Andersen-Tawil Syndrome-Slides

16 Pages·2007·3.2 MB·English

PPA 2007, Orlando
Andersen-Tawil syndrome (ATS)
Karin Jurkat-Rott
Frank Lehmann-Horn
Applied Physiology,
Ulm University, Ulm, Germany
ATS
• normo- or dyskalemic periodic paralysis
• ventricular arrhythmia (LQT 7)
• slight dysmorphic features in some patients
• no myotonia
• dominant mutations in KCNJ2 encoding the
K 2.1 K+ channel
ir
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
Development of LQT arrhythmia by prolonged
action potential
Arrhythmia improves at slight tachycardia
intracellular
Torsade de pointes
ECG
extracellular
Mg2+ outward cur-
rent blocks pore
Expression of the normal (WT)
and/or the mutated gene in COS cells
WT G215R
t t
G215R+ WT
t
10 µm
WT+ G215R
t
Currents through the mutant Kir2.1 channel
+40 mV
-60 mV
-120 mV membrane potential (mV)
A 200 ms B -120 -80 -40 0 40
20
y
W WT+G215 G215 nsit 0 WT+G215R
T R R e
nt dpF) -20 W
0.2 nA 50 ms k curre(pA/ -40 T
a G215
e
p R
-60
W WT+G215 G215 20
T D D y
nsit 0
e
current d (pA/pF) -20 WT WT+G215D
k -40
ea G215
p
D
-60
W WT+R82W R82W
20
T
y
sit 0
n
e
nt dpF) -20 W WT+R82W
curre (pA/ -40 T
k R82W
a -60
e
p
W WT+V93I V93I -80
T
0
y
sit
n
k current de(pA/pF) --6300 WTWV9T3+IV93I
a
e
p
-90
A,B: Depolarization and hypokalemia at reduced Kir2.1 function
C,D: Serum K+ depends on individual slow Na+ channel inactivation
A) B)
50 increasing block
of g to
Kir -60
40 destabilize the 4
resting state
30
]
2 -70 ]
m small increase of g ] M
/c 20 Kir mV 3 m
S due to raising [K+] [
[
[µKir 10 g shut-off e E m-80 +K]e
[
g Kir
2
0
-90
0 10000 20000 0 10000 20000
C) t [s] D)
t [s]
12
7
E = -100 mV
s
E = -90 mV
10
s
6
E = -80 mV
s
E = -70 mV
s 8
5 E = -60 mV ]
] s M
M
m
m 6
[
[ 4 e
e ]
] +
+ K 4
K
[
[ 3
2
2
0
0 5000 10000 15000 20000 10 20 30
t [s] K [mM]
mNa
Reduced- and increased-function mutations
are associated with different features
Hypertelorism Hypotelorism
R82W G215R V93I
characteristic
TU morphology
G215R
AT
V93I
ATS fibers were depolarized to -65 mV at 4.5 mM K+ and further at 1.5 mM
ATS fibers were depolarized to -65 mV