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The Urea Cycle Disorders

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 341

The Urea Cycle Disorders

Guy Helman, BS1,2 Ileana Pacheco-Colón, BS2,3 Andrea L. Gropman, MD1,4,5

1 Department of Neurology, Children’s National Medical Center, Address for correspondence Andrea L. Gropman, MD, Department of
Washington, District of Columbia Neurology, Children’s National Medical Center, 111 Michigan Avenue, N.W.,
2 Department of Neurology, Georgetown University Medical Center, Washington, D.C. 20010 (e-mail: agropman@childrensnational.org).
Washington, District of Columbia
3 Center for Functional and Molecular Imaging, Georgetown University
Medical Center, Washington, District of Columbia
4 Department of Genetics and Metabolism, Children’s National
Medical Center, Washington, District of Columbia
5 The George Washington University of the Health Sciences,

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Washington, District of Columbia

Semin Neurol 2014;34:341–349.

Abstract The urea cycle is the primary nitrogen-disposal pathway in humans. It requires the
coordinated function of six enzymes and two mitochondrial transporters to catalyze the
conversion of a molecule of ammonia, the α-nitrogen of aspartate, and bicarbonate into
urea. Whereas ammonia is toxic, urea is relatively inert, soluble in water, and readily
Keywords excreted by the kidney in the urine. Accumulation of ammonia and other toxic
► urea cycle disorders intermediates of the cycle lead to predominantly neurologic sequelae. The disorders
► cognitive function may present at any age from the neonatal period to adulthood, with the more severely
► asymptomatic affected patients presenting earlier in life. Patients are at risk for metabolic decompen-
carriers sation throughout life, often triggered by illness, fasting, surgery and postoperative
► metabolic disease states, peripartum, stress, and increased exogenous protein load. Here the authors
► ornithine address neurologic presentations of ornithine transcarbamylase deficiency in detail, the
transcarbamylase most common of the urea cycle disorders, neuropathology, neurophysiology, and our
deficiency studies in neuroimaging. Special attention to late-onset presentations is given.

Definition Neurobiology of Hyperammonemia

Urea cycle disorders (UCDs) constitute a group of rare con-
genital disorders resulting from a defect in the nitrogen
waste-disposal system responsible for the conversion of
ammonia to urea. Complete or partial deficiency of one of
the six enzymes, or one of the two involved transporter
systems have been described in cases of UCD. Defects in
this pathway, active in periportal hepatocytes, result in
hyperammonemia (HA), a metabolic state of elevated ammo-
nia that can cause cerebral edema and neurologic injury.1
These disorders have variable ages of onset, and prognosis
may range from a relatively mild encephalopathy to profound
developmental disability, usually dependent on severity,
duration, and frequency of HA episodes.
Ammonia accumulation is the result of deficiency or total
absence of one of the six enzymes of the urea cycle. The
entire urea cycle consists of six enzymes, include carba-
moyl-phosphate synthetase 1 (CPS1), ornithine transcar-
bamylase (OTC), argininosuccinate synthetase (ASS),
argininosuccinate lyase (ASL), arginase (ARG1), or N-ace-
tylglutamate synthase (NAGS) in combination with two
transporter systems: the ornithine/citrulline antiporter
ORNT1 and the glutamate/aspartate antiporter citrin, ex-
pressed completely in hepatocytes. 2 Ammonia is produced
by amino acid metabolism and intestinal urease-positive
bacteria,3 and is physiologically present in serum as an ion
(NH4þ) dependent upon pH.4

Issue Theme Neurogenetics; Guest Copyright © 2014 by Thieme Medical DOI http://dx.doi.org/
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342 The Urea Cycle Disorders Helman et al.

Ammonia, in its ionic form, is able to diffuse freely across
the blood–brain barrier into the brain independent of arterial
ammonia concentration.5 Astrocytes are responsible for
maintaining the blood–brain barrier. Ammonia is an impor-
tant enzymatic substrate for reactions in the brain and is
maintained at low concentrations (40–50 µmol/L in the
brain6) by the action of glutamine synthetase (GS) localized
to astrocytes (►Fig. 1). Glutamine synthetase is responsible
for the synthesis of glutamine from ammonia and glutamate,
also known as the glutamate–glutamine cycle.
In HA, metabolic trapping can occur, with the concentra-
tion in the brain tending to be higher than in peripheral
blood.4,7 Glutamine synthetase in astroglial cells near blood
physiology and contribution of elevated glutamine remains
uncertain. Current theories have focused on: (1) glutamine
accumulation, with associated impaired cerebral osmoregu-
lation, and (2) glutamate/NMDA receptor activation, with
resultant excitotoxic injury and energy deficits.13,14 However,
new data has shown that neurotoxicity of ammonia to the
brain can alter amino acid pathways, neurotransmitter sys-
tems, cerebral energy metabolism, nitric oxide synthesis,
oxidative stress, and signal transduction pathways.3,15
Amino Acids
In addition to astrocytic swelling under increased ammonia
and glutamine concentrations, glutamine that is cleaved back

vessels offer short-term buffering during HA. However, glu-
tamine produced as part of the glutamate–glutamine cycle is
osmotically active and can cause Alzheimer type II astrocy-
tosis, leading to cytotoxic edema.8–10 Studies in which the GS
inhibitor methionine sulfoximine is administered demon-
strate reduced ammonia-induced brain edema in both in
vivo11 and in vitro models.12 The astrocyte, therefore, is an
important intermediate in the interactions of glutamine and
ammonia via the glutamate–glutamine cycle.
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to ammonia upon entering the mitochondria produces oxy-
gen reactive species and induces the mitochondrial perme-
ability transition, leading to a cerebral energy deficit,
described below.16,17 Astrocytic swelling also leads to gluta-
mine release into the intercellular space, decreasing cellular
glutamine necessary for GS conversion to ammonia. De-
creased glutamine leads to the death of glutaminergic neu-
rons.18 Patients with UCD also have decreased plasma
arginine (except for those with arginase I deficiency), neces-
sary for nitric oxide and creatine synthesis.19

Ammonia Toxicity to the Brain

Alterations in Neurotransmitters
Excess ammonia (> 100 μM) is associated with deleterious Neurotransmission is also altered in cases of HA. Astrocytic
effects on the central nervous system (CNS), significantly so in swelling results in glutamate release based on pH and calcium
the developing brain. HoHowHHowever, the exact patho- ions as well as inhibition of glutamine reuptake by the astrocyte

Fig. 1 The Glutamate–Glutamine Cycle. Glutamine synthetase localized to astrocytes is responsible for the synthesis of glutamine from ammonia
and glutamate. Glutamate is taken up by neurons and transferred to astrocytes where it is used to synthesize glutamine. Glutamine then diffuses
back to the neuron and is converted to glutamate (Reprinted with permission from Gropman AL , Rigas A. Neurometabolic disorders: urea-cycle
disorder, outcomes, development and treatment. Ped Health 2008;2(6):701–713.)

Seminars in Neurology Vol. 34 No. 3/2014


and depolarization of glutaminergic neurons.15,20 As a
result, there is an accumulation of extracellular glutamate,
resulting in excitotoxic injury through N-methyl-D-aspartate
receptor activation affecting metabolic processes. The disrupted
processes result in poor mitochondrial function, ATP deficits, and
oxidative stress, culminating in cell death.3,14 Other alterations
affect the serotonergic system, with accumulation of serotonin
precursors tryptophan and 5-hydroxyindoleactic acid present in
cerebrospinal fluid (CSF) that are thought to contribute to
anorexia and sleep disturbance observed in the early HA
states.6,21
Cerebral Energy Deficit
Alterations in amino acids pathways may lead to inhibition of
processes necessary for cerebral energy production. Ammo-
nia detoxification by the conversion of α-ketoglutarate to
glutamine by glutamine dehydrogenase reduces the amount
available from the tricarboxylic acid cycle.18,22 The creatine/
phosphocreatine/creatine kinase system necessary for cellu-
lar energy is affected by a secondary creatine deficiency after
ammonia exposure.3,14,23–25 Excess ammonia is responsible
for the opening of the mitochondrial permeability transition,
resulting in modified oxidative phosphorylation and cessa-
tion of ATP production, ultimately ending in cell death.3,26
Elevated brain and CSF lactate levels have been found in UCDs,
most likely as a result of decreased pyruvate oxidation.27
Nitric Oxide Synthesis
Nitric oxide is produced from arginine in a reaction catalyzed
by nitric oxide synthase to make up the citrulline-NO cycle,
expressed throughout the CNS. Arginine deficiency in UCDs
inhibits this cycle, leading to decreased NO synthesis, seen in
plasma and urine nitric oxide metabolite levels.28–30
Signal Transduction Pathways, Channels, and Cell
Death
Ammonia exposure on the developing brain and CNS usually
results in cell death, shown in cultures by Braissant et al,
specifically by inducing neuronal apoptosis through caspase
and calpain activation.14,15 Ammonia is also responsible for
the upregulation of ciliary neurotrophic factor through the
activation of p38 mitogen-activated protein kinase,15 in an
effort to protect the astrocyte from damage endured during
HA episodes. These astrocyte pathways also function in
astrocyte swelling and glutamine uptake in HA states.31
Ammonia also activates Naþ-Kþ-Cl- cotransporter-1, which
increases water entry to astrocytes. In HA episodes, astrocytic
protective responses slow ammonia entry and retain water
and potassium; however, this leads to increased cerebral
edema.32,33
Clinical Presentation
Reports of the overall incidence of urea cycle disorders vary
between 1 in 35,000 and 1 in 46,000.34–37 The UCDs are
inherited as autosomal recessive disorders, with the excep-
tion of ornithine transcarbamylase deficiency (OTCD), which
is an X-linked condition.38 A three-generation family history
The Urea Cycle Disorders Helman et al. 343
may serve as a valuable diagnostic tool, as it may suggest a
mode of inheritance. Results of radiological, biochemical, and
genetic testing, as well as dietary preferences, should be
elicited for any relatives, especially children and young adults,
for whom neurologic symptoms are reported. Clinical man-
ifestations of the proximal UCDs (CPS1 and OTCD) are non-
specific to the individual enzyme deficiency and present with
the neurologic effects of HA on the developing CNS include
anorexia, hypotonia, and vomiting in addition to altered
mental status.39,40 Ammonia-induced astrocytic swelling
leads to further neurologic symptoms, including ataxia, seiz-
ures, asterixis, hypothermia, and ultimately coma. If undiag-
nosed, death or significant neurologic injury may occur. The
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severity of the condition is based on the length of hyper-
ammonemic decompensation and complete or partial defi-
ciency of one of the six urea cycle enzymes as well as age of
onset.2,41
Urea cycle disorders are classified as “intoxication-type”
disorders. The fetal-placental circulation is able to clear toxic
metabolites such as ammonia, thus preventing any in utero
sequelae. After delivery, in the absence of placental detoxifi-
cation, HA may result when the defective urea cycle is
challenged by the stress of delivery and the postpartum
environment, including protein feedings.
Neonatal Onset
Children with UCD are normal at birth. Complete enzyme
deficiency is associated with a neonatal onset, mainly present
within the first few days postpartum.42,43 The absence of urea
cycle function overlaps with weight loss and HA, and symp-
toms may become noticeable as soon as 24 hours after birth.
In addition to weight loss, poor feeding, vomiting, lethargy,
tachypnea, seizures, and coma are recorded symptoms. Pre-
sentation is similar to that of the organic acidemias or maple
syrup urine disease. However, a key differentiating feature is
the absence of metabolic acidosis.44 In UCDs, ammonia
stimulates respiratory alkalosis.
Without therapy, death may occur as a result of irrevers-
ible cerebral edema. The most severely affected children with
UCDs have permanent neurologic damage and poor cognitive
outcome. Poor cognitive outcome is not associated with the
peak ammonia level, but seems to correlate more significantly
with the number of days or episodes above a certain ammonia
threshold. These children are usually at risk for recurrent HA
episodes after a “honeymoon” period due to inadvertent high
protein intake or infection.
Late-Onset Presentation
Partial or milder enzyme deficiency can remain undiagnosed
for any amount of time in patients with UCD, including first
presentation in adulthood. The individual may function
relatively normally until ammonia accumulation is triggered
by environmental stress that increases the need for nitrogen
clearance or alters the function of one of the urea cycle
enzymes.45 Because these patients present with symptoms
other than those of typical onset UCDs, diagnosis is rarely
considered in adults, and without treatment the prognosis is
poor. Symptoms prompting consideration of UCD are chronic
Seminars in Neurology Vol. 34 No. 3/2014
344 The Urea Cycle Disorders Helman et al.
encephalopathy, autism, learning disability, hyperactive or
self-injurious behavior, vomiting associated with mental
status changes, and stroke-like episodes. In particular, pre-
sentation with psychiatric symptoms in teens and adults,
including episodic psychosis, bipolar disorder, and/or major
depression,39,46–53 is quite common in late-onset disease.
Hyperammonemia episodes in late-onset UCDs are gener-
ally attributable to genetic inheritance of a decreased enzyme
capacity coupled with environmental stressors. Patients with
late-onset OTC have been reported after surgery (e.g., ortho-
pedic, gastric bypass),45,54 fractures, severe bleeding, seiz-
ures,53 pregnancy and the postpartum period,55–58 chemical
exposure,59 and gastrointestinal bleeding.58,60–62 Dietary
change from low-protein to high-protein diets, as in the
case of weaning from a breast/formula-fed diet in infants,
the Atkins diet,63 or decreased access to low-protein foods
can also be triggers of HA. Patients with partial enzyme
deficiency may also encounter HA when taking medications
that can affect protein turnover, such as corticosteroids64 and
chemotherapy. Ornithine transcarbamylase deficiency has
been documented in association with other pathologic con-
ditions, notably in cases of Leigh syndrome, a severe mito-
chondrial respiratory chain disorder.65 These patients may
have been “protecting themselves” by adopting a low-protein
or vegan diet; therefore, a dietary history is of extreme
importance when a late-onset case is suspected.
Late-onset UCD postsurgery has been cited in several cases
presenting with altered mental status, coma, and possibly
death if proper treatment is not pursued. Hyperammonemia
caused by surgical stress and fasting with deficient calorie
supply via intravenous fluid is a trigger in patients with
underlying UCD.66 Other factors associated with major sur-
gery, such as elevated nitrogen levels due to tissue trauma or
tissue protein breakdown, may exacerbate urea synthesis,
leading to HA.
Increased protein turnover during pregnancy and in the
postpartum period have been associated with stress on the
urea cycle system resulting in late-onset UCD. Patients pre-
senting during pregnancy come to medical attention with
presumed liver failure after liver function testing. Absence of
serious liver injury with high ammonia and low urea levels
during pregnancy should prompt consideration to an under-
lying metabolic disorder.67 Previously asymptomatic carrier
females may also present during the pregnancy with altered
mental status,68 as well as in the postpartum state with
similar altered mental status and agitation as cited in the
case of a woman who had similar postpartum episodes after
the births of three of her children.69 In addition, postpartum
seizures and coma can be indicative of UCD.55,56 Not all
asymptomatic carriers present in periods of environmental
stress such as pregnancy70; however, a diagnosis is important
in preventing HA events that may lead to serious neurologic
consequences, and may also be helpful in family planning.
Late-onset UCDs presenting with other clinical manifes-
tations or in response to environmental stressors provide a
diagnostic challenge for providers. It appears that increased
awareness of the presentation of a partial enzyme deficiency
in UCD cases is attributable to increased detection of the
Seminars in Neurology Vol. 34 No. 3/2014
cause of patient symptoms. However, prompt detection and
treatment of the disorder is necessary to avoid poor prognosis
and improve patient outcomes. Partial inborn errors of me-
tabolism must be a consideration for clinicians in intensive
care settings with severe presentations that do not fit evident
clinical causes.71
Differential Diagnosis
Other disorders resulting in HA that must be of consideration
in the diagnostic workup of UCDs include other inherited
metabolic conditions, such as the organic acidurias, HA
secondary to medication, acute or chronic liver failure, and
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in premature infants, transient HA of the newborn.72
Organic acidopathies resulting in HA due to inhibition of the
urea cycle should be a strong consideration in the differential
diagnosis of UCDs due to a resultant neurologic phenotype.
Although propionic and methylmalonic acidemia present in
similar fashion to late-onset UCD, they can be differentiated on
the basis of profound acidosis and ketosis during initial
metabolic decompensation. The exact mechanisms are still
being studied, but these conditions are hypothesized to inter-
fere with the NAGS73–77 or CPSI78 reaction of the urea cycle,
thereby resulting in HA. This mechanism has also been pro-
posed to explain the uncommon instances of HA in other
inherited disorders, such as maple syrup urine disease,79 and
fatty acid oxidation disorders.80,81 Lysinuric protein intoler-
ance82 may result in a secondary deficiency of the urea cycle83
due to urinary excretion of the key intermediates ornithine and
arginine. Arginase deficiency can also be differentiated by
discrete HA and progressive spastic diplegia or quadriparesis
with intellectual disability.44 In addition, several medications
are also known to cause HA, including valproic acid,84,85
corticosteroids,64 and chemotherapy.86,87
Neuroimaging Findings
Neuroimaging has emerged as a powerful tool for the inves-
tigation of urea cycle disorders, allowing both clinicians and
researchers to study the timing, extent, and reversibility of
the neurologic injury sustained by these patients. It encom-
passes a variety of investigative modalities, each with its own
advantages that can be combined to create a more complete
picture of the neural mechanisms underlying these disorders,
including structural, functional, and metabolic elements.
Magnetic Resonance Spectroscopy
1
H magnetic resonance spectroscopy (MRS) is a neuroimag-
ing technique used to measure the neurochemical environ-
ment.88 Because MRS allows for the characterization of the
metabolic features of neurologic disease, it is of particular
importance in rare metabolic disorders, such as UCD. 1H MRS
studies in UCD, particularly OTCD, have shown impaired
metabolism, with elevated glutamine (gln) levels, and re-
duced myo-inositol (mI) and choline (Cho) levels in symp-
tomatic patients.89,90 Gropman et al used single-voxel 1H
MRS to investigate cerebral metabolism in OTCD patients.91
Results indicated significantly increased levels of gln in
posterior cingulate gray matter and parietal and frontal white

matter in the OTCD group. These metabolic disturbances were
present in symptomatic as well as asymptomatic patients,
although to a lesser degree.91 There was also significantly
decreased mI in all of these areas as well as the thalamus.91
For OTCD patients only, the level of brain gln was inversely
correlated with brain mI depletion.91
Structural Magnetic Resonance Imaging
One of the more frequently used neuroimaging modalities is
structural magnetic resonance imaging (MRI). Structural images
acquired through MRI can be T1- or T2-weighted or fluid
attenuated inversion recovery (FLAIR) images, all of which are
used to assess the brain’s macroscopic structure. T1-weighted
images can be used to perform voxel-based morphometry, an
analysis technique that allows the investigation of focal differ-
ences in brain volume between groups. To date, no such analyses
have been performed on UCD populations, but it would be
interesting to investigate differences in white matter volume
between UCD patients and healthy controls. Fluid attenuated
inversion recovery images, on the other hand, reveal hyperin-
tense lesions in the white matter, which has proved useful in
relating OTCD symptomatology to underlying neural pathology
(Gropman AL, manuscript in progress). Because FLAIR images
null the signal from the CSF, they often reveal smaller lesions that
would not appear on a regular T2-weighted image.
Diffusion Tensor Imaging
Diffusion tensor imaging (DTI) is another structural MR
technique, based on the differences in the diffusion of water
molecules that allow for mapping of white matter tracts in
the brain.92 Because HA leads to white matter injury, DTI has
become a useful tool in assessing the integrity of white matter
tracts in UCD, particularly in OTCD (►Fig. 2). In 2010, Grop-
man et al conducted a DTI study with adult OTCD patients and
age-matched control subjects to examine HA-induced
changes in the white matter microstructure in OTCD pa-
tients.93 Results indicated decreased fractional anisotropy
(FA), a marker of white matter integrity, in the frontal white
matter of OTCD patients compared with healthy controls.92,93
Both symptomatic and asymptomatic patients showed re-
duced FA, with the symptomatic group differing more signifi-
cantly from healthy subjects.93 Furthermore, findings of
lower FA in frontal white matter correlated with findings of
inferior performance in certain cognitive tests, including the
Comprehensive Trail-Making Test and the Stroop task, which
serve as measures of aspects of executive function such as
working memory, cognitive flexibility, set-shifting, process-
ing speed, and response inhibition.93 There were no such
correlations for controls. White matter tracts connecting
frontal brain regions support executive functioning. There-
fore, DTI revealed an anatomical correlate to the deficits in
executive function reported in OTCD patients.94 There was
also an inverse correlation between FA and disease severity,
with the more severe OTCD patients showing lower FA.93
Disease severity scores were derived from the number of
hyperammonemic episodes each patient reported. It could
thus be inferred that HA is the cause of significant damage to
the integrity of white matter, especially in frontal areas.
The Urea Cycle Disorders Helman et al. 345
Functional MRI and Functional Connectivity
Functional MRI (fMRI) is a modality used to detect differences
in brain activity between groups. fMRI measures the blood
oxygenation level dependent signal, which represents local
changes in hemoglobin oxygenation due to changes in cere-
bral blood flow.95 Gropman et al conducted an fMRI study in
adult OTCD patients and healthy controls in which partic-
ipants completed an N-back task, a measure of working
memory and sustained attention.95 Compared with control
subjects, OTCD patients displayed a greater blood oxygen-
ation-level-dependent signal in the right dorsolateral pre-
frontal cortex (PFC) and anterior cingulate cortex (ACC).95
This increased activity was present despite the lack of differ-
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ences in task performance, suggesting that this discrepancy is
not caused by behavioral output or task difficulty, but by
prefrontal inefficiency in OTCD patients.95 This inefficiency is
likely the cause of the HA-induced damage to PFC neurons
and white matter tracts, as revealed by DTI.14 Combined DTI
and fMRI findings suggest impaired functional connectivity
in OTCD.
Recently, a great deal of attention has been focused on
examining brain activity in a resting state. The most frequent-
ly studied resting state network is known as the default mode
network (DMN), and it consists of medial PFC/ACC, posterior
cingulate cortex/precuneus, and bilateral inferior parietal
lobule (IPL).96,97 The DMN is active at rest and suppressed
during cognitively engaging tasks.97 Most commonly, the
analyses performed on resting-state fMRI data aim to assess
functional connectivity between different regions of interest.
Recently, groups of OTCD patients and healthy controls
underwent resting-state fMRI scans. Analyses revealed that
the DMN of OTCD patients showed reduced overall functional
connectivity as compared with controls, especially between
the medial PFC/ACC node and the bilateral IPL nodes (Pa-
checo-Colón et al, manuscript in progress). These findings
provide preliminary evidence of reduced long-distance con-
nectivity in OTCD, likely reflecting damage to white matter
tracts caused by episodes of HA.
Neonatal Imaging
Neuroimaging studies are rarer in the case of UCD patients
with neonatal-onset due to the obvious constraints it carries
with it, such as the required sedation of infants. However,
several case studies have shed some light on the MR abnor-
malities associated with different types of UCD. One such
study observed that T1- and T2-weighted structural images
revealed almost identical lesions to the bilateral lentiform
nuclei and the deep sulci of the insular and perirolandic
regions in two females with deficiency of the carbamyl
phosphate synthetase I reaction step and one male with
OTCD.98 Presumably, this pattern of injury is caused by
hypoperfusion secondary to HA and hyperglutaminemia in
the newborn period.98 Another case study performed on a
young girl with citrullinemia yielded DTI data revealing
decreased FA throughout the brain, as well as several hyper-
intense abnormalities in both cortical and subcortical white
matter T2-weighted structural MR images.99 Recently, Gunz
et al reviewed the MRI findings of eight neonates after
Seminars in Neurology Vol. 34 No. 3/2014
346 The Urea Cycle Disorders Helman et al.

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Fig. 2 Diffusion tensor imaging. Diffusion tensor imaging reveals hyperammonemia-induced changes in the white matter microstructure in
patients with ornithine transcarbamylase deficiency. White matter injury occurs in motor tracts connecting parts of the brain important in
memory and attention. FA, fractional anisotropy. (Reprinted with permission from Gropman A, Prust M, Breeden A, Fricke S, VanMeter J. Urea cycle
defects and hyperammonemia: effects on functional imaging. Metab Brain Dis 2013;28:269–275.)

presenting with neonatal-onset of different UCD.100 They
interpreted two patterns of cerebral involvement on MRI: a
central and focal pattern consisting of changes to the basal
ganglia, perirolandic region and internal capsule, and a
diffuse pattern consisting of extensive involvement of the
cortex, basal ganglia, and sometimes the thalamus and brain-
stem.100 Gunz et al propose that UCD patients with more
diffuse patterns of injury tend to have worse neurologicout-
comes than those with central involvement.100
Further Comments
Our understanding of the neurocognitive challenges of OTCD
has been improved with the study of advanced MRI techni-
ques; however, many issues remain unresolved. There are
currently no specific neuroprotective therapies and this is an
important area of interest. Prompt recognition that adults
may manifest with a UCD for the first time in adulthood is
critical to avert disastrous outcome. The use of nitrogen
scavengers has resulted in improved survival rates in these
patients, but neurologic outcomes remain poor, especially in
neonatal onset cases.
Our neuroimaging studies have allow us to identify bio-
markers that reflect the downstream impact of UCDs on
intellect and neurocognition. Affected cognitive domains
include non-verbal learning, fine motor processing, reaction
time, visual memory, attention and executive function. Def-
icits in these capacities may be seen in symptomatic patients,
as well as asymptomatic carriers of OTCD with normal IQ and
correlate with variances in brain structure and function in
these patients (Sprouse et al, manuscript in progress).
Acknowledgments
Guy Helman and Ileana Pacheco-Colón share the role of
first author.
This work was supported by 5U54HD061221. We also
appreciate the support of the Intellectual and Develop-
mental Disorders Research Center (IDDRC) grant:
5P30HD040677–13. Guy Helman receives support from
the Delman Fund for Pediatric Neurology Education and
Research. Thank you to all participants for taking part in
our study, to all referring doctors, and the National Urea
Cycle Disorder Foundation.
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