Unique post-exercise electrophysiological test results in a new Andersen-Tawil syndrome mutation.

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Letter to the Editor
Unique post-exercise electrophysiological test results in a new
Andersen–Tawil syndrome mutation
Andersen–Tawil syndrome (ATS) is a rare autosomal dominant
disorder thatcommonlyproduces a triad of symptoms: dysmorphic
features, periodic paralysis (PP) and cardiac dysrhythmia. In almost
60%ofpatientsthediseaseiscausedbymutationsinthegeneKCNJ2,
which encodes the inward rectifier potassium channel Kir2.1.
Primary PPs are inherited muscular disorders caused by muta-
tions in the muscular sodium, calcium or potassium channels.
Due to the striking similarities in their clinical features, it is diffi-
cult to make a prediction of which ion channel could be altered
in a particular patient. Post-exercise electrophysiological tests
can be helpful because different patterns of the compound muscle
action potentials (CMAP) changes over time correlate with specific
channel mutations (Fournier et al., 2004). However literature
describing these tests in ATS patients is scarce (Bendahhou et al.,
2005). In this report we present two ATS patients, one of them with
a new mutation in the KJN2 gene, and describe their response to
the exercise test.
1. Case reports
1.1. Case 1
A 28-year-old male patient complained of recurrent episodes
consisting in generalized weakness in the upper and lower limbs
after exercise. The patient has two kinds of episodes: most com-
mon ones consist in moderate weakness beginning several hours
after exercise. They did not interfere significantly with his daily
activities and last no longer than 5–6 h. Less common ones consist
in severe weakness that appears during exercise and impairs his
daily live activities for 1 or 2 days. Potassium levels during epi-
sodes were normal. He was diagnosed of cardiac arrhythmia at
age 25. Familiar history was unremarkable. General examination
showed hypertelorism, low implanted ears and mandible hypopla-
sia. Muscular strength between acute episodes was normal. DNA
mutation screening of the KCNJ2 gene revealed the presence of a
heterozygous C to T transition (c.C652T), leading to the aminoacid
exchange arginine to tryptophan (p.R218W).This mutation has
been previously reported as pathogenic (Plaster et al., 2001).
1.2. Case 2
A 37-year-old male complained of episodic weakness in both
upper and lower limbs. He had his first episode at age 15, and con-
sisted in unilateral weakness in the left leg that lasted about a
week. At 19 years old, he had an episode that left him bed-ridden
for a week. Since then he has had similar symptoms every 2 years,
until last year, when he presented four moderate attacks, all of
them, a week long. He was not able to identify any trigger, though
he thought they could be related to strong exercise. He had an iso-
lated episode of seizures when he was 18 years old but no other
remarkable medical or family history. General examination dis-
closed low-set ears and clinodactilia in his left hand. During the
episodes he exhibits limb weakness, more severe in proximal mus-
cles. Serum potassium levels were high, low or normal. ECG
showed a prominent U wave and episodic bigeminism during
sleep. Sequencing of the KCNJ2 gene revealed a novel heterozygous
G to C transversion in codon 300 (c.G899C), which altered the ami-
noacid glycine to alanine (p.G300A). A different missense mutation
within the same residue has been previously described as patho-
genic (p.G300V) (Plaster et al., 2001). This mutation was neither
present in his unaffected parents nor in 100 controls from the
same population, and was considered a de novo mutation.
2. Electrophysiological studies
Conventional electrophysiologic studies were normal between
the episodes in both patients and electromyography did not dem-
onstrate myotonia or other abnormalities.
We performed the exercise test following the protocol
described by Fournier (Fournier et al., 2004). Short exercise test
produced an important reduction of the ulnar CMAP amplitude
(28%, 50 s after exercise) in patient 1 only (Fig. 1). In contrast, long
exercise test produced a decrement in the ulnar CMAP amplitude
2 min after the effort that was maximum at 25 min, when a 47%
reduction was recorded. The response was similar, but delayed,
in patient 2. Abnormal reduction appeared 5 min after the effort
and slowly progressed until a maximum decrease of 29% in the ul-
nar CMAP at 40 min. We did not find other changes in CMAP char-
acteristics including latency or duration. Both patients developed
weakness in the abductor digiti minimi during the test that com-
pletely recovered 3 days after the exercise.
We had the opportunity to perform a new neurophysiological
study in patient 2 during an acute episode of weakness. We
observed a medium reduction of 30% in CMAP amplitudes com-
pared with basal intercritical studies. This decrement was compa-
rable to the maximum reduction reached with the exercise test.
The duration of the CMAP was also modified during the crisis:
the ulnar CMAP duration was 4.9 ms, significantly longer than
the one obtained in basal studies, when it was 3.6 ms. We neither
observed myotonic discharges nor other abnormalities in the nee-
dle EMG study during the acute episode.
3. Discussion
Periodic paralyses are due to the dysfunction of the sodium,
potassium or calcium muscle channels. The diagnosis of PP is
based on clinical findings, neurophysiologic studies and genetic
testing. Clinical features and serum potassium levels during
1388-2457/$36.00 ? 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2011.04.025
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attacks may help to differentiate between channelopathies, but
these data are not sufficient for the diagnosis. Diagnostic tests that
could help in PP syndromes classification are important as genetic
studies of channel subunits are time-consuming and expensive. In
1986, McManis published an exercise protocol test for the study of
PP patients (McManis et al., 1986). In this test, patients’ CMAPs are
recorded before and after a long term physical effort. The electro-
physiological findings elicit the clinical findings and confirm, in
most cases, the clinical suspicion. Fournier modified the McManis
test by adding electromyographic analyses to search for the pres-
ence of myotonia and a CMAP analysis after short term exercise
(Fournier et al., 2004). Fournier test differentiates between five
main electrophysiological patterns (I to V) that correlate with
mutations in different genes causing PP. This study clarified the
genetic test algorithm to be done in each patient and it is generally
accepted as one of the recommended tests to be performed in all
PP patients. Despite of this, data concerning the response of ATS
patients to the Fournier test are scarce. Bendahhou published
two cases showing a significant decrease of the ulnar CMAP only
after long term exercise, confirming the previous observations of
significant decrement in the ulnar CMAP using the McManis test
in ATS patients (Katz et al., 1999; Davies et al., 2005). This kind
of response is compatible with Fournier type V that is also present
in PP patients harboring mutations in the calcium channel
(Bendahhou et al., 2005).
We report our experience with Fournier test in 2 patients af-
fected of ATS with mutations in the KJN2 gene. Patient 1 experi-
enced a significant reduction in ulnar CMAP both after short and
long post-exercise test. This has not been previously described in
other PP syndromes. A significant decrement after short and long
post-exercise tests has been reported in PP caused by sodium
channel mutations. However, in those cases, patients had myotonic
discharges, absent in ours (Fournier et al., 2004). In contrast, pa-
tient 2 presented a significant decrement only after long exercise,
as has been described in other ATS patients, including two differ-
ent families carrying the mutation R218W, the same we detected
on patient 1 (Davies et al., 2005). We do not know the exact reason
for this difference, but it reproduces the clinical situation: patient 1
suffered transient weakness every time he performed a physical ef-
fort. In the other hand the ulnar CMAP decrement recorded during
a relapse in patient 2 was very similar to the maximum decrease
obtained after the long exercise test. These findings support the
notion that Fournier test may reflect what happens in ATS patients
during relapses and highlight the utility of this test for the study of
PP patients.
References
Bendahhou S, Fournier E, Sternberg D, Bassez G, Furby A, Sereni C, et al. In vivo and
in vitro functional characterization of Andersen’s syndrome mutations. J Physiol
2005;565:731–41.
Davies NP, Imbrici P, Fialho D, Herd C, Bilsland LG, Weber A, et al. Andersen–Tawil
syndrome: new potassium channel mutations and possible phenotypic
variation. Neurology 2005;65:1083–9.
FournierE,ArzelM,SternbergD,VicartS,LaforetP,EymardB,etal.Electromyography
guides toward subgroups of mutations in muscle channelopathies. Ann Neurol
2004;56:650–61.
Katz JS, Wolfe GI, Iannaccone S, Bryan WW, Barohn RJ. The exercise test in Andersen
syndrome. Arch Neurol 1999;56:352–6.
McManis PG, Lambert EH, Daube JR. The exercise test in periodic paralysis. Muscle
Nerve 1986;9:704–10.
Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, et al.
Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes
of Andersen’s syndrome. Cell 2001;105:511–9.
Fig. 1. The compound muscle action potentials (CMAPs) of the abductor digiti minimi (ADM) were recorded with skin electrodes following the ulnar nerve stimulation at
wrist before and after exercise. (A and C) Changes in CMAP amplitude of ADM muscle following short and long exercises, respectively. The amplitude of the CMAPs is
expressed as a percentage of its pre-exercise value is plotted against the time elapsed after the exercise trial (B and D). Pre-exercise (top trace) and post-exercise recordings
(below) at different times following the trial (Exercise) as indicated by an arrow are represented. Patient 2 left ulnar CMAP amplitude was registered also during a crisis and is
represented at the bottom of panel D.
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Letter to the Editor/Clinical Neurophysiology xxx (2011) xxx–xxx

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J. Díaz-Maneraa,b,*
L. Querola
J. Clarimónb,c
S. Yagüed
I. Illaa,b
aNeuromuscular Disorders Unit,
Neurology Department,
Hospital de la Santa Creu i Sant Pau,
Universitat Autònoma de Barcelona, Barcelona, Spain
bCentro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Madrid 28031,
Spain
cNeurology Department,
Hospital de la Santa Creu i Sant Pau,
Barcelona, Spain
dDepartment of Neurology, USP Dexeus University Institute,
Barcelona,
Spain
⇑Corresponding author at: Neurology Department,
Hospital de la Santa Creu i Sant Pau,
Sant Antoni M. Claret Street,
No. 167, 08025 Barcelona, Spain
Tel.: +34 935565986; fax: +34 935565602.
E-mail address: JDiazM@santpau.es (J. Díaz-Manera)
Letter to the Editor/Clinical Neurophysiology xxx (2011) xxx–xxx
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