Eur J Pediatr (2003) 162: 259–263
DOI 10.1007/s00431-002-1135-1

O R I GI N A L P A P E R

C.E. Keegan Æ D.M. Martin Æ D.J. Quint Æ J.L. Gorski

Acute extrapyramidal syndrome in mild ornithine transcarbamylase
deficiency: metabolic stroke involving the caudate and putamen
without metabolic decompensation
Received: 26 July 2002 / Revised: 28 October 2002 / Accepted: 5 November 2002 / Published online: 7 February 2003
Ó Springer-Verlag 2003

Abstract A 6-year-old male with partial ornithine
transcarbamylase (OTC) deficiency had acute and
rapidly progressive symmetrical swelling of the head of
the caudate nuclei and putamina. Clinical presentation
was ataxia and dysarthria progressing to seizures and
coma; these symptoms gradually resolved with supportive management. Although he had been recently
treated for mild hyperammonemia, there was no evidence of acute metabolic decompensation prior to
presentation, and plasma ammonia and amino acids
were consistent with good metabolic control. This case
is novel in that the neurological insult affected the
neostriatum of the basal ganglia and the episode
occurred in the absence of an apparent metabolic abnormality, unique observations in a patient with OTC
deficiency. Conclusion: This case suggests that the
pathophysiology of metabolic stroke is complicated. It
also argues for an evaluation for metabolic stroke in
patients with known inborn errors of metabolism who
present with unusual neurological symptoms in the
absence of biochemical abnormalities. Similarly, this
case suggests that patients presenting with unexplained
neurological insults might benefit from an evaluation
for an inborn error of metabolism.

C.E. Keegan Æ D.M. Martin Æ J.L. Gorski (&)
Department of Pediatrics and Communicable Diseases,
Division of Pediatric Genetics, University of Michigan
School of Medicine, 3570 MSRB II, P.O. Box 0688,
Ann Arbor, MI, 48109-0688, USA
E-mail: jlgorski@umich.edu
Tel.: +1-734-7635276
Fax: +1-734-7639512
D.M. Martin Æ J.L. Gorski
Department of Human Genetics, University of
Michigan Medical School, 48109 Ann Arbor, MI
D.J. Quint
Department of Radiology, University of Michigan Medical
School, 48109 Ann Arbor, MI

Keywords Metabolism Æ Amino acid metabolism
Inborn errors Æ Basal ganglia Æ Neostriatum
Abbreviations OTC Ornithine transcarbamylase Æ CPS
Carbamyl phosphate synthetase Æ MELAS
Mitochondrial myopathy-encephalopathy-lactic acidosis
and stroke-like episodes

Introduction
Ornithine transcarbamylase (OTC) deficiency (MIM
311250) is the most common urea cycle disorder, with an
estimated incidence of 1/14,000 [2]. Urea cycle disorders
usually present in the neonatal period with encephalopathy and hyperammonemia (typically greater than
200 lM; normal 11–35 lM) without increased anion
gap. Older patients with hyperammonemia due to metabolic decompensation commonly present with ataxia,
dysarthria and/or mental status changes. Hyperammonemia is a medical emergency; untreated it leads to
astrocyte swelling and generalized cerebral edema [2].
Unless treatment is rapidly instituted, developmental
delay and mental retardation are likely; neurological
outcome is correlated with the frequency and duration
of hyperammonemic encephalopathy [17, 18, 23].
Metabolic stroke, defined as acute focal neurological
deficits with correlated lesions on brain imaging, is a
well-documented but poorly understood complication of
certain inborn errors of metabolism. In previously reported patients, these episodes were typically accompanied by acute metabolic decompensation with significant
biochemical abnormalities [4, 5, 11, 12, 13, 15, 20, 22].
Some cases were reversible [4, 12, 20, 22], while other
cases were fatal [5, 8, 9, 10, 13]. Here we describe a
patient with OTC deficiency who, despite evidence of
good metabolic control at the onset of symptoms, developed a reversible neurological insult to the neostriatum (caudate and putamen). This case is novel; to our
knowledge, acute reversible insults to the neostriatum
have not been reported in patients with OTC deficiency.

260

This observation suggests that factors other than acute
systemic metabolic decompensation may account for
this stroke-like syndrome.

Case History
D.A. was born to a 31-year-old woman who had a confirmed
family history of OTC deficiency (Fig. 1). Biochemical abnormalities consistent with the diagnosis of OTC deficiency, including
hyperammonemia, elevated plasma glutamine and urinary orotic
acid with low plasma arginine and citrulline were noted in infancy.
Previous mutational analyses of the OTC gene in a maternal cousin
showed a Y202H missense mutation (CAC>TAC) (Fig. 1); this
mutation was reported in an unrelated individual with OTC deficiency who presented at 2 years of age with hyperammonemia and
encephalopathy [1]. Diagnostic biochemical abnormalities, a family
history of OTC deficiency, and DNA diagnostic studies in an affected maternal cousin confirmed the diagnosis of OTC deficiency
in our patient.
D.A. had numerous hospitalizations for hyperammonemia
presenting as lethargy and transient ataxia; these had been successfully treated with protein restriction and intravenous sodium
benzoate and sodium phenylacetate. Laboratory values from a
typical hospitalization at age 5.5 years are shown in Table 1. D.A.
had delayed developmental milestones; at age 4, he was ambulatory
and had minimal expressive language. By age 5, he used utensils
and was toilet trained. He was diagnosed with attention deficit
hyperactivity disorder and had significant behavioral problems
including property destruction and the mistreatment of animals.
At age 5 and 11/12 years, he presented with a broad based gait,
hyperammonemia (131 lM), and a presumed viral infection. He
was treated with intravenous sodium benzoate, sodium phenylacetate, and arginine and was discharged after a 3-day hospitalization
with a normal neurological examination and a normal ammonia
level. Twenty-four hours after discharge, he presented with acute
onset of ataxia, drooling, and slurred speech without associated
symptoms. His ammonia was 22 lM (normal, 11–35). Plasma
glutamine was moderately elevated at 721 lM (normal, 123–600);
citrulline and arginine were within normal limits. Essential amino
acids, albumin, and total protein were normal, reflecting adequate
nutritional status and liver protein synthesis (Table 1). A
non-contrast head CT scan was normal, with no evidence of
acute hemorrhage, ischemia, or infarction. He remained stable

Fig. 1 Four-generation pedigree showing males (h), females (s),
and obligate carrier females ( ). P indicates the propositus, D.A.
(IV-11). Individuals III-8, -10, and -23 and IV-6, -8, -10, and -11
had biochemical evidence of OTC; individual IV-13 had a Y202H
missense OTC mutation. Males who died in infancy (individuals II3, III-3, -4, -15, -16, and IV-5) are presumed to have had OTC
deficiency. Spontaneous abortions are indicated (’). Ages are given
for deceased individuals (III-12) or infants (inf )

metabolically, but worsening ataxia and dysarthria prompted a
brain MRI on hospital day 2, which showed mild increased signal
intensity in the putamina and head of the caudate nuclei, consistent
with gray matter swelling (Fig. 2A). On hospital day 3, he developed right-sided seizures and coma. He had brisk deep tendon
reflexes, ankle clonus and a left Babinski sign; intermittent choreiform movements of the arms were noted. Repeat non-contrast
head CT scans on hospital days 3 and 4 showed subtle interval
development of decreased attenuation in the basal ganglia, consistent with focal edema (Fig. 2B). There was no evidence of diffuse
cerebral edema, acute hemorrhage or ischemia. A prothrombin
time was slightly elevated; serum albumin and total protein
remained normal, indicating normal liver function (Table 1).
Just prior to the onset of seizures, D.A.’s ammonia level was
98 lM (Table 1). He was treated with intravenous sodium benzoate, sodium phenylacetate and arginine, and his ammonia level
quickly normalized. During his acute ataxia and seizures, his
plasma glutamine was normal (267 lM) and he had a normal urine
organic acid profile. Serial arterial lactate and pyruvate measurements during his hospitalization were normal. CSF for lactate and
quantitative amino acids were also normal (Table 1). Additionally,
mitochondrial DNA mutational analyses for tRNA leucine mutations associated with MELAS (mitochondrial myopathyencephalopathy-lactic acidosis and stroke-like episodes; MIM 540000) were
normal. Lumbar puncture showed normal white and red blood cell
counts, protein, glucose, Gram stain and culture. Blood and CSF
viral cultures, and CSF PCR for herpes simplex virus were negative. A blood lead level, carboxyhemoglobin determination, and
hair analysis for heavy metals were normal; an HIV antibody test
was also negative.
An EEG on hospital day 4 showed diffuse suppression, consistent with moderate encephalopathy. Repeat brain MRI on
hospital day 9 showed increased signal intensity in the head of the
caudate nuclei and putamina, consistent with progression of the
edema in these regions (Fig. 2C and D). His neurological status
gradually improved with supportive care, and he was extubated on
hospital day 15. At discharge on hospital day 33, he was eating
normally, speaking with some dysarthria, walking with assistance,
and riding a tricycle. After 3 additional weeks, he had returned to
his baseline behavioral and neurological status; he was walking,
running, and speaking in full sentences. He continued to have mild
difficulties with balance and a resting hand tremor.

Discussion
We present a 6-year-old male with partial OTC deficiency who acutely developed edema of the neostriatum
with correlative symptoms in the setting of normal
biochemical parameters. The presenting symptoms of
ataxia and dysarthria were more severe than those previously observed during previous episodes of hyperammonemia. His ammonia at the time of presentation was

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Table 1 Blood and CSF laboratory values

NH3a
Glutaminea
Alaninea
Citrullinea
Argininea
Threoninea
Valinea
Cystinea
Isoleucinea
Leucinea
Phenylalaninea
Tryptophana
Lysinea
Histidinea
Lactateb
Pyruvateb
CSF glutaminea
CSF lactateb
Albuminc
Total proteinc
Prothrombinetime/INR

Past hospitalization

3 days prior
to episode

Acute
episode

Onset of
seizures

Day of
discharge

3 weeks following
discharge

Normal
values

264
1207
185
1
42
45
99
33
34
59
33
24
207
77
–
–
–
–
4.8
7.7
–

131
910d
1210d
76d
74d
110d
116d
25d
25d
40d
48d
0d
164d
94d
–
–
–
–
4.5
7.2
–

22
721
843
26
78
95
177
30
37
79
42
18
141
61
–
–
–
–
3.9
6.5
–

98
267
510
6
112
42
55
39
12
22
37
17
75
65
0.6
0.05
454
2.2
3.4
6.1
11.8/1.2

12
471
682
22
136
66
47
40
10
18
24
22
92
45
–
–
–
–
3.2
–
–

17
499
303
13
47
157
130
18
43
72
31
20
102
54
–
–
–
–
–
–
–

11–35
123–600
141–343
2–41
40–145
85–196
112–284
3–48
35–79
60–168
30–70
0–123
81–213
47–104
0.5–2.2
0.03–0.15
161–533
0.5–2.2
3.2–5.2
5.8–8
9.3–11.1

a

Plasma or CSF concentrations; all values in micromolar (lM)
Serum or CSF concentrations in milliequivalents/liter
Serum concentrations in grams/deciliter
d
Values obtained 2 weeks prior to presentation
e
Values are in seconds. Dashes (–) denote values not obtainedf
b
c

in the normal range and his glutamine was only modestly elevated. Essential amino acids, total protein and
serum albumin concentrations were normal, reflecting
adequate nutritional status. Although he had recently

been hospitalized with mild hyperammonia, he had
returned to his baseline status 24 h prior to the onset of
his new acute symptoms. Head MRI scans showed evidence of injury to the basal ganglia, specifically in the
head of the caudate nuclei and the putamina. Ultimately, his neurological status improved and he was left
with minimal residual neurological deficits. To our
knowledge, metabolic stroke affecting the basal ganglia
without associated metabolic derangement in a patient
with OTC deficiency has not been described previously.
Metabolic stroke has been described in patients with
urea cycle defects, including several patients with OTC
deficiency and in one patient with carbamyl phosphate
synthetase (CPS) deficiency (MIM 237300) [4, 5, 13, 15,
20]. Each of these patients presented with hemiparesis
and hyperammonemia in the range of 300–400 lM, and
all had a CT or MRI pattern consistent with infarction
b

Fig. 2A–D Results of neuroimaging studies. A Axial fluid attenuated inversion recovery (FLAIR) MR scan on hospital day 2
demonstrates mild increased signal from the putamina (long
arrows) and more subtle increased signal from the head of the
caudate nuclei (short arrows) bilaterally. The globi pallidi (arrow
heads) display normal signal. B Non-contrast axial CT scan on
hospital day 4 demonstrates subtle decreased attenuation from
region of the putamina (long arrows). C Axial fluid attenuated
inversion recovery (FLAIR) MR scan on hospital day 9 demonstrates progressive increase in signal from the putamina (long
arrows) and head of the caudate nuclei (short arrows) over 7 days.
D Contrast-enhanced T1-weighted MR scan shows mild local mass
effect associated with the putaminal abnormalities, no enhancement is seen (long arrows). The globi pallidi (arrow heads) are
normal on both FLAIR and T1-weighted images

262
Table 2 CNS regions affected in metabolic stroke
Disorder

Cortex

Cerebellum

Basal ganglia/
globus pallidus

Basal ganglia/caudate
and putamen

Current patient
OTC
CPS
Propionicacidemia
Methylmalonicacidemia
Glutaricacidemia type I
Isovalericacidemia
3-methylcrotonyl CoA carboxylase
Leighsyndrome
MELAS

–
+
+
–
–
–
–
+
+
+

–
–
–
+
+
–
+
–
+
+

–
–
–
+
+
–
–
–
+
+

+
–
–
–
–
+
–
–
+
+

Refs.

[4, 5,13, 15]
[20]
[8, 9,10]
[3, 11,12, 22]
[7, 14]
[6]
[21]
[16, 19]
[19]

OTC ornithine transcarbamylase deficiency; CPS carbamyl phosphate synthetase deficiency; MELAS mitochondrial myopathy encephalopathy lactic acidosis stroke-like episodes

or ischemia of the cerebral cortex. None of these patients
had evidence of damage to the basal ganglia as seen in
our patient. Interestingly, the four patients with OTC
deficiency were heterozygous females, and the diagnosis
of OTC deficiency was made after the onset of strokelike symptoms [4, 5, 13, 15].
Stroke-like symptoms are relatively uncommon in
patients with inborn errors of metabolism. Excluding
mitochondrial disorders, such as Leigh syndrome (MIM
256000) and MELAS (MIM 540000), metabolic stroke
has been reported in approximately 20 patients. There
appears to be some specificity for certain affected regions
of the brain, depending on the type of metabolic disorder (Table 2). Patients with organic acidemias, including
methylmalonic acidemia (MIM 251000) and propionic
acidemia (MIM 606054), have been described with acute
injuries to the basal ganglia; however, of note, these
patients had injuries to the globus pallidus, not the
neostriatum [8, 11, 12, 22]. In addition, all but one of
these patients had metabolic decompensation with significant acidosis at the time of presentation [8]. The recent observation of a patient with methylmalonic
acidemia who suffered a metabolic stroke while in good
metabolic control almost 5 years after liver transplantation suggests that factors other than hepatic correction
of enzyme activity may predispose to metabolic stroke
[3].
A number of mechanisms have been proposed to
account for the neurological abnormalities associated
with metabolic stroke. These include the accumulation
of toxic substances within the basal ganglia [22], hypoxic-ischemic (watershed) injury [13, 15], severe ketoacidosis [11], and accumulation of glutamine in the brain
[20]. The basal ganglia are thought to be especially
susceptible to hypoxic and/or ischemic damage, and
necrosis of the globus pallidus is a frequent acute complication of exposure to both carbon monoxide and
cyanide [11], both of which were ruled out in our patient.
Given this increased requirement for oxidative metabolism, it has been hypothesized that basal ganglia injuries
in patients with metabolic stroke are due to a deficiency
of mitochondrial energy metabolism [9]; however, the
exact mechanism of injury to the brain is unknown.

In summary, metabolic stroke is a recognized complication of several different inborn errors of metabolism. The etiology of this neurological insult is unknown,
but possibly involves accumulation of toxic intermediates or disruption of mitochondrial function. To our
knowledge, this is the first report of metabolic stroke in
OTC deficiency involving the basal ganglia and occurring in the absence of acute metabolic decompensation.
Our report suggests that patients with inborn errors
presenting with neurological symptoms and normal
biochemical parameters should be evaluated carefully
for the development of metabolic stroke. Similarly, patients with acute, unexplained neurological insults
should be evaluated for inborn errors of metabolism.
This case adds to the expanding list of disorders with a
variety of presentations that can be classified as metabolic stroke.

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