Clinical Case Report Medicine ®

Delayed recognition of autism spectrum disorder

and attention-deficit/hyperactivity disorder in a
girl with ornithine transcarbamylase deficiency
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A case report
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Shin Kadono, MDa, Dai Miyawaki, MD, PhDa,* , Ayako Goto, MD, PhDa, Kaoru Hirai, MD, PhDb,
Shoko Sakamoto, MDa, Hiroki Hama, MDa, Sayaka Nishiura, MDa, Takashi Hamazaki, MD, PhDb,
Koki Inoue, MD, PhDa

Abstract
Rationale: Ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder, is a rare congenital metabolic error that leads to
hyperammonemia. Psychiatric symptoms of hyperammonemia are nonspecific and can cause autism spectrum disorder (ASD)-
like symptoms and attention-deficit/hyperactivity disorder (ADHD)-like symptoms. Some studies report that OTC deficiency is
often initially diagnosed as ASD or ADHD. However, there are no reports of OTC deficiency comorbid with ASD and ADHD.
Patient concerns: The patient is 17-year-old girl diagnosed with OTC deficiency at 3 years of age. She had behavioral
problems since childhood, including depressed mood, irritability, and impulsive behavior; however, they were considered OTC-
mediated nonspecific psychiatric symptoms. Therefore, the patient had not been appropriately assessed for ASD and ADHD. She
presented with depressed mood and self-harm at 17 years of age.
Diagnoses: We diagnosed her with ASD and ADHD based on her medical history and semistructured interviews.
Interventions: We focused her ASD and ADHD traits and discussed strategies with her for better adaptive living.
Outcomes: Our interventions resulted in her better social adjustment.
Lessons: Physicians should consider the possibility of comorbid ASD and ADHD in individuals with OTC, facilitating appropriate
and intervention for better outcomes.
Abbreviations: ADHD = attention-deficit/hyperactivity disorder, ASD = autism spectrum disorder, OTC = ornithine
transcarbamylase, SOFAS = social and occupational functioning assessment scale.
Keywords: attention-deficit/hyperactivity disorder, autism spectrum disorder, hyperammonemia, ornithine transcarbamylase defi-
ciency, urea cycle disorder

1. Introduction We describe the case of a 17-year-old girl with ASD and

Ornithine transcarbamylase (OTC) deficiency, an X-linked dis-
order caused by mutations in the OTC gene, results in elevated
blood ammonia levels. Autism spectrum disorder (ASD) is a
neurodevelopmental disorder characterized by impaired social
communication and repetitive patterns of behaviors, frequently
comorbid with attention-deficit/hyperactivity disorder (ADHD).
Moreover, it is characterized by hyperactivity, impulsivity, and
difficulty concentrating. Psychiatric symptoms of hyperam-
monemia are nonspecific, and several studies report case of
patients with OTC deficiency, initially diagnosed with ASD or
ADHD.[1–4]
ADHD combined with OTC deficiency. She was diagnosed and
treated for OTC deficiency early in her development, but her
psychiatric symptoms were considered OTC-mediated nonspe-
cific psychiatric symptoms. Although OTC deficiency and ASD
and ADHD can be comorbid, there are no reports of OTC defi-
ciency comorbid with ASD, in addition to ADHD.
2. Case report
Here, we describe the case of a 17-year-old Japanese girl with
OTC deficiency. She did not undergo screening tests for OTC

Written consent was obtained from the patient and her mother to present this
case.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or
analyzed during the current study.
a
Department of Neuropsychiatry, Osaka Metropolitan University (Osaka City
University) Graduate School of Medicine, Abeno-ku, Osaka, Japan, b Department
of Pediatrics, Osaka Metropolitan University (Osaka City University) Graduate
School of Medicine, Abeno-ku, Osaka, Japan.
* Correspondence: Dai Miyawaki, Department of Neuropsychiatry, Osaka
Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi,
Abeno-ku, Osaka 5458585, Japan. (e-mail: miyawakidai@omu.ac.jp).
Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly
cited.
How to cite this article: Kadono S, Miyawaki D, Goto A, Hirai K, Sakamoto
S, Hama H, Nishiura S, Hamazaki T, Inoue K. Delayed recognition of
autism spectrum disorder and attention-deficit/hyperactivity disorder in a
girl with ornithine transcarbamylase deficiency: A case report. Medicine
2023;102:8(e33055).
Received: 25 January 2023 / Accepted: 1 February 2023
http://dx.doi.org/10.1097/MD.0000000000033055

1
 Kadono et al. • Medicine (2023) 102:8Medicine
deficiency, because it is not included in newborn screening tests
in Japan. She was examined by a pediatrician at the age of 3
years because of gait disturbance and somnolence. Previously,
she had been displaying tantrums, hitting and injuring other chil-
dren, and breaking things. She had liver dysfunction and hyper-
ammonemia. Following a detailed examination that detected
elevated blood glutamine levels and an OTC gene mutation
(IVS4-1 G > C heterozygous), she was diagnosed with OTC
deficiency. She had no relevant family history of OTC deficiency.
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She was prescribed a low-protein diet, levocarnitine, l-arginine,
and benzoic acid, resulting in her blood ammonia levels being
normalized. Moreover, her gait disturbance and somnolence
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disappeared. She was examined using the Wechsler Intelligence
Scale for Children-Third Edition at 7 years of age. The results
were full-scale intelligent quotient, 88, verbal comprehension
index, 95, and perceptual reasoning index, 88.[5]
Despite an early and appropriate diagnosis of OTC deficiency
and stabilized ammonia levels for a prolonged period, she was
often reprimanded by her teachers after entering elementary
school for not following their instructions in class or for leaving
a room without putting the toys away after playing. Moreover,
she did not develop good friendships. She often refused to
attend school after the age of 10. At 11 years of age, her parents
divorced, with her mother obtaining custody. Subsequently, her
access to medications became irregular and she could no lon-
ger adequately adhere to the dietary protein restrictions. Her
blood ammonia levels increased to 80 to 90 μg/dL, which is
above the normal range, and she was repeatedly admitted to the
pediatric hospital for hyperammonemia. After entering junior
high school, she gradually became depressed and was unable to
attend school. The situation persisted after entering high school,
and she began to engage in self-harm including arm cutting and
self-choking. At 17 years of age, she was referred to our hospital
by a pediatrician, who led her first visit to a psychiatrist.
We conducted a detailed interview of her life history and
confirmed consistently impaired social communication, repeti-
tive behavior patterns, hyperactivity, impulsivity, and difficulty
concentrating, which persisted since her early childhood. We
assessed her for comorbid ASD and ADHD. She displayed poor
nonverbal communication skills. Moreover, she faced difficul-
ties in developing and maintaining relationships with other chil-
dren. For example, she occasionally responded to angry people
by laughing, which made them angrier. She has had restricted
and fixed interests, such as immersing herself only in a specific
character in animation. Moreover, she displayed poor impulse
control. These symptoms were consistent from childhood and
persisted regardless of metabolic control. She had impaired
social communication skills, restricted and repetitive behavioral
patterns, and difficulty focusing. We assessed her symptoms
using the Pervasive Developmental Disorders Autism Society
Japan Rating Scale and Kiddie Schedule for Affective Disorders
and Schizophrenia.[6,7] Based on her medical history and infor-
mation, she was diagnosed with ASD and ADHD.
We hypothesized that her depressed mood and self-harm
were caused by the difficulty in social adjustment owing to her
inability to interact with others, which was in turn caused by
ASD and ADHD. During her visit to our hospital, her social and
occupational functioning assessment scale (SOFAS) score was
35, indicating major impairment in school and friendships.[8]
We decided to educate her about ASD and ADHD and to fol-
low-up on her neuropsychiatric symptoms. Her blood ammonia
level ranged from 80 to 90 μg/dL at baseline. Occasionally, she
responded to psychosocial events and became more depressed,
leading to more frequent self-harm. Concurrently, she could
not adequately adhere to the low-protein diet or medications,
and her ammonia levels were further elevated. The pediatrician
continued the treatment for hyperammonemia, and we moni-
tored her neuropsychiatric symptoms. She was occasionally
admitted to a psychiatric ward upon experiencing a particularly
2
strong depressive episode. We discussed strategies with her for
better adaptive living, considering her ASD and ADHD traits.
We observed her failure to sufficiently understand the intended
meaning communicated and discussed this observation with
her. We aimed to help her develop more adaptive relationships.
Consequently, we drafted subgoals for her daily life and struc-
tured the environment such that she could achieve them. For
example, we visualized her daily schedule on a piece of paper
and used the alarm function on her watch to remind her of her
appointments.
After graduating from high school, she continued to receive
outpatient psychiatric treatment and was able to secure a part-
time job with employment support that considered her ASD and
ADHD symptoms. We continued to provide her with support-
ive outpatient treatment, not medication, and her SOFAS score
improved to 70, indicating slight impairment in social and occu-
pational functioning.[8] Written consent was obtained from the
patient and her parents to present this case.
3. Discussion
Here, we reported a case of ASD and ADHD, comorbid with
OTC deficiency. We deciphered 2 findings in this case. First,
OTC deficiency can be comorbid with ASD and ADHD. Second,
appropriate and timely interventions for ASD and ADHD traits
in patients with comorbid OTC deficiency may improve their
psychiatric symptoms, resulting in better long term prognosis.
Patients with urea cycle disorders present with psychiatric
symptoms of varying severity, including neurocognitive, behav-
ioral, attentional, and executive functioning deficits.[9] In some
cases, patients are initially diagnosed with ASD or ADHD and
only later diagnosed with an inborn error of metabolism.[1–4]
Kim et al[1] reported a case of the patient, initially diagnosed
and treated for ADHD, subsequently diagnosed with OTC defi-
ciency owing to hemiplegia. Moreover, her neuropsychiatric
symptoms improved with the normalization of ammonia levels.
Serrano et al[2] reported the case of a boy with carbamoyl phos-
phate synthesis disorder, initially diagnosed with ASD, whose
delayed language development and social skills improved with
dietary therapy. Children with urea cycle disorders demonstrate
cognitive deficits, despite mild symptoms; therefore, it is import-
ant to maintain meticulous metabolic control.[10] In the case dis-
cussed by Niwinski et al[3], the ASD traits in a patient improved
after treatment for OTC deficiency, but her blood ammonia level
remained around 200 μg/dL. In our case, the patient’s blood
ammonia level was around 80 μg/dL, but her ASD and ADHD
traits were consistently present. This suggests that in this case,
hyperammonemia and neurodevelopmental disorders exist inde-
pendently. However, there is limited evidence for the comorbid-
ity of inborn metabolic errors and ASD or ADHD. In this case,
we used a detailed history from childhood and semi structured
interview responses to diagnose the comorbidity of ASD and
ADHD with OTC deficiency. This novel report demonstrated
OTC deficiency comorbidity with ASD and ADHD.
ASD can be complicated by various comorbidities, such as
intellectual development, ADHD, and depression.[11] Particularly,
depression and anxiety are common comorbidities.[12] Daviss et
al[13] reported that the rate of depression in youths with ADHD
was higher than in youths without ADHD. Moreover, ADHD
and ASD coexist at high rates.[14] Patients with ASD complicated
by ADHD or ADHD complicated by ASD exhibit more severe
anxiety and depressive symptoms.[15,16] This necessitates assess-
ment of comorbid depression in ASD and ADHD. Furthermore,
neurodevelopmental disorder comorbidities affect the treatment
interventions for depression.[11,13] In this case, depressive symp-
toms and self-harm were supposedly caused by difficulties in
social adjustment. The patient, caregivers, and medical staff rec-
ognized the presence of ASD and ADHD traits as the trigger
of psychiatric symptoms, leading to improvement in psychiatric
 Kadono et al. • Medicine (2023) 102:8www.md-journal.com
symptoms and social prognosis. Moreover, the individualized
treatment of ASD is likely to lead to employment.[17] Routine,
structured, and continuous support from trusted people is
essential for maintaining occupational activities in patients with
ADHD.[18] Thus, considering neurodevelopmental disorders to
improve psychiatric symptoms and social prognosis, is neces-
sary. However, its role in comorbid metabolic diseases in patients
with ASD and ADHD is unclear. In this case, we supported her
employment activities following a better understanding of the
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traits of ASD and ADHD through disease education, leading to
employment and improvement in SOFAS. These efforts were
made in the presence of mild hyperammonemia as the baseline.
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The interventions for ASD and ADHD may be effective even
during comorbid OTC deficiency.
4. Conclusions
Clinicians need to pay more attention to the comorbidity of ASD
and ADHD in patients with OTC deficiency. Neurodevelopmental
disorders-like symptoms in patients with OTC deficiency have
been reported to be treatable by controlling hyperammonemia,
leading to the possibility of underestimating the comorbid ASD
and ADHD. The diagnosis of ASD and ADHD may improve
the long term prognosis by allowing patients to take individual-
ized measures based on their specific traits. Therefore, clinicians
should consider the possibility of comorbid neurodevelopmen-
tal disorders when psychiatric symptoms and social adjustment
do not improve with the appropriate management of urea cycle
abnormalities. However, there is limited evidence for the effec-
tiveness of therapeutic interventions for patients with ASD and
ADHD with hyperammonemia-associated metabolic diseases,
including OTC deficiency; this necessitates further research in
this field.
Acknowledgments
The authors thank the patient and her mother for the agreement
to publish this study.
Author contributions
Writing – original draft: Shin Kadono, Dai Miyawaki.
Writing – review & editing: Ayako Goto, Kaoru Hirai,
Shoko Sakamoto, Hiroki Hama, Sayaka Nishiura, Takashi
Hamazaki, Koki Inoue.
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