Intermittent Hyperammonemic Encephalopathy in a

Child with Ornithine Transcarbamylase Deficiency

Sheffali Gulati, Shaji M e n o n , Madhulika Kabra and Veena Kalra

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Abstract. Omithine transcarbamylase (OTC) deficiency is an X-linked disorder and the most common inherited cause of
hyperammonemia. Clinical manifestations are more severe in hemizygous males who often present in neonatal period.
Heterozygous females may be asymptomatic until juvenile or adulthood. Fluctuating concentration of ammonia, glutamine and
other excitotoxic amino acids result in a chronic or episodically recurring encephalopathy. The authors report a heterozygous
female with OTC deficiency who presented with recurrent encephalopathy. [Indian J Pediatr 2004; 71 (7) : 645-648]
E- mail: sheffalig @yahoo.com

Key words : Ornithine transcarbamylase deficiency; Hyperammonemia; Recurrent encephalopathy

Ornithine transcarbamylase ( s y n o n y m ornithine visual or a u d i t o r y disturbances, drug intake,

carbamoyl transferase, OTC) deficiency is an X-linked
disorder and the most common inherited cause of
hyperammonemia.1,20TC is an mitochondrial urea cycle
enzyme. 2 Clinical manifestations are more severe in
hemizygous male, most male patients present with severe
hyperammonemia leading to seizures, and coma in
neonatal period due to severe h y p e r a m m o n e m i a .
Heterozygous females show widespread variation in
onset and severity of symptoms. Females with OTC
deficiency m a y be asymptomatic until juvenile or
adulthood. 3,4 Fluctuating concentration of ammonia,
glutamine and other excitotoxic amino acids result in a
chronic or episodically recurring encephalopathy.4~In late
presentation diagnosis is often delayed because
s y m p t o m s are non-specific. 4 The authors report a
heterozygous female with OTC deficiency who presented
with recurrent episodic hyperammonemic
encephalopathy.
CASE REPORT
A 389 female child presented to us with history of
episodes of lethargy and excessive daytime somnolence
for 8 months. These episodes of excessive lethargy and
drowsiness lasted for 8-18 hrs and progressed from one or
two episodes per month to one episode per week in a
period of 8 months. Later episodes were associated with
vomiting, unsteady gait, irrelevant and incoherent speech,
headache and aggressive behavior. Between the episodes
child's behavior was normal. There was no associated
complaints of fever, convulsion, unconsiousness, pica,
Correspondenceand Reprintrequests : Dr. SheffaliGulati,Assistant
Professor, Department of Pediatrics,All India Institute of Medical
Sciences,New Delhi-110029,India.Fax:91-011-2658863
photosensitivity, fast breathing or abnormal sweat or
urinary odor.
The patient was a product of non-consanguineous
marriage with no perinatal complications and normal
psychomotor development. Family history was non
contributory. On examination child was irritable but
conscious and oriented. There was no dysmorphism,
abnormal hair, neurocutaneous markers or any
characteristic body odor. Breathing was normal. During
her hospital stay she had episodes of excessive
somnolence, lethargy and drowsiness and in awake state
she showed aggressive behavior characterized by hitting,
biting and breaking objects. Each episode lasted for 4-5
hrs. She also complained of headache and occasional
vomiting. In-between episodes neurological examination
was normal except for brisk deep tendon reflexes in lower
limbs. Plantars were flexor. There were no meningeal or
cerebellar signs and gait was normal. During episodes of
encephalopathy child was drowsy and had ataxic gait.
Rest of the systemic examinations were normal.
Investigation revealed a normal hemogram, renal and
liver function tests. Serum electrolytes were normal.
Arterial blood gases done during and in between episodes
were also normal and revealed no acidosis. Urinary
metabolic screening tests like Dinitro phenyl hydrazine,
Nitroprusside, ferric chloride and screening for reducing
substances, Ketones and porphyria were negative. Blood
lactate done during and in-between the episodes were
also normal (1 mmol/L) [n<2mmol/L]. Plasma ammonia
during the episode was very high (265 laM) compared'to
a normal of less than 35 pM. Plasma ammonia repeated
during an abating episode was also marginally high 89
1JM.

Indian Journal of Pediatrics, Volume 71--July, 2004 645

 Sheffali Gulati et al
The urine showed moderate increase in glutamine /
glutamate amInoacids. The organic acids revealed and
increased orotic acid which was quantified by high
performance liquid chromatography. One sample had
orotic acid 41.8 lamol/mmol creatinine, the other had
168Iamol/mmol creatinine (Normal: 0-5 lamol/mmol
creatinine). These results suggest that the patient is a
female carrier for OTC deficiency. Neuroirnaging studies
including c o m p u t e d t o m o g r a p h y and magnetic
resonance imaging revealed no abnormalities.
Electroencephalogram was also normal.
In the light of the mentioned clinical features and
investigations a diagnosis of urea cycle defect, late onset
ornithine transcarbamylase deficiency was made. Late
onset (post neonatal) of symptoms, episodic nature of
neuropsychiatric illness, high ammonia in absence of
metabolic acidosis or ketosis led us to the diagnosis of
urea cycle defect and a high urinary orate was
confirmatory of OTC deficiency.
The patient was put on the protein restricted diet
(1.5g/kg/day) and sodium benzoate (5.5 g/m2/d) for
excess ammonia disposal. Carnitine supplementation was
also given. The symptoms improved rapidly on initiation
of treatment and the episodes of encephalopathy stopped
recurring. Since the initiation of treatment for the last 24
months patient is symptom free and has normal ammonia
levels.
DISCUSSION
OTC is a key urea cycle enzyme and its deficiency is the
most common inherited cause of hyperammonaemia and
urea cycle defect. 1 The overall prevalence of urea cycle
defect in the United States is considered to be
approximately 1:30,000 births; however, due to the lack of
newborn mass screening programs exact prevalence data
is not available. 6
Homozygous male patients present in neonatal period
with non specific symptoms like feeding difficulty,
lethargy, hypothermia, hyperventilation (respiratory
distress), respiratory alkalosis, coma and death.
Heterozygous females show wide variability in age of
onset and severity depending on degree of residual
enzyme activity. In late onset group, episodic vomiting,
protein intolerance, mental retardation, psychiatric
manifestations (bizarre behavior, irritability and
aggression), ataxia, f o c a l / g e n e r a l i z e d seizures and
disturbances of consciousness are typical symptoms of
the chronic and episodically exacerbating encephalopathy
in partial OTC deficiency. L4Hyperammonemia and these
symptoms may be precipitated by high protein diet,
infection, postpartum state or valproate therapy. 4~ Our
patient being a female heterozygous for OTC deficiency
presented late at 3!6 years of age with history of
episodically recurring encephalopathy There was no
evidence of any precipitating factor in our patient. Other
646
causes of recurrent episodic encephalopathy including
organic acid disorders (Isovaleric aciduria, Maple syrup
urine disease, Multiple carboxylase deficiency etc), amino
acid disorders (5. 10-Methyleneterahydrofolate reductase
deficiency, Non ketotic hyperglycinemia),
Mitochondriopathies, Porphyria, cyclical vomiting,
complex partial seizures and atypical migraine were
ruled out.
The diagnosis of OTC deficiency is based on X-linked
inheritance, increased blood ammonia levels, high serum
glutamine and alanine and low serum citrulline, raised
urinary concentrations of orotic acid and increased
orotidine excretion in urine after allopurinol challenge3 ~
Further diagnostic tests include liver or skin biopsy for
measurement of enzyme activity and molecular genetic
studies. 3,4
Treatment of hyperammonemia requires restriction of
protein intake 1.5 g m / k g / d a y s with adequate essential
amino acid as a part of their protein intake (25% to 50%).
Intercurrent h y p e r a m m o n e m i a can be treated b y
pharmacological measures to increase non protein
nitrogen excretion using arginine hydrochloride (600 rag/
kg in 10% solution) and a combination of sodium
benzoate and sodium phenylacetate (250 mg/kg of each
drug) all infused in 25 to 35 ml/kg of 10% dextrose. 6 Our
patient was treated with dietary protein restriction and
oral sodium benzoate (5.5 gm/m2/day) orally (due to non
availability of intravenous preparation). Carnitine
supplementation was also given. Long-term treatment
improves the clinical outcome considerably in terms of
recurrence of symptoms and intellectual development.
Since the initiation of treatment our patient is symptom
free for the last 24 months.
Urea cycle defect should be included in the differential
diagnosis of any recurrent encephalopathy of unclear
origin and blood ammonia should be determined early in
the evaluation of such patients. Metabolic defects like
OTC deficiency should be considered in older patients
with unknown encephalopathy. 1~
Acknowledgement
Dr Guy Besley,WiUinksBiochemicalGeneticsUnit for doing urinary
organic acid estimation
REFERENCES
1. PridmoreCL, Clarke JT, BlaserS. Ornithine transcarbamylase
deficiencyin females: an often overlookedcause of treatable
encephalopathy. J Child Neuro11995; 10 (5) : 369-374.
2. Rowe PC, Newman SL, Brusilow SW. Natural history of
symptomaticpartial ornithine transcarbamylasedeficiency.N
EngJMed 1986;314 : 541-547.
3. Schwartz S, Schwab S, Hoffman GF. Enzyme detects of the
urea cyclein differential acute encephalopathy diagnosis in
adulthood, diagnosisand current therapy concepts. Nervenarzt
1999;70 (2) : 111-118.
4. Oechsner M, Steon C, Sturenburg HJ, Huhlschutter A.
Hyperammonemic encephalopathy after initiation of
valproate therapy in unrecognizedornithine transcarbamylase
Indian Journal of Pediatrics, Volume 71~July, 2004
 Hyperammonemic Encephalopathy with Ornithine Transcarbamylase Deficiency

deficiency.J Neurol Neurosurg Psychiatr 1998;64 (5) : 680-682. Contributors

5. Maestri ME, Clissold D, Brusilow SW. Neonatal onset
ornithine transcarbamylase deficiency : A retrospective
analysis. J Pediatr 1990;134 (3) : 268-272.
6. SummarM. Current strategiesfor the management of neonatal
urea cycledisorder. J Pediatr 2001;138:$31-39.
VK and SG were Pediatric Neurologists incharge of the case;
MK was Pediatric Geneticist incharge of the case; SG and SM
drafted the manuscript; VK and MK critically reviewed the
manuscript; VK will act as guarantor for the paper.

Book Received

Biomedical Waste Management in India

By Dr. J Kishore and Dr GK Ingle
P u b l i s h e d b y C e n t u r y Publications, 46 M a s i h Garh, Jamia Nagar, N e w Delhi-110025.
First Edition: 2004
Price Rs 1 4 0 / -

This b o o k l e t is a serious concern to national a n d international health a n d e n v i r o n m e n t a l

agencies. N o t o n l y to health authorities, this edition p r o v i d e s p u r p o s e to n u r s i n g h o m e s ,
polyclinics, p r i v a t e clinics, m a t e r n i t y h o m e s , a c a d e m i c i a n s , s t u d e n t s of p u b l i c health,
e n v i r o n m e n t , w a s t e m a n a g e m e n t , m e d i c a l a n d n u r s i n g sciences.

IndianJournal of Pediatrics, Volume 71---July, 2004 647