Derrame

1. Case Report
A patient with type II citrullinemia who developed refractory
complex seizure☆
Shigeaki Sakamoto, M.D.a
, Hideto Shinno, M.D., Ph.D.a,⁎, Misao Ikeda, M.D.a
,
Hisaaki Miyoshi, M.D.b
, Yu Nakamura, M.D., Ph.D.a
a
Department of Neuropsychiatry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan
b
Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kida, Kagawa 761-0793, Japan
Received 19 December 2011; accepted 23 March 2012
Abstract
A 31-year-old Japanese male was admitted to our hospital for refractory complex seizures. He had no history on medical or psychiatric
illness. He began to exhibit aberrant behavior accompanied by cloudiness of consciousness. Thereafter, he exhibited partial seizures followed
by a twilight state or abnormal behavior. Previous treatment with valproate and carbamazepine failed to improve his seizures. Because an
increase in plasma ammonia was noted, anticonvulsant was discontinued within a week. He was then transferred to our department. Blood
examination revealed an increase in ammonia. Amino acid analysis demonstrated a marked increase in citrulline and decrease in arginine. He
was diagnosed with type II citrullinemia. After being treated with arginine hydrochloride, the seizures and disturbed consciousness improved.
He was then discharged, and remains in remission.
Accumulations of citrulline and ammonia and a reduction of arginine are noted in argininosuccinate synthetase deficiency, which
results in the sudden emergence of consciousness disturbance and abnormal behavior. It is essential to examine amino acid levels
as well as ammonia levels in patients with unexplained neuropsychiatric symptoms, especially those with altered consciousness levels
and seizures.
© 2013 Elsevier Inc. All rights reserved.
Keywords: Arginine; Citrulline; Complex seizure; Soybeans; Urea cycle disorder
1. Introduction
The incidence of urea cycle disorder (UCD) in the United
States is estimated to be at least 1 in 25,000 births [1]. A
Japanese study reported that the incidence was 1 in 46,000
[2]. Type II citrullinemia is adult-onset, while types I and III
are neonatal/infantile-onset. [3]. Type II citrullinemia is
usually characterized by the sudden emergence of con-
sciousness disturbance, restlessness, and abnormal behavior
[4]. Because UCDs often become fatal [4], early diagnosis
and treatment are mandatory for successful treatment.
Here, we report a case of type II citrullinemia who
developed refractory complex seizures.
2. Case
A 31-year-old Japanese male was admitted to our
hospital for refractory complex seizures. He had no history
on medical or psychiatric illness. Although he had lived a
normal life, he had a peculiar dietary habit. His favorite
foods were beans, and he had eaten large quantities of nuts
and soybean foods every day. At 31 years old, he married.
About 2 months after marriage, he began to exhibit
aberrant behavior accompanied by cloudiness of con-
sciousness. Thereafter, he demonstrated tonic-clonic sei-
zures followed by a twilight state or abnormal behavior.
He was admitted to psychiatric hospital (hospital A), and
treated with valproate and carbamazepine, which failed to
improve his seizures. Because an increase in plasma
ammonia was noted, anticonvulsant use was discontinued
within a week. Psychiatrists at hospital A had considered
that anticonvulsants elevated the ammonia level, and he
Available online at www.sciencedirect.com
General Hospital Psychiatry 35 (2013) 103.e1–103.e3
☆
Conflict of interest: none.
⁎ Corresponding author. Tel.: +81 87 891 2165; fax: +81 87 891 2168.
E-mail address: shinnoh@med.kagawa-u.ac.jp (H. Shinno).
0163-8343/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.genhosppsych.2012.03.019

2. was then transferred to our department. Electroencepha-
lography (EEG) demonstrated that basic activity was 3–4
Hz (Fig. 1A). Blood examination demonstrated an
increase in ammonia (598 mg/dl). Although phenytoin
resulted in transient improvement of the cognitive func-
tion such as orientation and communication for 3 days,
the level of ammonia increased. Thereafter, he began to
present partial seizures and a twilight state with abnormal
behavior. Amino acid analysis demonstrated a marked
increase in citrulline [563 nmol/L in plasma (normal
range: 28–41), 979 μmol/l in urine (normal range: 0–
15)]. Abdominal ultrasonography and histological exam-
ination by liver biopsy demonstrated no specific patho-
logical findings (such as cirrhosis and carcinoma) that
may be responsible for hyperammonemia. He was diag-
nosed with type II citrullinemia [1]. After treatment with
arginine hydrochloride, the seizures and disturbed con-
sciousness improved. EEG after treatment showed alpha
activity (Fig. 1B). He was then discharged, and remains
in remission.
3. Discussion
The urea cycle was first described in 1932 by Krebs
and Henseleit [5]. Argininosuccinate synthetase (ASS) is
the rate-limiting enzyme of the urea cycle, and a deficiency
of ASS causes accumulations of citrulline and ammonia,
and reduction of arginine. ASS is the rate-limiting enzyme
of the urea cycle, and catalyzes the formation of arginino-
succinate from citrulline [5]. A deficiency of ASS causes an
increased plasma level of ammonia. Type II citrullinemia
is adult-onset, while types I and III are neonatal/infantile-
onset [3]. He had no history on medical or psychiatric
illness, and had lived a normal life. He had eaten large
quantities of nuts and cooked soybeans, which helped to
compensate for the shortage of arginine. After he married,
his wife cooked well-balanced dishes for him, which
paradoxically worsened arginine deficit. Arginine is a con-
ditionally non-essential amino acid. It is usually synthesized
in the human body and does not need to be obtained
through the diet. In patients with citrullinemia, it is common
to tailor diets (e.g., excess intake of soybean products) to
manage an inborn error of metabolism. Recent dietary
changes and intercurrent infection were reported to be
major perceived triggers that preceded hyperammonemic
episodes [6].
A large longitudinal study reported that patients exhibited
the sudden emergence of neurological symptoms such as
consciousness disturbance and an altered mental status.
Seizures are sometimes presented, while they are less
prevalent (b10%) [4]. Blood biochemical tests demonstrate
no characteristic abnormalities, although an increase in the
plasma level of ammonia is significant. In addition, no
specific findings are obtained by examinations of the liver
with ultrasonography or magnetic resonance imaging.
Fp1 Fp1
Fp2 F7
F3 F3
F4 C3
C3 T3
C4 P3
P3 T5
P4 O1
O1 Fp2
O2 F8
F7 F4
F8 C4
T3 T4
T4 P4
T5 T6
T6 O2
respiration
ECG ECG
A before admission B at remission
Fig. 1. Electroencephalography. Electroencephalography was carried out based on the standard guidelines. The figure represents EEG performed before
admission to our hospital (A) and at remission (B).
103.e2 S. Sakamoto et al. / General Hospital Psychiatry 35 (2013) 103.e1–103.e3

3. Most patients with UCD present with an elevated plasma
ammonia level in association with only mild or no liver
dysfunction and in the absence of ketoacidosis. In the present
case, anticonvulsive agents had been administered for
complex seizures, which failed to improve complex seizures
and aberrant behavior accompanied by cloudiness of
consciousness. An increased serum level of ammonia was
noted. It may be difficult to identify causes of hyperammo-
nemia when patients have been treated with anticonvulsive
agents. The typical presentation of valproate-induced
hyperammonemic encephalopathy (VHE) is impaired con-
sciousness and lethargy [7]. There are non-specific abnor-
malities of laboratory data in UCD and VHE, and amino acid
analysis is essential for differential diagnosis.
It is not rare for UCD to be erroneously diagnosed as
epilepsy, schizophrenia, or delirium with seizures. Early
diagnosis and treatment for UCD are mandatory, because it
often becomes severe and fatal. It is, therefore, essential to
examine amino acid levels as well as the ammonia level
in patients with unexplained or nonresponsive neuropsy-
chiatric symptoms, especially those with altered conscious-
ness levels and seizures.
Acknowledgment
We certify that there was no financial support for this study.
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