Journal of Human Genetics (2010) 55, 186–188
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SHORT COMMUNICATION

A novel neuropsychiatric phenotype of KCNJ2
mutation in one Taiwanese family with
Andersen–Tawil syndrome
Hoi-Fong Chan1, Meng-Ling Chen2, Jen-Jen Su2, Li-Chin Ko2, Chin-Hsien Lin2,3 and Ruey-Meei Wu2
Andersen–Tawil syndrome (ATS) is a rare familial potassium channelopathy characterized by the clinical triad of periodic
paralysis, cardiac arrhythmia and dysmorphic facial/skeletal features. The majority of ATS patients are caused by mutations of
the KCNJ2 gene, which encodes the inward-rectifying potassium channel protein Kir2.1. However, the effects of the KCNJ2
mutation on the central nervous system are rarely studied. In this report, we describe a heterozygous missense mutation
(p.Thr192Ile) in the KCNJ2 gene, which segregates with the disease phenotype in an ATS family. It is noted that in addition to
the classical clinical phenotypes of ATS, the index patient exhibited major depression and pyramidal tract signs with diffuse
periventricular white matter lesions without contrast enhancement. This mutation and the unusual clinical manifestations
observed underscore the phenotypic complexity underlying ATS. Our observations expand the current knowledge of the
phenotypic variability of ATS caused by the KCNJ2 mutation. Patients with ATS, especially those carrying the KCNJ2 mutations,
should be monitored for their potential neuropsychiatric system involvement.
Journal of Human Genetics (2010) 55, 186–188; doi:10.1038/jhg.2010.2; published online 29 January 2010
Keywords: ATS; cardiac arrhythmia; periodic paralysis; Taiwanese; white matter

INTRODUCTION
Andersen–Tawil syndrome (ATS) is a rare autosomal-dominant
potassium channelopathy characterized by periodic paralysis, cardiac
conduction abnormalities and characteristic facial and skeletal dysmorphic features.1 The latter included short stature, small head size,
ocular hypertelorism, broad nose, low-set ears, cleft palate, mandibular hypoplasia, bilateral transverse palmar creases and clinodactyly of
the fifth fingers and toes.1 It is estimated that B62% of patients with
ATS have mutations in the KCNJ2 gene on chromosome 17q23, which
encodes the pore-forming subunit of an inward-rectifying potassium
channel protein, Kir2.1. Mutations in the KCNJ2 gene cause loss of
function and dominant-negative suppression effects on the Kir2.1
protein, which result in reducing the cellular resting membrane
potential and disturbing the cardiac and skeletal muscle excitability.2
Although the potassium channel protein Kir2.1 is widely expressed
with predominance in the skeletal muscles, heart and brains, the
clinical expressivity and severity are variable. In addition, given that
the importance of potassium channels in neural development is
indisputable, as evidenced by the weaver mouse model, the neuropsychiatric phenotypes of ATS are rarely reported.3–5 One recent study
showed that patients with mutations in the KCNJ2 gene are frequently
associated with deficits in executive function and abstract reasoning,
suggesting that the clinical phenotypes of ATS may involve the central

nervous system (CNS).4 In addition, although infantile afebrile
seizures were observed in 4 of 23 Japanese ATS patients, it remains
unclear why these 4 patients only experienced seizures in infancy.5 To
further characterize the neuropsychiatric phenotype of ATS, we herein
describe a patient with a genetically confirmed KCNJ2 mutation, who
had major depression and diffuse intracranial white matter lesions
with pyramidal tracts signs in addition to the clinical triad of ATS.
CASE REPORT
A 35-year-old woman first presented at age 27 with episodic paralysis.
The onset of four-limb weakness was acute and progressed to near
quadriplegia within 3 days. The duration of each episode was 5–6 days
and there were no obvious triggering factors. There was no history of
remarkable developmental milestone delay. She had typical ATS facial/
skeletal features, including short stature, broad forehead, ocular
hypertelorism, small head size, low-set ears, mandibular hypoplasia
and clinodactyly of the fifth fingers and toes. Neurological examinations revealed symmetric quadriparesis with proximal muscle group
predominance and truncal weakness. It is noted that her deep tendon
reflex was hyperreflexia with positive Babinski’s sign on the left side.
All sensory modality was intact and no fatigability was shown. There
were no cranial nerves or cerebellum abnormalities. Laboratory test
showed mild hypokalemia (K¼2.7) and normal thyroid function.

1Department of Neurology, En Chu Kong Hospital, Taipei, Taiwan; 2Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan and 3Department of Neurology,
National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan
Correspondence: Dr C-H Lin, Department of Neurology, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan.
E-mail: q93421022@ntu.edu.tw
Received 16 November 2009; revised 26 December 2009; accepted 28 December 2009; published online 29 January 2010

Expansion of the clinical spectrum of KCNJ2 mutation
H-F Chan et al
187

She regained her muscle power after oral potassium supplement.
A 24 h Holter electrocardiography showed transient ventricular
bigeminy and prolonged QT interval, which fulfilled the criteria for
long-QT syndrome. Series of image analysis were arranged for her
positive pyramidal signs. The cervical magnetic resonance image
(MRI) was unremarkable, but head MRI showed multiple white
matter lesions without gadolinium enhancement in bilateral hemispheres (Figures 1a and b). As the patient did not have any vascular
risk factors of atherosclerosis and young age at clinical presentation,
lacunar infarcts are unlikely. Further cerebrospinal fluid examination
for suspected demyelinating process was refused by the patient. The
result of visually evoked potential exam was symmetric and normal.
Electroencephalogram (routine and with photic stimulations) showed
no epileptiform activity. Peripheral nerve conduction study was
arranged for asymmetrical Babinski’s sign and the result was normal.
Complete neuropsychiatric examination revealed normal intellectual
functions. There were no deficits in executive function or abstract
reasoning, which was mentioned in the patients with ATS in one
previous study, but severe depressed mood was noted.4 Suicide
ideation and frequent self-injury attempts were noted thereafter. Her
case was later diagnosed as major depression at the age of 35 years
according to DSM-IV criteria.6
Tracing back her family history, her 8-year-old older son is also
affected with ATS with the clinical presentation of cardiac long-QT
syndrome and characteristic facial/skeletal features. There are no
similar white matter lesions on the MRI scan as the proband.
However, complete neuropsychiatric test revealed normal intellectual
function but borderline decreased executive function, which was

measured by the Trail Making Test. His school performance was poor
and was recognized as being learning-disabled, which required modified educational programs by his school. Family history was also
significant for her mother having cardiac arrhythmia and dysmorphic
facial features (Figure 1c). Analysis of the KCNJ2 gene revealed a
heterozygous c.575C4T (p.Thr192Ile) mutation, which segregates
with the disease phenotype (Figures 1c and d).
DISCUSSION
The patient described here had clinical, electrophysiological and
genetic features suggestive of the rare cases previously reported as
ATS.1 Nowadays, more than 30 point mutations of the KCNJ2 gene
have been described in patients with ATS, but no obvious phenotype–
genotype correlations are observed.2,7,8 In our study, we identified one
heterozygous missense mutation, p.Thr192Ile (T192I), in the KCNJ2
gene which segregates with the disease phenotype in this index family.
T192I, which was located in the putative cytoplasmic chain after the
second transmembrane region M2 of Kir2.1, is postulated to have a
crucial role in arranging the location of the phosphatidylinositol-4,
5-bisphosphate (PIP2) binding motif (PKKR, 186–189).9 This codon
has been reported to have one confirmed mutation, p.Thr192Ala, in
two independent Japanese patients with ATS.5,9 Therefore, given its
amino acid position and co-segregation with disease clinical phenotype, we postulate that T192I is most likely the cause of disease in our
index patient.
In addition to the well-known triad of clinical signs, our case
provides direct evidence that ATS could be associated with neuropsychiatric phenotypes, manifesting as diffuse periventricular white

AAACGAGANTCTTGTCTT

wt

wt

wt

8 Y/O
m

Kir 2.1
Kir 1.1

wt

m

7 Y/O
wt

T192I

Kir 3.1
Kir 4.1
Kir 5.1
Kir 6.1

Figure 1 Family pedigree, MRI images and genetic findings in our index patient with KCNJ2 mutation. (a, b) Fluid-attenuated inversion recovery MRI shows
multifocal oval lesions involving the periventricular and subcortical white matter. (c) Family pedigree of our index family. Black symbols denote family
members affected with ATS. The proband we described is marked with an arrow. The patient’s age at the time of the study is indicated on the top right.
m, mutated alleles; wt, normal alleles. (d) Chromatograms of direct sequencing of the KCNJ2 genomic sequence. The position of the mutations identified in
this study is indicated. (e) Amino-acid alignment of one subunit from each of the seven members of the inward-rectifying potassium channels. The mutation
identified in this study is denoted above the alignment. The conserved protein residues are marked in yellow. The amino-acid residues were aligned using the
program Vector NTI (http://www.invitrogen.com/site/us/en/home/LINNEA-Online-Guides/LINNEA-Communities/Vector-NTI-Community/Vector-NTI.html).
Journal of Human Genetics

Expansion of the clinical spectrum of KCNJ2 mutation
H-F Chan et al
188

matter lesions with pyramidal tract signs and major depression.
To prove the connectivity between major depression and ATS is not
easy, especially depression is common in patients carrying chronic
disease. However, the white matter lesions are not commonly seen
clinical signs in a previously healthy subject. Therefore, it is logical to
correlate this phenotype with ATS and worth investigating the impact
of the KCNJ2 mutation on the CNS. Our observations support
previous studies that Kir2.1 has an important role in neural development.3 It is noted that there is one similar case reported in the
previous literature that multiple white matter hyperintense lesions
were found in a 24-year-old woman with ATS caused by the KCNJ2
mutation, who also had diffuse pyramidal signs.10 Consistent with our
neuropsychiatric findings, one recent study that performed neuropsychological tests on ten ATS patients from eight unrelated families
showed that cognitive dysfunctions, including defects in executive
functions and abstract reasoning, could be part of the ATS clinical
spectrums.4 Combined with our observations, these findings suggest
that the neuropsychiatric phenotypes of ATS may be largely underestimated by clinicians and further large sample studies are warranted
to clarify the detail of the CNS involvement in ATS.
The inwardly rectifying potassium channel family (Kirs) is crucial
for numerous cellular functions, including regulating the membrane
potentials of neurons and potassium siphoning in glia cells.11–13
The proper buffering and siphoning of extracellular potassium levels
by the glia cells is instrumental for providing an electrochemical
gradient for driving potassium into glia and thus regaining the
propagation of neuronal action potential between the nodes of
Ranvier.14 Therefore, dysfunction of Kirs may lead to cell death
and structure lesions in the CNS. Deletion of Kirs in mouse models
has been shown to cause hypomyelination of white matter structures
mimicking leukodystrophy, which is supportive with the multiple
periventricular hyperdense lesions in our patient.15 In our study,
we found that the KCNJ2 T192I mutation is the genetic cause of
ATS in our index family. T192I is located on the highly conserved
region of the C-terminal intracellular domain of the Kir2.1 protein
(Figure 1e), highlighting the importance of this residue in the
evolution.5 Given the conservation at this amino acid position
across different members of the inward-rectifying potassium channels,
this substitution may disrupt the functional inward-rectifying
currents and possibly the protein–protein interaction of the Kir2.1
protein. Therefore, we propose that the loss of function mutation of
the KCNJ2 gene noted in our patient may have a dominant-negative
effect on the function of the Kir2.1 protein, which impairs the
maintenance of neuronal action potential on the myelin sheath with
resultant hypomyelination. Future studies with a larger number of
patients are warranted to confirm our hypothesis.

Journal of Human Genetics

In conclusion, our case provides a direct link between ATS and
white matter disease and expands the clinical phenotype of this rare
familial syndrome. Patients with ATS, especially those carrying KCNJ2
mutations, should be monitored for their potential neuropsychiatric
system involvement.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
We thank the patients who have participated in this study and the staff of
the Second Core Lab, Department of Medical Research of National Taiwan
University Hospital, for technical support during the study.

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