is preserved
Bulbar and respiratory muscles are
only mildly affected, if at all
Attacks vary in frequency and duration.
more frequent (occurring as often as
several times in one day)
less severe
shorter in duration (minutes to hours)
WEAKNESS OF
PROXIMAL
MUSCLE,SPARING
BULBAR MUSCLE
BETWEEN ATTACKS Normal Normal, may have ​myotonia (delayed
muscle relaxation after contraction)
TRIGGERS High carbohydrate
High Salt,
Drugs- beta agonists, Insulin
Rest following prolonged Exercise
Rest after exercise
Stress
Fatigue
Food high in K
INVESTIGATIONS
HYPOK HYPERK
PATHOGENESIS Above sodium channel closes too slowly, and sodium
ions continue to leak into the muscle cell
leading to oversensitivity and stiffness in the
muscle (myotonia). Gradully, muscle becomes
desensitized & paralyzed.
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SerumK Low N to high
ECG Hypokalemic changes Hyperkalemic 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
ELECTROMYGR
APHY
Electrically silent Electrically silent
Myotonic discharge
Between attacks
GENETIC STUDY CALCL1A3, SCN4A SCN4A
Provocative testing oral glucose load
(2 gm/kg) and/or insulin
administration (10 units
subcutaneously)
Exercise, such as 30 minutes of
running on the treadmill,
ACTH
oral potassium load (1 to 2 meq/kg
Exercise, such as 30 minutes of running on the
treadmill
ACTH
TREATMENT ORAL KCL
SUPPLEMENTATION
KCL VIA INFUSION
DONOT GIVE IN DEXTROSE
Potassium administration during an
acute episode may lead to
posttreatment hyperkalemia as
potassium moves back out of the
cells
posttreatment potassium levels
should be monitored for 24 H
Cardiac monitoring
MILD SUSTAINED
EXERCISE
LOW POTASSIUM DIET
BETA AGONIST
THIAZIDES
HIGH SUGAR LOAD
CALCIUM GLUCONATE
PROPHYLAXIS AVOID TRIGGERS
PATIENT EDUCATION
ACETAZOLAMIDE
(125-1000 Mg)
potassium-sparing diuretic,
either ​spironolactone​ (100 mg
daily) or ​triamterene​
ACETAZOLAMIDE ,
MEXILETINE
(125-1000 Mg)
Beta 2 Agonist
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Pinacidil, a potassium channel
opener
PROGNOSIS Usually good
Rarely develop Proximal myopathy
Good
MOA of
Acetazolamide
The mechanism of effect of
acetazolamide is not discovered.
but appears to be independent of
carbonic anhydrase inhibition
kaliopenic effect of acetazolamide may
account for its
therapeutic action in hyperkalemic periodic
paralysis.
D/D - ​'Thyrotoxic periodic paralysis'
PARAMYOTONIA
CONGENITA
ANDERSON TAWIL
SYNDROME
MYOTONIA CONGENITA
GENE SCN4A KCNJ2 ClCN1
CHROMOSOME 17q 17q 7q35
DEFECTIVE
CHANNEL
Na Inwardly rectifying
Potassium current
(Kir2.1.)
chloride channel
INHERITANCE Autosomal dominant Autosomal dominant Autosomal dominant –
Thomson disease
Autosomal recessive -
Becker disease
C/F Usually mild attacks
Cold induced or
spontaneous
Pardoxical
stiffning/myotonia
Episodic weakness
Cardiac arrthymias
Dysmorphic fearures
infancy and early childhood
• stiffness decreases with
activity
• worsen by cold
• muscle hypertrophy
K Variable
CPK Mildy elevated
NCV Normal
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Coolng of muscle
drastically reduces
compound action
potential
EMG Diffuse myotonic
potential
GENETIC STUDY SCN4A
TREATMENT Glucose,
Carbohydrate rich
foods
Acetazolamide ,
Mexiletine,
Thiazide diuretics
ACETAZOLAMIDE USUALLY DONOT
REQUIRE TREATMENT
– PHENYTOIN
– MEXILETINE
CARDIAC CHANNELOPATHIES
Long QT Syndrome (types 1-12, various genes)
• Short QT Syndrome (Kir2.1, L-type Ca2+ channel)
• Burgada Syndrome (Ito, Na+, Ca2+ channels)
• Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (RyR2, SR Ca release)
LQTS-
Normal QT interval: 360-440 ms
• Delayed repolarization of the myocardium, QT prolongation (>450 in man; > 470 in women)
risk for syncope, seizures, and SCD in the setting of a structurally normal heart
Mean age- 12-14 years. Manifest with syncope and SCD
Cardiac action potential
• Phase 0. Influx of Na+
• Phase 1. Efflux of K+
• Phase 2. Influx of Ca2+
• Phase 3. Efflux of K+
• Phase 4. Restoration of the resting potential
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LQTS1 LQTS2 LQTS3
Channel K K Na
Phase affected 3 3 1
Trigger Emotional stress,
swimming
Emotional stress,
auditory triggers
Slow HR during sleep
Mx
ICD
Survivors of cardiac arrest have a high risk of recurrence
even on beta-blockers
Syncope and/or VT on beta-blockers
QTc>500ms
Avoidance of QT prolonging drugs
Beta-blockers
Left cardiac sympathetic denervation (LCSD) i​​n symptomatic LQTS
when beta-blockers & ICD not effective/not tolerated
Sodium channel blockers ​​(mexiletine,flecainide or ranolazine) add on therapy for ​LQTS3 with
QTc>500ms
BRUGADA SYNDROME
Right bundle branch block, persistent ST segment elevation, and sudden death syndrome
Autosomal dominant
3rd to 4th decade
M:F= 8:1(hormones)
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During sleep or rest.
Incidence of arrhythmic events VT/VF
24 genes have been associated
Management =ICD
Survivors of cardiac arrest and/or documented sustained VT
Spontaneous type 1 ECG pattern and h/o syncope
VF during EPS
Catheter ablation may be considered with h/o electrical storms or repeated appropriate ICD
shocks.
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