Karin Jurkat-RottFrank Lehmann-Horn

Applied Physiology, Ulm University, Ulm, Germany

PPA 2007, Orlando

Andersen-Tawil syndrome (ATS)

ATS• normo- or dyskalemic periodic paralysis• ventricular arrhythmia (LQT 7)• slight dysmorphic features in some patients• no myotonia • dominant mutations in KCNJ2 encoding theKir2.1 K+ channel

KCNJ2 expressed in skeletal and cardiac muscle

Long QT syndromes- episodic arrhythmias known as torsade de points- conversion into ventricular fibrillation- sudden death in young otherwise healthy individuals

LQT7 is similar to LQT1

Torsade de pointesECG

Development of LQT arrhythmia by prolonged action potential

Arrhythmia improves at slight tachycardia

intracellular

extracellular

Mg2+ outward cur-rent blocks pore

WTt

WTt+ G215R

G215Rt

10 µm

G215Rt+ WT

Expression of the normal (WT) and/or the mutated gene in COS cells

WT+G215R

WT+G215D

WT+R82W

WT

WT

WT+G215R

G215R

G215D

WT+G215D

R82W

V93IWT+V93IWT

WT+R82WWT

WT

G215R

WT

WT

WT

G215D

R82W

WT+V93IV93I

0.2 nA

50 ms

+40 mV

-120 mV-60 mV

200 msA B

-80

-60

-40

-20

0

20

peak

cur

rent

den

sity

(pA

/pF)

-60

-40

-20

0

20

peak

cur

rent

den

sity

(pA

/pF)

-90

-60

-30

0

peak

cur

rent

den

sity

(pA

/pF)

-60

-40

-20

0

20-120 -80 -40 0 40

membrane potential (mV)

peak

cur

rent

den

sity

(pA/

pF)

Currents through the mutant Kir2.1 channel

0 10000 20000

0

10

20

30

40

50A)

small increase of gKir

due to raising [K+]e

gKir shut-off

increasing blockof gKir to

destabilize theresting state

g Kir [

µS/c

m2 ]

t [s]

10 20 300

2

4

6

8

10

12D)

[K+ ] e [m

M]

KmNa [mM]0 5000 10000 15000 20000

2

3

4

5

6

7

C)

Es = -100 mV Es = -90 mV Es = -80 mV Es = -70 mV Es = -60 mV

[K+ ] e [

mM

]

t [s]

0 10000 20000

-90

-80

-70

-60

E m [m

V]

t [s]

2

3

4

B)

[K+ ] e [m

M]

A,B: Depolarization and hypokalemia at reduced Kir2.1 functionC,D: Serum K+ depends on individual slow Na+ channel inactivation

Reduced- and increased-function mutationsare associated with different features

Hypotelorism

V93IR82W G215R

G215R

V93I

AT

Hypertelorism

characteristicTU morphology

ATS fibers were depolarized to -65 mV ATS fibers were depolarized to -65 mV at 4.5 mM K+ and further at 1.5 mM

twitch force

n.d.n.d.No (1/1)weeksHypoPP1.9Paralysis301;1V93I

R218Q

R218W

G215R

G215D

R82W

D78G

R67W

Kir2.1 muta-tions

Severe sideeffects

Beneficial

Worsening

No effect

n.d.

Beneficial

n.d.

Reactionto CAI

Vacuoles

Vacuoles

Vacuoles

n.d.

n.d.

Vacuoles

Vacuoles

Musclehistology

Yes (1/3)h/daysHypoPP2.7Para/Arrh9,33;0

No (6/6)HoursHyperPP5.7Paralysis8,32;4

Yes (1/2)DaysHypoPP2.4Paralysis9,50;2

Yes (1/1)DaysHyperPP5.8Paralysis31;0

No (1/1)DaysHypoPP2.6 Para/Arrh332;0

Yes (1/1)DaysHypoPPlowParalysis80;1

Yes (1/6)DaysHypoPPvery lowPara/Arrh126;1

chronicweakness

Maxim. duration

PP typeK+/mMparalysis

1st symptom

on-set

SexM;f

ATS patients: paralytic attacks

-

-

Iodide

Low-K, stress, work

-

Hyperthyroidism

Hyperthyroidism

Stress, work, CAI

Provoked by

-< 440ATV93I

R218Q

R218W

G215R

G215D

R82W

D78G

R67W

Kir2.1mutation

amiodarone< 440PVC, VT, bigeminus

Exercise, β-blocker, amioderone

< 440PVC

-> 440PVC, VT

--PVC, bigeminus

Digoxin> 440PVC

??PVC

Exercise, no effective drug< 440PVC, bigeminus

Effective therapyECGQTc

Type ofarrhythmia

Cardiac features

HypoPP_vacuole1.ppt

Electrolyte and water dysequilibrium during paralytic attackscauses vacuolar myopathy

0,7

0,9

1,1

1,3

1,5

1,7

1,9

2,1

Con

trols

Hyp

oPP-

1

Hyp

oPP-

1tre

ated

Hyp

oPP-

2

ATS

23N

a si

gnal

Ca-IV

Ca-II

Na-II

At rest

Therapy of ATS

Therapy of paralytic attacks:Hypokalemic paralytic attacks as in HypoPPHyperkalemic paralytic attacks as in HyperPPIf type of attack is unknown: try potassium since ingestion-induced hyperkalemia is much less dangerous to the heart thanhypokalemia!

Therapy of arrhythmia:Na+ channel blockers like propafenone (1st choice)Imipramine according to old reports on HyperPP with arrhythmiaAmiodarone only in older patients (late side effects)Pacemaker/defibrillator in drug-resistant ventricular tachycardia

Our experience: arrhythmias are improved by slight exercise butworsened by strenuous work